Nöraminidazların inhibitörleri olarak pirolidinler.

PYRROLIDINES AS INHIBITORS OF NEURAMINIDASESTechnical Field The present invention relates to novel compounds, compositions and methods for inhibiting neuraminidase, especially influenza neuraminidase. The invention also contemplates a composition and methods for preventing and treating an influenza infection and processes for making such compounds and synthetic intermediates employed in these processes.

Background of the Invention Many disease-causing microorganisms possess a neuraminidase (also known as sialidase) which is involved in the replication process of the microorganism. In particular, viruses of the orthomyxovirus and paramyxovirus groups possess a neuraminidase. Diseases associated with paramyxoviruses include RSV (respiratory syncytial virus-related diseases), pneumonia and bronchiolitis (associated with paramyxovirus type 3) and laryngotracheobronchitis (associated with paramyxovirus type 1). Some of the more important diseasecausing microorganisms in man and/or animals which possess a neuraminidase include Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae,Arthrobacter sialophilus, influenza virus, parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, equine influenza virus and Sendai virus.

Mortality due to influenza is a serious problem throughout the world. The disease is devastating to man, lower mammals and some birds. Although vaccines containing attenuated influenza virus are available, those vaccines only provide immunological protection toward a few influenza strains and are less effective in otherwise immunologically compromised populations such as the elderly, young children, and in those who suffer from chronic respiratory illness.

The productivity loss from absence due to sickness from influenza virus infection has been estimated to be more than $1 billion per year.

There are two major strains of influenza virus (designated A and B).

Currently, there are only a few pharmaceutical products approved for treating influenza. These include amantadine and rimantadine, which are active only against the A strain of influenza viruses, and ribavirin, which suffers from dose-limiting toxicity. Mutant virus which is resistant to amantadine and rimantadine emerges quickly during treatment with these agents.

Neuraminidase is one of two major viral proteins which protrude from the envelope of influenza virus. During the release of progeny virus from infected cells, neuraminidase cleaves terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides on the cell surface. Inhibition of neuraminidase enzymatic activity leads to aggregation of progeny virus at the surface. Such virus is incapable of infecting new cells, and viral replication is therefore retarded or blocked. X-ray crystallographic studies and sequence alignments have shown that the residues which directly contact the sialic acid portion of the substrate are strictly conserved in the neuraminidase from all A and B influenza strains.STDC0173 Thus, a compound which binds to the sialic acid binding region of the neuraminidase active site will block the replication of both the A and B strains of influenza virus.

Compounds which are influenza neuraminidase inhibitors will be useful for the prevention of influenza infection and will be useful for the treatment of influenza infection.

The following references disclose neuraminic acid derivatives with the disclosed utility listed after each reference:L. Von Itzstein, et al., European Patent Application No. EP539204, publishedApril 28,1993 (antiviral agent);T. Honda, et al., European Patent Application No. EP823428, published February 11,1998 (sialidase inhibitor; influenza treatment);T. Honda, et al., International Patent Application No. W098/06712, publishedFebruary 19,1998 (sialidase inhibitor; influenza remedy);L. Von Itzstein, et al., International Patent Application No. W095/20583, published August 3,1995 (viral neuraminidase inhibitor; influenza treatment);P. Smith, International Patent Application No. W095/18800, published July 13, 1995 (viral neuraminidase inhibitor);P.STDC0583 Colman, et al., International Patent Application No. W092/06691, publishedApril 30,1992 (viral neuraminidase inhibitor);L. Von Itzstein, et al., U. S. Patent No. 5,648,379, issued July 15,1997 (influenza treatment);P. Reece, etal., International Patent Application No. W097/32214, publishedSeptember 4,1997 (bind to influenza virus neuraminidase active site); andP. Reece, et al., International Patent Application No. W098/21243, publishedMay 23,1998 (anti-influenza agent).

The following references disclose sialic acid derivatives with the disclosed utility listed after each reference: Y. Ohira, et al., International Patent Application No. W098/11083, publishedMarch 19,1998 (antiviral agent);Y. Ohira, European Patent Application No. EP882721, published December 9, 1998 (antiviral agent); andB. Glanzer, et al., Helvetica Chimica Acta 74 343-369 (1991) (Vibrio cholerae neuraminidase inhibitor).

The following references disclose benzene derivatives, cyclohexane derivatives or cyclohexene derivatives with the disclosed utility listed after each reference:Y. Babu, et al., U. S. Patent No. 5,602,277, issued February 11,1997 (neuraminidase inhibitors);M. Luo, et al., U. S. Patent No. 5,453,533, issued September 26,1995 (influenza neuraminidase inhibitor; influenza treatment);Y. Babu, et al., International Patent Application No. W096/30329, publishedOctober 3,1996 (neuraminidase inhibitor; viral infection treatment);N. Bischofberger, et al., U. S. Patent No. 5,763,483, issued June 9,1998 (neuraminidase inhibitor); andK. Kent, et al., International Patent Application No. 98/07685, published February 26,1998 (intermediates for the preparation of neuraminidase inhibitors).

C. Kim, et al., International Patent Application No. W098/17647, publishedApril 30,1998 discloses piperidine derivatives which are useful as neuraminidase inhibitors.

N. Bischofberger, et al., International Patent Application No. W096/26933, published September 6,1996 discloses various substituted 6-membered ring compounds which are useful as neuraminidase inhibitors.

The following references disclose dihydropyran derivatives which are useful as viral neuraminidase inhibitors:D. Andrews, et al., International Patent Application No. W097/06157, publishedFebruary 20,1997; andP. Cherry, et al., International Patent Application No. W096/36628, publishedNovember 21,1996.

C. Kim, et al., U. S. Patent No. 5,512,596, issued April 30,1996 discloses 6-membered aromatic ring derivatives which are useful as neuraminidase inhibitors.

G. Diana, et al., International Patent Application No. W098/03487, published January 29,1998 discloses substituted pyridazines which are useful for treatment of influenza.

B. Horenstein, et al., International Patent Application No. W099/06369, published February 11,1999 discloses piperazine derivatives which are useful as neuraminidase inhibitors.

Y. Babu, et al., International Patent Application No. W097/47194, published December 18,1997 discloses substituted cyclopentanes which are useful as neuraminidase inhibitors and treatments for influenza.

L. Czollner, et al., Helvetica Chimica Acta 73 1338-1358 (1990) discloses pyrrolidine analogs of neuraminic acid which are useful as Vibrio cholerae sialidase inhibitors.

The following references disclose siastatin B analogs which are useful as neuraminidase inhibitors:Y. Nishimura, et al., Natural Product Letters 1 39-44 (1992); andY. Nishimura, et al., Natural Product Letters 1 33-38 (1992).

C. Penn, UK Patent Application No. GB2292081, published February 14,1996 discloses the use of a neuraminidase inhibitor in combination with an influenza vaccine.

An object of the invention is to provide compounds which inhibit neuraminidase of disease-causing microorganisms; especially, viral neuraminidase; and, most especially, influenza neuraminidase.

An object of the invention is also to provide compounds which inhibit neuraminidase from both A and B strains of influenza.

Another object of the invention is to provide prohylaxis of influenza infection in humans and other mammals.

Another object of the invention is to provide treatment of influenza infection in humans and other mammals.

Another object of the invention is to provide compounds which exhibit activity against influenza A virus and and influenza B virus by virtue of inhibiting influenza neuraminidase when such compounds are administered orally.

Another object of the invention is to provide a compound which can be effectively transported from the plasma into the lung bronchoaveolar fluid of humans and other mammals in order to block the replication of influenza virus in that tissue.

Disclosure of the InventionThe present invention discloses compounds having Formula I:EMI7.1 or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R'is selected from the group consisting of (c)-SO3H,(d)-CH2SO3H,(e)-SO2H,(a)-CO2H,(b)-CH2CO2H, (f)(f)-CH2SO2H, (i)-PO2H,(j)-CH2PO2H,(h)-CH2PO3H2, (k) tetrazolyl, (I)-CH2-tetrazolyl, (m)-C (=O)-NH-S (O) 2-R1, and(n)-CH2C(=O)-NH-S(O)2R11,(o)-SO2N(T-R11)R12 (p)-CH2SO2N (T-R'1) R'2 wherein T is selected from the group consisting of (i) a bond, (ii)-C (=O)-, (iii)-C (=O) O-, (iv)-C (=O) S-, (v)-C (=o) NR36-, (vi)-C (=S) O-, (vii)-C (=S) S-, and (viii)-C (=S) NR R"is selected from the group consisting of (i) C1-C12 alkyl, (ii)STDC0336 02-612 alkenyl, (iii) cycloalkyl, (iv) (cyclo alkyl) alkyl, (v) (cycloalkyl) alkenyl, (vi) cycloalkenyl, (vii) (cycloalkenyl) alkyl, (viii) (cycloalkenyl) alkenyl, (ix) aryl, (x) (aryl) alkyl, (xi) (aryl) alkenyl, (xii) heterocyclic, (xiii) (heterocyclic) alkyl and (xiii) (xiv) (heterocyclic) alkenyl;STDC0728 and R12 and R36 are independently selected from the group consisting of (i) hydrogen, (ii) C1-C12 alkyl, (iii) ?2-012 alkenyl, (iv) cycloalkyl, (v) (cycloalkyl) alkyl, (vi) (cycloalkyl) alkenyl, (vii) cycloalkenyl, (viii) (cycloalkenyl) alkyl, (ix) (cycloalkenyl) alkenyl, (x) aryl, (xi) (aryl) alkyl, (xii) (aryl) alkenyl, (xiii) heterocyclic, (xiv) (heterocyclic) alkyl and (xv) (heterocyclic) alkenyl;X is selected from the group consisting of (a)-C (=O)-N (R*)-, (b)-N (R*)-C (=O)-, (c)-C (=S)-N (R*)-, (d)-N (R*)-C (=S)-, (e)-N (R*)-SO2-, and (f)-SO2-N (R*)-wherein R* is hydrogen, Ct-C3 loweralkyl or cyclopropyl;STDC0366 R2 is selected from the group consisting of (a) hydrogen, (b) Ci-Ce alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl, (e) C5-C6 cycloalkenyl, (f) halo Ci-Ce alkyl and (g) halo C2-C6 alkenyl;STDC0456 or R2-X-is EMI8.1 wherein Y'is-CH2-,-O-,-S-or-NH-and Y2 is-C (=O)-or-C (Raa) (Rbb)-wherein Raa and Rbb are indepedently selected from the group consisting of hydrogen, Cl-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl,N-methylaminomethyl and methylthiomethyl;STDC0891R3 and R4 are independently selected from the group consisting of (a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl, (d) heterocyclic, (e) aryl and (f)-Z-R'4 wherein Z is (ii)-C(R47)=C(R48)-,(iii)-C#C-,(iv)-C(=O)-,(i)-C(R37a(R37b)-, (v) -C(=S)-, (vi) =C(R37a)(OR37c)-,(viii)-(vii) C(R37a)(SR37c)-, (ix) -C(R37a)(N(R37b)(R37c))-, (x) -C(R37A)(R37b)-O-, (xii)-C(R37a)(r37b)-N(O)(R37c)-,(xi)-C(R37a)(R37b)-N(R37c)-, (xiv)-C(R37a)(R37b)-S-,(xiii)-C(R37a)(R37b)-N(OH)-, (xvi)-C(R37a)(R37b)-S(O)2-,(xv)-C(R37a)(R37b)-S(O)-, (xvii) (xviii)-C(R37a)(R37b)-C(=S)-, (xx)-C(R37a)(OR37c)-C(=O)-,(xix)-C(R37a)(R37b)-C(=NR15-, (xxii)-C(R37a)(OR37c)-C(=S)-,(xxi)-C(R37A)(SR37c)-C(=O)-, (xxiv)-C(=O)-C(R37a)(OR37c)-,(xxiii)-C(R37a)(SR37c)-C(=S)-, (xxvi)-C(=S)-C(R37a)(OR37c)-,(xxv)-C(=O)-C(R37a)(SR37c)-, (xxviii)-C(R37a)(OR37c)-C(R37a)(OR37c)-,STDC0889(xxvii)-C(=S)-C(R37a)(SR37c)-, (xxix)-C(R37a)(SR37c)-C(R37a)(OR37c)-, (xxx)-C(R37a)(OR37c)-C(R37a)(SR37c)-, (xxxii)-C(=O)-C(=O)-,(xxxi)-C(R37a)(SR37c)-C(R37a)(SR37c)-, (xxxiii) -C(=S)-C(=S)-, (xxxv)-C(=O)-S-,-C(=O)-O-, (xxxvii)(xxxvi)-C(=S)-O-, -C(=S)-S-, -C(=O)-N(R37a)-, (xxxix)(xxxix)-C(=S)-N(R37a)-, -C(R37a)(R37b)-C(=O)-N(R37a)-, (xlii)-C(R37a)(R37b)-C(=O)-O-,(xli)-C(R37a)(R37b)-C(=S)-N(R37a)-, (xliv)-C(R37a)(R37b)-C(=S)-O-,(xliii)-C(R37a)(R37b)-C(=O)-S-, (xlvi)-C(R37a)(R37b)-N(R37b)-C(=O)-,(xlv)-C(R37a(R37b)-C(=S)-S-, (xlviii)-C(R37a)(R37b)-O-C(=O)-,(xlvii)-C(R37a)(R37b)-N(R37b)-C(=S)-, (xlix) -C(R37a)(R37b)-S-C(=O)-, (l) -C(R37a)(R37b)-O-C(=S)-, (lii)-C(R37a)(R37b)-N(R37b)-C(=O)-N(R37a)-,(li)-C(R37a)(R37b)-S-C(=S)-, (liii)-C(R37a)(R37b)-N(R37b)-C(=S)-N(R37a)-, (liv)-C(R37a)(R37b)-N(R37b)-C(=O)-O-, (lv) -C(R37a)(R37b)-N(R37b)-C(=O)-S-, (lvi)-C(R37a)(R37b)STDC0487-N(R37b)-C(=S)-O-, (lvii)-C(R37a)(R37b)-N(R37b)-C(=S)-S-, (lvii)-C(R37a)(R37b)-O-C(=O)-N(R37a)-, (lix)-C(R37a)(R37b)-S-C(=O)-N(R37a)-, (lx)-C(R37a)(R37b)-O-C(=S)-N(R37a)-, (lxii)-C(R37a)(R37b)-O-C(=O)-O-,(lxi)-C(R37a)(R37b)-S-C(=S)-N(R37a)-, (lxiv)-C(R37a)(R37b)-O-C(=O)-S-,(lxiii)-C(R37a)(R37b)-S-C(=O)-O-, (lxvi)-C(R37a)(R37b)-O-C(=S)-O-,(lxv)-C(R37a)(R37b)-S-C(=O)-S-, (lxviii)-C(R37a)(R37b)-O-C(=S)-S-,(lxvii)-C(R37a)(R37b)-S-C(=S)-O-, or(lxx)-C(R37a)(R37b)-C(R37a)(OR37c)-;STDC0895(lxix)-C(R37a)(R37b)-S-C(=S)-S-R14is (i)hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) thiol-substituted alkyl, (vi) alkyl, (vii) R37CS-substituted alkyl, (viii) aminoalkyl, (ix) (R 37c) NH-substituted alkyl, (x) (R37a) (R37C) N-susbstituted alkyl (xi) R37aO-(O=)C-substituted alkyl, (xii) R37aS-(O=) C-substituted alkyl, (xiii) R37aO- (S=) C-substituted alkyl, (xiv) R37aS-(S=) C-substituted alkyl, (xv) (R37aO) 2-P (=O)-substituted alkyl, (xvi) cyanoalkyl, (xvi) C2-C12 alkenyl, (xviii) haloalkenyl, (xix) C2-C12 alkynyl, (xx) cycloalkyl, (xxi) (cycloalkyl) alkyl, (xxii) (cycloalkyl) alkenyl, (xxiii) (cycloalkyl) alkynyl, (xxiv) cycloalkenyl, (xxv)STDC0659 (cycloalkenyl) alkyl, (xxvi) (cycloalkenyl) alkenyl, (xxvii) (cycloalkenyl) alkynyl, (xxviii) aryl, (xxix) (aryl) alkyl, (xxx) (aryl) alkenyl, (xxxi) (aryl) alkynyl, (xxxii) heterocyclic, (xxxiii) (heterocyclic) alkyl, (xxxiv) (heterocyclic) alkenyl or (xxxv) (heterocyclic) alkynyl, with the proviso that R14 is other than hydrogen when Z is -C(R37a)(R37b)-N(R37b)-C(=O)-O-,-C(R37a)(R37b)-N(R37b)-C(=S)-O -C(R37a)(R37b)-C(=O)-S-,-C(R37a)(R37b0-N(R37b)-C(=S)-S-, -C(R37a)(R37b)-O-C(=O)-O-,-C(R37a)(R37b)-O-C(=S)-O-, -C(R37a)(R37b)-S-C(=O)-O-,-C(R37a)(R37b)-S-C(=S)-O-, -C(R37a)(R37b)-O-C(=O)-S-,-C(R37a)(R37b)-O-C(=S)-S-, -C(R37a)(R37b)-S-C(=S)-S-;STDC0756-C(R37a)(R37b)-S-C(=O)-S-or R48ateachR37a,R37b,R47,and occurrence are independently selected from the group consisting of (i) hydrogen, (ii) Ci-Ci2 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) alkoxyalkyl, (vi) C2-C12 alkenyl, (vii) haloalkenyl, (viii) C2-C12 alkynyl, (ix) cycloalkyl, (x) (cycloalkyl) alkyl, (xi) (cycloalkyl) alkenyl, (xii) (cycloalkyl) alkynyl, (xiii) cycloalkenyl, (xiv) (cycloalkenyl) alkyl, (xv) (cycloalkenyl) alkenyl, (xvi) (cycloalkenyl) alkynyl, (xvii) aryl, (xviii) (aryl) alkyl, (xix) (aryl) alkenyl, (xx) (aryl) alkynyl, (xxi) heterocyclic, (xxii) (heterocyclic) alkyl, (xxiii) (heterocyclic) alkenyl and (xxiv) (heterocyclic) alkynyl;STDC0880 R37c at each occurrence is independently selected from the group consisting of (i) hydrogen, (ii) Cl-Cl2 alkyl, (iii) haloalkyi, (iv) C2-Ci2 alkenyl, (v) haloalkenyl, (vi) C2-C, 2 alkynyl, (vii) cycloalkyl, (viii) (cycloalkyl) alkyl, (ix) (cycloalkyl) alkenyl, (x) (cycloalkyl) alkynyl, (xi) cycloalkenyl, (xii) (cycloalkenyl) alkyl, (xiii) (cycloalkenyl) alkenyl, (xiv) (cycloalkenyl) alkynyl, (xv) aryl, (xvi) (aryl) alkyl, (xvii) (aryl) alkenyl, (xviii) (aryl) alkynyl, (xix) heterocyclic, (xx) (heterocyclic) alkyl, (xxi) (heterocyclic) alkenyl, (xxii) (heterocyclic) alkynyl, (xxiii)-C (=O)-R'4, (xxiv)-C (=S)-R14, (xxv)-S (O) 2-R'4 and (xxvi) hydroxyalkyl;STDC0470 or when Z is-C (R37a) (R37b)-N (R37C)-then N (R37C) and R14 when taken together are an azido group; or when Z is c (R37a) (R37b)-N (o) (R37c)-1 then N (O) (R37C) and R when taken together are an N-oxidized 3-7 membered heterocyclic ring having at least one N-oxidized ring nitrogen atom;STDC0835 or when Z is-C (R37a)(OR37c)-, -C(R37a)(SR37c)- or -C (R37a) (N (R37b)(R37c))-, then R37a, R14 and the carbon atom to which they are bonded when taken together form a cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl ring;R15 is selected from the group consisting of (i) hydrogen, (ii) hydroxy, (iii) amino, (iv) Cl-C12 alkyl, (v) haloalkyl, (vi) C2-Ci2 alkenyl, (vii) haloalkenyl, (viii) cycloalkyl, (ix) (cycloalkyl) alkyl, (x) (cycloalkyl) alkenyl, (xi) cycloalkenyl, (xii) (cycloalkenyl) alkyl, (xiii) (cycloalkenyl) alkenyl, (xiv) aryl, (xv) (aryl) alkyl, (xvi) (aryl) alkenyl, (xvii) heterocyclic, (xviii) (heterocyclic) alkyl and (xix) (heterocyclic) alkenyl;STDC0543 or R3 and R4 taken together, with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 8 ring atoms;R5 is selected from the group consisting of (a) hydrogen, (b)-CH (R38) 2, (c)-o-R40, (d) C2-C4 alkynyl, (e) cyclopropyl, cyclobutyl, (g)-C (=Q')-R 17, and (h)-N (R'9) 2 wherein Q1 is O, S, or N (Rr8); R17 and R18 are independently selected, at each occurrence, from the group consisting of hydrogen, methyl, and ethyl;STDC0578 R19, R38, and R40 are independently selected, at each occurrence, from the group consisting of (i) hydrogen, (ii) Cl-Cl2 alkyl, (iii) haloalkyl, (iv) C2-Ci2 alkenyl, (v) haloalkenyl, (vi) cycloalkyl, (vii) (cycloalkyl) alkyl, (viii) (cycloalkyl) alkenyl, (ix) cycloalkenyl, (x) (cycloalkenyl) alkyl, (xi) (cycloalkenyl) alkenyl, (xii) aryl, (xiii) (aryl) alkyl, (xiv) (aryl) alkenyl, (xv) heterocyclic, (xvi) (heterocyclic) alkyl and (xvii) (heterocyclic) alkenyl;STDC0809Y is selected from the group consisting of (a) hydrogen, (b) Cl-C5 alkyl, (c) Cl-C5 haloalkyl, (d) C2-C5 alkenyl, (e) C2-C5 haloalkenyl, (f) C2-C5 alkynyl, (9) C3-C5 cycloalkyl, (h) C3-C5 cycloalkyl-C1-to-C3-alkyl, (i) Cs cycloalkenyl, (j) C5 cycloalkenyl-C1-toC3-alkyl, (k) C5 cycloalkenyl-C2-to-C3-alkenyl, (I)-(CHR39) nOR20, (m)-CH (OR20)- CH2 (OR20), (n) -(CHR39)nSR21,(o)-(CHR39)nCN,(p)-(CHR39)nN3, (q) phenyl, (r) halo-substituted phenyl, (s)-(CHR39)nC(=Q2)R22, (t) -(CHR39)nN(=Q3), (u)-N (O) =CHCH3, (v)-(CHR39) nNR23R24, (w) halo and (x) a heterocyclic ring having from 3 to 6 ring atoms; wherein n is 0, 1, or 2;STDC0711 Q2 is O, S, NR25, or CHR26; and Q3 is NR41, or CHR42 ; R20 at each occurrence is independently (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) Cl-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x) allyl, (xi) C2-C3 haloalkenyl, (xii) amino, (xiii)-NHCH3, (xiv)-N (CH3) 2, (xv)-NHCH2CH3, (xvi)-N (CH3) (CH2CH3), (xvii)-N (CH2CH3) 2 or (xviii)-N (=CH2);STDC0890 R 21 is hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) Ci-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x) allyl or (xi) C2-C3 haloalkenyl; R22 is (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) hydroxy, (vii) thiol, (viii) methoxy, (ix) ethoxy, (x) n-propoxy, (xi) isopropoxy, (xii) cyclopropyloxy, (xiii) methylthio, (xiv) ethylthio, (xv) n-propylthio, (xvi) isopropylthio, (xvii) cyclopropylthio, (xviii) vinyl, (xix) propenyl, (xx) isopropenyl, (xxi) allyl, (xxii)-N (R28a) (R28b), (xxiii)-CH2R29, (xxiv) aminomethyl, (xxv) hydroxymethyl, (xxvi) thiolmethyl, (xxvii)-NHNH2, (xxviii)-N (CH3) NH2 or (xxix)STDC0754-NHNH (CH3); R23 and R39 are independently hydrogen or methyl; Rand R42 are independently hydrogen, methyl, or ethyl; R24 is selected from the group consisting of (i) hydrogen, (ii) Ci-C4 alkyl, (iii) C2-C4 alkenyl, (iv) C2-C4 alkynyl, (v) -C(=Q4)-R30,(v)-OR31,and(vi)-N(R32)2,(vi) wherein Q4 is O, S, or N (R33); R25 is hydrogen, hydroxy, methyl, ethyl, amino,-CN, or-NO2; R26 group is hydrogen, methyl or ethyl; R28a hydrogen, hydroxy, methyl, ethyl, amino,-NHCH3,-N (CH3) 2, methoxy, ethoxy, or-CN; R28b is hydrogen, methyl or ethyl;STDC0758 or R28a, R28b and the nitrogen to which they are bonded taken together represent azetidinyl; R29 group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino; R30 group is hydrogen, methyl, ethyl,-OR34,-SR34,-rR3,-NHOH, -NHNH2,-N (CH3) NH2, or-N (CH2CH3) NH2; Rand R32 substituents, at each occurrence, are independently hydrogen, methyl or ethyl; R33 group is hydrogen, hydroxy, methyl, ethyl, amino,-CN, or-NO2; R34 group is methyl or ethyl; R35 group is independently hydrogen, methyl or ethyl;STDC0828 with the proviso that when Q2 is CHR 26 then R22 is selected from the group consisting of hydrogen,-CH3,-C2H5,-C3H7,-OCH3,-SCH3,-O-C2H5, and -S-C2H5, and with the proviso that when R3 and R4 are each hydrogen, then Y is other than hydrogen; R6 and R7 are independently selected from the group consisting of (a) hydrogen, (b) Ci-Ci2 alkyl, (c) ?2-012 alkenyl, (d) cycloalkyl, (e) (cycloalkyl) alkyl, ( (cycloalkyl) alkenyl, (g) cycloalkenyl, (h) (cycloalkenyl) alkyl, (i) (cycloalkenyl) alkenyl, (j) aryl, (k) (aryl) alkyl, (I) (aryl) alkenyl, (m) heterocyclic, (n) (heterocyclic) alkyl and (o) (heterocyclic) alkenyl;STDC0525 and R8, R9, and R' are independently selected from the group consisting of (a) hydrogen, (b) Ci-Ce alkyl, (c) C2-C6 alkenyl, (d) C3-C6cycloalkyl, (e) C3-C6 cycloalkenyl, and ( fluorine, with the proviso that the total number of atoms, other than hydrogen, in each of R8, R9, and R10, is 6 atoms or less.

Preferred compounds of the invention are compounds having the relative sterochemistry depicted by Formula II: EMI18.1 or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R', R2, R3, R4, R5, R6, R7, R8, R9, R' , X and Y are as defined above and wherein R3 and R4 are not both the same.

Other preferred compounds of the invention are compounds having the relative sterochemistry depicted by Formula III:EMI18.2 or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R', R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined above and wherein R3 andR4 are not both the same.

Other preferred compounds of the invention are compounds havingFormula I or 11 or III or a salt, ester or prodrug thereof wherein R1 is defined as above; -X-R2 is R2-NH-SO2-orR2-SO2-NH-R2-NH-C(=O)-, wherein R2 is Cl-C3 loweralkyl, halo Cl-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or-X-R2 isEMI19.1 wherein Y is-CH2-,-O-,-S-or-NH-and y2 is-C (=O)-or-C (Raa) (Rbb)-wherein Raa and Rbb are independently selected from the group consisting of hydrogen, Cl-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl,STDC0860N-methylaminomethyl and methylthiomethyl; R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R'4 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen; R5 is hydrogen or loweralkyl; R6 and R7 are independently hydrogen or loweralkyl; R8 and R9 are independently hydrogen, fluoro or loweralkyl; R10 is hydrogen, fluoro or loweralkyl; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl, -C(=Q2)R22, -N (=Q3),-N (O) =CHCH3,-NR23R24 or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R23, R24, Q2 and Q3 are defined as above.

More preferred compounds of the invention are compounds havingFormula I or # or III or a salt, ester or prodrug thereof wherein R1 is defined as above; -X-R2 is R2-C (=O)-NH-, R2-NH-C (=O)-, R2-NH-SO2-or R2-SO2-NH- wherein R2 is Cl-C3 loweralkyl, halo Cl-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or-X-R2 isEMI20.1 wherein Y1 is -CH2- and Y2 is-C (=O)- or-C (Raa) ( Rbb) ? wherein Raa and Rbb are independently selected from the group consisting of hydrogen,C,-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;STDC0770 R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R'4 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen; R5 is hydrogen or loweralkyl; R6 and R7 are independently hydrogen or loweralkyl; R8 and R9 are independently hydrogen or loweralkyl; R' is hydrogen or loweralkyl; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl, -C(=Q2)R22, -N (=Q3),-N (O) =CHCH3 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, Q2 and Q3 are defined as above.STDC0495 Even more preferred compounds of the invention are compounds havingFormula I or 11 or III or a salt, ester or prodrug thereof wherein R1 is defined as above; -X-R2 is R2-C (=O)-NH-, R2-NH-C (=O)-, R2-NH-S02-or R2-SO2-NH- wherein R2 is C-C3 loweralkyl, halo Y is C2-C5 alkenyl, ?2. 05 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

More highly preferred compounds of the invention are compounds havingFormula I or 11 or III or a salt, ester or prodrug thereof wherein R'is-C02H; -X-R2 is R2-C (=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is Cl-C3 loweralkyl or halo-Cl-C3 loweralkyl; R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-Rr4 wherein Z and R'4 are defined as above and wherein one of R3 and R4 is other than hydrogen; R5 is hydrogen or loweralkyl; R6 and R7 are hydrogen independently hydrogen or loweralkyl;STDC0308 R8 and R9 are hydrogen independently hydrogen or loweralkyl; R' is hydrogen or loweralkyl; and Y is C2-C5 alkenyl, 02-05 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

Even more highly preferred compounds of the invention are compounds having Formula I or 11 or III or a salt, ester or prodrug thereof wherein R is- CO2H; -X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is Cl-C3 loweralkyl or halo-C-C3 loweralkyl; R4 is hydrogen or loweralkyl and R3 is heterocyclic or-Z-R'4 wherein Z and R14 are defined as above; R5 is hydrogen; R6 and R7 are hydrogen; R and R9 are hydrogen; R10 is hydrogen; and Y is C2-C5 alkenyl, 02-05 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

Other even more highly preferred compounds of the invention are compounds having Formula I or 11 or III or a salt, ester or prodrug thereof wherein R'is-C02H; -X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is Cl-C3 loweralkyl or halo Cl-C3 loweralkyl;STDC0837 R4 is hydrogen or loweralkyl and R3 is (a) heterocyclic, (b) alkyl, (b) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g)-C (=O)-R'4, (h)(i)-C(R37a)(R37b)-N(O)(R37c)R14whereinR14isor (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic) alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)-(O=) C-substituted alkyl or (xv) (R37aO) 2-P (=O)-substituted alkyl; R373 and R37b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl;STDC0387 and R370 is hydrogen, (ii) loweralkyl or (iii) loweralkenyl; R5 is hydrogen; R6 and R7 are hydrogen; R8 and R9 are hydrogen; R is hydrogen; and Y is C2-C5 alkenyl, 02-05 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

Most highly preferred compounds of the invention are compounds havingFormula I or 11 or III or a salt, ester or prodrug thereof wherein R'is-C02H; -X-R2 is R2-C (=O)-NH-, R2-NH-C (=O)-, R2-NH-SO2-or R2-S02-NH-wherein R2 is C-C3 loweralkyl or halo C,-C3 loweralkyl;STDC0674 R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c)-C (R37a) (OR37C)- R'4 wherein R14 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic) alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)-(O=)C-substituted alkyl or (xv) (R37aO) 2-P (=O)-substituted alkyl; R37a and R37b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl;STDC0386 and R370 is hydrogen, (ii) C,-C3 loweralkyl or (iii) allyl; R5 is hydrogen; R6 and R7 are hydrogen; R and R9 are hydrogen; R10 is hydrogen; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

Other most highly preferred compounds of the invention are compounds having Formula I or 11 or III or a salt, ester or prodrug thereof wherein R'is- CO2H; -X-R2 is R2-C (=O)-NH- or R2-S02-NH-wherein R2 is C,-C3 loweralkyl or halo Ci- C3loweralkyl; R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)R'4 wherein R14 is (i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyl or (iv) alkoxy-substituted loweralkyl; R373 is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and R370 is (i) hydrogen, (ii) C,-C3 loweralkyl or (iii) allyl; R5 is hydrogen; R6 and R7 are hydrogen; R and R9 are hydrogen; R is hydrogen;STDC0161 and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

Other most highly preferred compounds of the invention are compounds having Formula I or 11 or III or a salt, ester or prodrug thereof wherein R1 isC02H; -X-R2 is R2-C (=O)-NH-or R2-SO2-NH-wherein R2 is C,-C3 loweralkyl or halo Ci- C3 loweralkyl; R4 is hydrogen and R3 is -C(R37a)(OR37c)-R14 wherein R14 is loweralkyl or loweralkenyl; R373 is loweralkyl or loweralkenyl; and R370 is hydrogen, Cl-C3 loweralkyl or allyl; R5 is hydrogen; R6 and R7 are hydrogen; R8 and R9 are hydrogen; R10 is hydrogen; and Y is C2-C5 alkenyl, Cz-Cs haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

Preferred substituents R'include-C02H or esters or prodrugs thereof.

Preferred esters include C2-C6 loweralkyl esters or substituted or unsubstituted benzyl esters. Preferred substituents R'also include-S (O) 2NHC (=O) R" wherein R"is defined as above.

Most highly preferred substituents R'include-C02H or esters or prodrugs thereof. Most highly preferred esters include C2-C6 loweralkyl esters or substituted or unsubstituted benzyl esters.

Preferred substituents-X-R2 include R2-C (=O)-NH-, R2-NH-C (=O)-, R2-NH-S02-or R2-SO2-NH-wherein R2 is Cl-C3 loweralkyl, halo Ci-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or-X-R2 isEMI27.1 wherein -CH2,-O-,-S-or-NH-andY2is-C(O)-or-C(Raa)(Rbb)-whereinisRaa and Rbb are independently selected from the group consisting of hydrogen, Cl-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl,N-methylaminomethyl and methylthiomethyl.

More preferred substituents-X-R2 include R2-C (=O)-NH-, R2-NH-C (=O)-, R2-NH-S02-or R2-SO2-NH-wherein R2 is C,-C3 loweralkyl, halo Cl-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl or-X-R2 isEMI27.2 is-CH2andY2is-C(=O)-or-C(Raa)(Rbb)-whereinRaaandRbbarewhereinY1 independently selected from the group consisting of hydrogen, Cl-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl.

Even more preferred substituents-X-R2 include R2-C (=O)-NH-, R2-NH-C (=O)-, R2-NH-S02-or R2-SO2-NH-wherein R2 is C,-C3 loweralkyl, halo Cl-C3 loweralkyl, C2-C3 alkenyl or halo C2-C3 alkenyl.

More highly preferred substitutents -X-R2 include R2 -C(=O)-NH-, R2-NH-C(=O)-,R2-NH-SO2-R2-NH-SO2-or R2isC1-C3loweralkylorhalo-C1-C3wherein loweralkyl.

Even more highly preferred substituents-X-R2 include R2-C (=O)-NH-, R2-NH-C (=O)-, R2-NH-S02-or R2-S02-NH-wherein R2 is C-C2 loweralkyl or halo Ci-C2 loweralkyi, and especially, CH3-C (=O)-NH-, CF3-C (=O)-NH-, CH3-S02-NH- or CF3-SO2-NH-. <RTI ID=28.12>

Preferred substituents R3 and R4 are independently selected from the group consisting of hydrogen, heterocyclic and-Z-R14 wherein Z and R14 are</RTI> defined as most broadly defined previously herein and wherein one of R3 and R4 is other than hydrogen. <RTI ID=28.13>

More highly preferred, substituent R4 is hydrogen or loweralkyl and R3 includes heterocyclic or-Z-R14 wherein Z and R14 are defined as most broadly</RTI> defined previously herein.

Even more highly preferred, substituent R4 is hydrogen or loweralkyl andR3 includes (a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (h)-C(R37a)(OR37c)-R14or(i)-C(R37a)(R37b)-N(O)(R37c)R14(g)-C(=O)-R14, wherein R14 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic) alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)-(O=) C-substituted alkyl or (xv) (R37aO) 2-P (=O)-substituted alkyl; R37a and Rob are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl;STDC0094 and R37c is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl.

Most highly preferred, substituent R4 is hydrogen and R3 includes (a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)-R14 wherein R14 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic) alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37aO)-(O=) C-substituted alkyl or (xv) (R37aO) 2-P (=O)-substituted alkyl; R373 and R37b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and R37c is (i) hydrogen, (ii) C-C3 loweralkyl or (iii) allyl.

Also most highly preferred, substituent R4 is hydrogen and R3 includes (a) heterocyclic, (b) alkyl or (c)-C(R37a)(OR37c)-R14 wherein R14 is (i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyl or (iv) alkoxy-substituted loweralkyl; R37a is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and R37 is. (i) hydrogen, (ii) Cl-C3 loweralkyl or (iii) allyl.

Also most highly preferred, substituent R4 is hydrogen and R3 includes -C (R37a) (OR37C)-R'4 wherein R14 is loweralkyl or loweralkenyl; R373 is loweralkyl or loweralkenyl; and R37c is hydrogen, Cl-C3 loweralkyl or allyl, and especially, wherein R370 is hydrogen or methyl.

Preferred substituents R5 include hydrogen or loweralkyl. Most highly preferred, R5 is hydrogen.

Preferred substituents R6 and R7 include independently hydrogen and loweralkyl. Most highly preferred, R6 and R7 are hydrogen.

Preferred substituents R8, R9 and R10 incude independently hydrogen, fluoro and loweralkyl. Most highly preferred, R8, R9 and R are hydrogen.

Preferred substituent Y includes C2-C5 alkenyl, 02-05 haloalkenyl, -C (=Q2) R22,-N (=Q3),-N (O) =CHCH3,-NR23R24 or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R23, R24, Q2 and Q3 are defined as above.

More preferred substituent Y includes C2-C5 alkenyl, C2-C5 haloalkenyl,-C (=Q2) R22,-N (=Q3),-N (O) =CHCH3 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, Q2 and Q3 are defined as above.

Even more preferred substituent Y includes C2-C5 alkenyl, ?2-05 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. Representative alkenyl and haloalkenyl substituents Y include: -CH=CH2,-CH=CHF,-CH=CH-CH3,-CH=CH-CF3,-CH=CHCI,-CH=CHBr, -CH=CF2,-CH=CF (CH3),-CH=CF (CF3),-CH=CFCI,-CH=CFBr,-CH=C (CH3) 2, -CH=C (CH3) (CF3),-CH=CCI (CH3),-CH=CBr (CH3),-CH=C (CF3) 2,-CH=CCI (CF3), -CH=CBr (CF3),-CH=CC12,-CH=CCIBr,-CF=CH2,-CF=CHF,-CF=CH-CH3, -CF=CH-CF3,-CF=CHCI,-CF=CHBr,-CF=CF2,-CF=CF (CH3),-CF=CF (CF3), -CF=CFCI,-CF=CFBr,-CF=C (CH3) 2,-CF=C (CH3) (CF3),-CF=CCI (CH3), -CF=CBr (CH3),-CF=C (CF3) 2,-CF=CCI (CF3),-CF=CBr (CF3),-CF=CC12, -CF=CCIBr,-C (CH3) =CH2,-C (CH3)STDC0886 =CHF,-C (CH3) =CH-CH3,-C (CH3) =CH-CF3, -C (CH3) =CHCI,-C (CH3) =CHBr,-C (CH3) =CF2,-C (CH3) =CF (CH3), -C (CH3) =CF (CF3),-C (CH3) =CFCI, -C (CH3) =CFBr,-C (CH3) =C (CH3) 2,-C (CH3) =C (CH3) (CF3),-C (CH3) =CCI (CH3), -C (CH3) =CBr (CH3),-C (CH3) =C (CF3) 2,-C (CH3) =CCI (CF3),-C (CH3) =CBr (CF3), -C (CH3) =CC12,-C (CH3) =CCIBr, -C (CF3) =CH2,-C (CF3) =CHF,-C (CF3) =CH-CH3,-C (CF3) =CH-CF3,-C (CF3) =CHCI, -C (CF3) =CHBr,-C (CF3) =CF2,-C (CF3) =CF (CH3),-C (CF3) =CF (CF3),C (CF3) =CFCI,-C (CF3) =CFBr,-C (CF3) =C (CH3) 2,-C (CF3) =C (CH3) (CF3),C (CF3) =CCI (CH3), -C (CF3) =CBr (CH3),-C (CF3) =C (CF3) 2,-C (CF3)STDC0877 =CCI (CF3),-C (CF3) =CBr (CF3), -C (CF3) =CC12,-C (CF3) =CCIBr, -CCI=CH2,-CCI=CHF,-CCI=CH-CH3,-CCI=CH-CF3,-CCI=CHCI,-CCI=CHBr, -CCI=CF2,-CCI=CF (CH3),-CCI=CF (CF3),-CCI=CFCI,-CCI=CFBr,-CCI=C (CH3) 2, -CCI=C (CH3) (CF3),-CCI=CCI (CH3),-CCI=CBr (CH3),-CCI=C (CF3) 2, -CCI=CCI (CF3),-CCI=CBr (CF3),-CCI=CC12,-CCI=CCIBr, -CH=CH-CH2CH3,-CH=CF-CH2CH3,-CF=CH-CH2CH3,-CF=CF-CH2CH3, -CH=C (CH3) (CH2CH3),-CF=C (CH3) (CH2CH3),-CH=CCI (CH2CH3), -CF=CCI (CH2CH3),-C (CH3) =CH-CH2CH3,-C (CH3) =CF-CH2CH3, -CCI=CH-CH2CH3,-CCI=CF-CH2CH3,-C (CH2CH3) =CH2,-C (CH2CH3) =CHF,STDC0159 -C (CH2CH3) =CF2,-C (CH2CH3) =CH-CH3,-C (CH2CH3) =CF-CH3, -C (CH2CH3) =CH-CI,-C (CH2CH3) =CFCI.

Representative Y substituents which are heterocyclic rings having 5 ring atoms and also containing one or two double bonds include: furanyl, dihydrofuranyl, didehydrodioxolanyl, dithiolyl, imidazolyl, imidazolinyl, isothiazolyl, isothiazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl, oxadiazolinyl, oxathiolyl, oxazolyl, oxazolinyl, pyrazolyl, pyrazolinyl, pyrrolyl, dihydropyrrolyl, tetrazolyl, tetrazolinyl, thiadiazolyl, thiadiazolinyl, thiazolyl, thiazolinyl, thienyl, dihydrothienyl, triazolyl, triazolinyl.

More highly preferred substituents Y include cis-propenyl, trans-propenyl, isobutenyl, cis-2-chlorovinyl, vinyl, 2,2-difluorovinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl.

Most highly preferred substituents Y include cis-propenyl, cis-2-chlorovinyl, vinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl.

Preferred compounds of the invention include compounds selected from the group consisting of: ()- (2R, 3S, 5R, 1'R)-2-(1-Acetamido-2-ethyl-2-hydroxy) butyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen1-yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-ethyl-2-hydroxy) pentyl-3- (cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-hydroxy) pentyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt;STDC0315 ()- (2R, 3R, 5R, 1'R,2'R)-2-(1-Acetamido-2, 3-dihydroxy) propyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1yl)-pyrrolidine-5-carboxylic Acid;.

(-)- (2R, 3S, 5R, 1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-rpopen-1-yl)-pyrrolidine-5 carboxylate Ammonium Salt; ()- (2R, 3S, 5R, 1'R,2'R)-2-(1-Acetamido-2, 3-dimethoxy) propyl-3- (cis-propen-1-yl)pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-methoxy-2-vinyl) ethyl-3-(cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'S)-2-(1-Acetamido-2-ethyl) butyl-3-(cis-propen-1-yl)-pyrrolidine-5carboxylic Acid;STDC0683 ()- (2R, 3S, 5R, 1'S, 3'S)-2- (1-Acetamido-2- (N-isopropyl-N-methylamino-Noxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid; ()- (2R, 3S, 5R, 1'S, 3'S)-2- (1-Acetamido-2- (N-ethyl-N-methylamino-N-oxide)) ethyl3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid ; ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-methoxy) butyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylicAcid; ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylicAcid;STDC0801 ()- (2R, 3R, 5R, 1'R, 2'S)-2- (1-Acetamido-2-hydroxy) butyl-3- (pyrazol-3-yl)pyrrolidine-5-carboxylicAcid; ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'R)-2- (1-Acetamido-1- (3, 6-dihydro-2-H-pyran-2-yl)) propyl-3(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-methoxy-2-allyl) ethyl-3- (cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S, 3'S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis propen-1-yl)-pyrrolidine-5-carboxylic Acid;STDC0126 (#)-(2,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid;.

()- (2R, 3S, 5R, 1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen1-yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-1- (3,6-dihydro-2-H-pyran-2-yl)) methyl-3(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2, 3-dimethoxy) propyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-hydroxymethyl-2-hydroxy) pentyl-3- (cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic Acid;STDC0753 ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen1-yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1- yl)-pyrrolidine-5-carboxylicAcid; ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-hydroxy-2-(propeny-2-yl)ethyl-3-(cispropen-1-yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'S)-2-(1-acetamido-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine5-carboxylicAcid;STDC0860 ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-hydroxy) butyl-3-vinyl-pyrrolidine-5- carboxylicAcid; ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-hydroxy) pentyl-3-vinyl-pyrrolidine-5- carboxylicAcid; (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxyethyl-2-hydroxy)pentyl-3-(cispropen-1-yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'R)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5carboxylicAcid; ()- (2R, 3S, 5R, 1'R, 2'R)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'R)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5carboxylicAcid;STDC0820 ()- (2R, 3S, 5R, 1'R)-2-(1-Acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'S)-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)- pyrrolidine-5-carboxylic Acid; ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-methyl) butyl-3- (pyrazol-3-yi)-pyrrolidine-5- carboxylic Acid; ()- (2R, 3S, 5R, 1'S, 3'R)-2- (1-Acetamido-3-hydroxy) pentyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid; ()- (2R, 3R, 5R, 1'S)-2-(1-Acetamido-3-methyl)butyl-3-(thiazol-4-yl)-pyrrolidine-5carboxylic Acid;STDC0816 ()- (2R, 3R, 5R, 1'S)-1- t-Butoxycarbonyl-2- (1-acetamido-3-methyl) butyl-3- (thiazol2-yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'S)-2- (1-Acetamido-3-methyl) butyl-3-vinyl-pyrrolidine-5-carboxylicAcid; ()- (2R, 3S, 5R, 1'S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-difluoro-vin-1-yl)pyrrolidine-5-carboxylic Acid; ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-methyl) butyl-3- (pyrazol-3-yl)-pyrrolidine-5carboxylic Acid; (#)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-3-yl)-pyrrolidine-5- carboxylic Acid; ()- (2R, 3R, 5R, 1'S)-2-(1-acetamido-3-methyl) butyl-3-(isoxazol-5-yl)-pyrrolidine-5- carboxylic Acid;STDC0452 ()- (2R, 3R, 5R, 1'S)-2- (1-Acetamido-3-methyl) butyl-3- (imidazol-2-yl)-pyrrolidine-5Carboxylic Acid; ()- (2R, 3R, 5R, 1'S)-2- (1-Acetamido-3-methyl) butyl-3- (imidazol-4-yl)-pyrrolidine-5- carboxylic Acid; and ()- (2S, 3R, 5R, 1'S)-2- (1-acetamido-3-methyl) butyl-3-amino-pyrrolidine-5carboxylic Acid; or a pharmaceutically acceptable salt, ester or prodrug thereof.

More preferred compounds of the invention include compounds selected from the group consisting of: ()- (2R, 3S, 5R, 1'R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-hydroxy-2-methyl) pentyl-3- (cis-propen- 1-yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-ethyl-2-hydroxy) pentyl-3- (cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid;STDC0572 ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-hydroxy) pentyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt; ()- (2R, 3R, 5R, 1'R, 2'R)-2- (1-Acetamido-2, 3-dihydroxy) propyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-hydroxy-4-vinyl) butyl-3- (cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid;.

(-)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cispropen-1-yl)-pyrrolidine-5carboxylate Ammonium Salt; ()- (2R, 3S, 5R, 1'R, 2'R)-2- (1-Acetamido-2, 3-dimethoxy) propyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-methoxy-2-vinyl) ethyl-3- (cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'S)-2- (1-Acetamido-2-ethyl) butyl-3- (cis-propen-1-yl)-pyrrolidine-5- carboxylic Acid; ()- (2R, 3S, 5R, 1'S, 3'S)-2- (1-Acetamido-2- (N-isopropyl-N-methylamino-N- oxide))ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;STDC0811 ()- (2R, 3S, 5R, 1'S, 3'S)-2- (1-Acetamido-2- (N-ethyl-N-methylamino-N-oxide)) ethyl3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid; ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-methoxy) butyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-methoxy)pentyl3-3(cis-propen-1-yl)pyrrolidine-5-carboxylic Acid; ()- (2R, 3R, 5R, 1'R,2'S)-2- (1-Acetamido-2-hydroxy)butyl-3- (pyrazol-3-yl)- pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic Acid;STDC0712 ()- (2R, 3S, 5R, 1'R, 2'R)-2- (1-Acetamido-1- (3, 6-dihydro-2-H-pyran-2-yl)) propyl-3 (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S, 3'S)-2- (1-Acetamido-2-hydroxy-3-methyl) pentyl-3- (cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1yl)-pyrrolidine-5-carboxylic Acid;STDC0809 ()- (2R, 3S, 5R, 1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen1-yl)pyrrolidine-5-carboxylicAcid; ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-1-(3, 6-dihydro-2-H-pyran-2-yi)) methyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2, 3-dimethoxy) propyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cispropen-1-yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R,2'S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic Acid;STDC0755 ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen1-yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R,2'S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1yl)-pyrrolidine-5-carboxylic Acid; ()- (2R, 3S, 5R, 1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-(propeny-2-yl))ethyl-3-(cispropen-1-yl)-pyrrolidine-5-carboxylic Acid; and ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-hydroxy) hexyl-3-(cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid; or a pharmaceutically acceptable salt, ester or prodrug thereof.

The term"acid protecting group"as used herein refers to groups used to protect acid groups (for example,-CO2H,-S03H,-S02H,-P03H2,-PO2H groups and the like) against undesirable reactions during synthetic procedures.

Commonly used acid protecting groups are disclosed in T. H. Greene and P. G. M.

Wuts, Protective Groups in Organic Synthesis. 2nd edition, John Wiley & Sons,New York (1991). Most frequently, such acid protecting groups are esters.

Such esters include: alkyl esters, especially loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like; arylalkyl esters including, but not limited to, benzyl, phenethyl, 3phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined herein;STDC0641 silylesters, especially, (tri-loweralkyl) silyl esters, (di-loweralkyl) (aryl) silyl esters and (loweralkyl) (di-aryl) silyl esters, including, but not limited to, trimethylsilyl, triethylsilyl, isopropyidimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, phenyidiisopropylsilyl esters and the like; and the like.

Preferred acid protecting groups are loweralkyl esters.

The term"activated carboxylic acid group"as used herein refers to acid halides such as acid chlorides and also refers to activated ester derivatives including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, anhydrides derived from reaction of the carboxylic acid with N, N'-carbonyldiimidazole and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hydroxy-5-norbornene-2,3-dicarboximide derived esters, 2,4,5trichlorophenol derived esters, p-nitrophenol derived esters, phenol derived esters, pentachlorophenol derived esters, 8-hydroxyquinoline derived esters and the like.

The term"acyi"as used herein, refers to groups having the formula -C (=O)-R95 wherein R95 is hydrogen or an alkyl group. Preferred alkyl groups asR95 are loweralkyl groups. Representative examples of acyl groups include groups such as, for example, formyl, acetyl, propionyl, and the like.

The term"acylamino"as used herein, refers to groups having the formula -NHR89 wherein R89 is an acyl group. Representative examples of acylamino include acetylamino, propionylamino, and the like.

The term"alkenyl"as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. The term"lower alkenyl"refers to straight or branched chain alkenyl radicals containing from 2 to 6 carbon atoms.

Representative examples of alkenyl groups include groups such as, for example, vinyl, 2-propenyl, 2-methyl-1-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and the like.

The term"alkenylene"as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. The term "lower alkenylene"refers to a divalent group derived from a straight or branched chain alkene group having from 2 to 6 carbon atoms. Representative examples of alkenylene groups include groups such as, for example,-CH=CH-, -CH2CH=CH-,-C(CH3) =CH-,-CH2CH=CHCH2-, and the like.

The term"alkenyloxy"as used herein, refers to groups having the formula -OR8'where R8'is an alkenyl group.

The term"alkoxy"as used herein, refers to groups having the formula -OR99 wherein R99 is an alkyl group. Preferred R99 groups are loweralkyl groups.

Representative examples of alkoxy groups include groups such as, for example, methoxy, ethoxy, tert-butoxy, and the like.

The term"alkoxyalkoxy"as used herein, refers to groups having the formula-O-R96-O-R97 wherein R97 is loweralkyl, as defined herein, and R96 is a lower alkylene group. Representative examples of alkoxyalkoxy groups include groups such as, for example, methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.

The term"alkoxyalkyl"as used herein refers to an alkyl radical to which is appended an alkoxy group, for example, methoxymethyl, methoxylpropyl and the like.

The term"alkoxycarbonyl"as used herein, refers to groups having the formula,-C (=O)- R80, where R80 is an alkoxy group.

The term"alkoxycarbonylalkyl"as used herein, refers to groups having the formula (=O)- R79, appended to the parent molecular moiety through an alkylene linkage, where R79 is an alkoxy group.

As used herein, the term"alkyl"refers to straight or branched chain hydrocarbon radicals containing from 1 to 12 carbon atoms. The term "loweralkyl"refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms. Representative examples of alkyl groups include groups such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyi, n-hexyl, and the like.STDC0507 The hydrocarbon chains in alkyl groups or the alkyl portion of an alkyl-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen,-N (R27)- and sulfur wherein R27 at each occurrence is independently hydrogen, loweralkyl, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.

The term"alkylamino"as used herein, refers to groups having the formula -NHR9'wherein R9'is an alkyl group. Preferred R91 groups are loweralkyl groups. Representative examples of alkylamino include methylamino, ethylamino, and the like.

The term"alkylene"as used herein, refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 15 carbon. The term"lower alkylene"refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms. Representative examples of alkylene groups include groups such as, for example, methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,1-ethylene (-CH (CH3)-), 1,3-propylene (-CH2CH2CH2-), 2,2-dimethylpropylene (-CH2C (CH3) 2CH2-), and the like.STDC0513 The hydrocarbon chains in alkylene groups or the alkylene portion of an alkylene-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen,-N (R27)- and sulfur wherein R27 at each occurrence is independently hydrogen, loweralkyl, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.

The term"alkylsulfonyl"as used herein refers to the group having the formula,-S02-R78, where R78 is an alkyl group. Preferred groups R78 are loweralkyl groups.

The term"alkylsulfonylamino"as used herein refers to the group having the formula,-S02-R77, appended to the parent molecular moiety through an amino linkage (-NH-), where R77 is an alkyl group. Preferred groups R77 are loweralkyl groups.

The term"alkynyl"as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term"lower alkynyl"refers to straight or branched chain alkynyl radicals containing from 2 to 6 carbon atoms.

Representative examples of alkynyl groups include groups such as, for example, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.

The term"alkynylene"as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term "lower alkynylene"refers to a divalent group derived from a straight or branched chain alkynylene group from 2 to 6 carbon atoms. Representative examples of alkynylene groups include groups such as, for example,-C=-C-,-CH2-C=-C-, -C?C-CH2-,-CH(CH3)-C-C-, and the like.

The term"aminoalkyl"as used herein refers to an alkyl radical to which is appended an amino (-NH2) group.

The term"aryl"as used herein refers to a carbocyclic ring system having 6-10 ring atoms and one or two aromatic rings. Representative examples of aryl groups include groups such as, for example, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.

The aryl groups can be unsubstituted or substituted with one, two or three substituents, each independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxy, oxo (=O), hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, thioalkoxy, amino, alkylamino, alkylsulfonyl, dialkylamino, acylamino, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted arylalkoxy, unsubstituted aryloxy, mercapto, cyano, nitro, carboxy, carboxaldehyde, NH2C (=O)-, cycloalkyl, carboxyalkyl, alkylsulfonylamino, unsubstituted heterocyclic, unsubstituted (heterocyclic) alkyl, unsubstituted (heterocyclic) alkoxy, unsubstituted (heterocyclic)STDC0542 oxy and-SO3H. Preferred aryl substituents are each independently selected from the group consisting of loweralkyl, halo, haloaikyl, hydroxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, alkylsulfonyl, acylamino, cyano and nitro. Examples of substituted aryl include 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 4-methylsulfonylphenyl, and the like.

The term" (aryl) alkenyl" refers to a lower alkenyl group having appended thereto an aryl group. Representative examples of (aryl) alkenyl groups include groups such as, for example phenylethylenyl, phenylpropenyl, and the like.

The term" (aryl) alkyl" refers to a loweralkyl group having appended thereto an aryl group. Representative examples of (aryl) alkyl groups include groups such as, for example benzyl and phenylethyl.

The term"arylalkoxy"as used herein refers to the group having the formula,-0-R76 where R76 is an arylalkyl group.

The term" (aryl) alkynyl" refers to an alkynylene group having appended thereto an aryl group. Representative examples of (aryl) alkynyl groups include groups such as, for example phenylacetylenyl, phenylpropynyl, and the like.

The term"aryloxy"as used herein refers to the group having the formula, -0-R, where R72 is an aryl group.

The term"carbamoyl"as used herein refers to the group having the formula,-C (=O)-NH2.

The term"carboxyalkyl"as used herein, refers to the group having the formula,-R64-COOH, where R64 is a lower alkylene group.

The term"cyanoalkyl"as used herein refers to an alkyl radical to which is appended a cyano group (-CN).

The term"cycloalkenyl"as used herein refers to an aliphatic ring system having 5 to 10 carbon atoms and 1 or 2 rings containing at least one double bond in the ring structure. Representative examples of cycloalkenyl groups include groups such as, for example, cyclohexene, cyclopentene, norbornene and the like.

Cycloalkenyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyl. Preferred substitutents are independently selected from loweralkyl, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.

The term" (cycloalkenyl) alkenyl" as used herein refers to a cycloalkenyl group appended to a lower alkenyl radical. Representative examples of (cycloalkenyl) alkenyl groups include groups such as, for example, cyclohexenylethylene, cyclopentenylethylene, and the like.

The term" (cycloalkenyl) alkyl" as used herein refers to a cycloalkenyl group appended to a lower alkyl radical. Representative examples of (cycloalkenyl) alkyl groups include groups such as, for example, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, and the like.

The term" (cycloalkenyl) alkynyl" as used herein refers to a cycloalkenyl group appended to a lower alkynyl radical. Representative examples of (cycloalkenyl) alkynyl groups include groups such as, for example, cyclohexenylacetylenyl, cyclopentenylpropynyl, and the like.

The term"cycloalkyl"as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 or 2 rings. Representative cylcoalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornane, bicyclo [2.2.2] octane and the like.

Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyl. Preferred substitutents are independently selected from loweralkyl, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.

The term" (cycloalkyl) alkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical. Representative examples of (cycloalkyl) alkyl groups include groups such as, for example, cyclohexylmethyl, cyclopentylmethyl, cyclohexylethyl, cyclopentylethyl, and the like.

The term" (cycloalkyl) alkenyl" as used herein refers to a cycloalkyl group appended to a lower alkenyl radical. Representative examples of (cycloalkyl)alkenyl groups include groups such as, for example, cyclohexylethylene, cyclopentylethylene, and the like.

The term" (cycloalkyl) alkynyl" as used herein refers to a cycloalkyl group appended to a lower alkynyl radical. Representative examples of (cycloalkyl)alkynyl groups include groups such as, for example, cyclohexylacetylenyl, cyclopentylpropynyl, and the like.

The term"dialkylamino"as used herein, refers to groups having the formula-N (R9 ) 2 wherein each R90 is independently a lower alkyl group.

Representative examples of dialkylamino include dimethylamino, diethylamino, Nmethyl-N-isopropylamino and the like.

The term"halo"as used herein refers to F, Cl, Br or I.

The term"haloalkenyl"as used herein refers to a loweralkenyl group in which one or more hydrogen atoms is replaced with a halogen. Examples of haloalkenyl groups include 2-fluoroethylene, 1-chloroethylene, 1,2difluoroethylene, trifluoroethylene, 1,1,1-trifluoro-2-propylene and the like.

The term"haloalkoxy"as used herein refers to the group having the formula,-OR69, where R69 is a haloalkyl group as defined herein. Examples of haloalkoxy include chloromethoxy, fluoromethoxy, dichloromethoxy, trifluoromethoxy and the like.

The term"haloalkyl"as used herein, refers to a loweralkyl group in which one or more hydrogen atoms has been replaced with a halogen including, but not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl, pentafluoroethyl and the like.

The term"heterocyclic ring"or"heterocyclic"or"heterocycle"as used herein, refers to any 3-or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6-or 7-membered ring containing one, two, three, or four nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen atom and one sulfur atom; two nitrogen atoms and one sulfur atom; one nitrogen atom and one oxygen atom; two nitrogen atoms and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen atom and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions.

The 5-membered ring has 0-2 double bonds and the 6-and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized.

The term"heterocyclic"also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring, such as, for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like.

Heterocyclic groups include, but are not limited to groups such as, for example, aziridinyl, azetidinyl, epoxide, oxetanyl, thietanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, tetrahydropyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thienyl, dihydrothienyl,STDC0860 tetrahydrothienyl, triazolyl, triazolinyl, tetrazolyl, tetrazolinyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, oxadiazolinyl,, 1,2,3thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, thiadiazolinyl, 1,3-dithiolinyl, 1,2-dithiolyl, 1,3-dithiolyl, 1,3-dioxolinyl, didehydrodioxolanyl, 1,3-oxathiolinyl, oxathiolyl, pyrimidyl, benzothienyl and the like. Heterocyclic groups also include compounds of the formulaEMI50.1 where X* is-CH2 or-O-and Y* is-C (O)- or [-C (R92) 2-] v where R92 is hydrogen or Cl-C4 alkyl where v is 1,2, or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like.STDC0113 Heterocyclic groups also include bicyclic rings such as quinuclidinyl and the like.

Heterocyclic groups can be unsubstituted or substituted with from one to three substituents, each independently selected from loweralkyl, hydroxy, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino and halogen. In addition, nitrogen containing heterocyclic rings can be N-protected.

The term" (heterocyclic) alkenyl" as used herein refers to a heterocyclic group appended to a lower alkenyl radical including, but not limited to, pyrrolidinylethenyl, morpholinylethenyl and the like.

The term" (heterocyclic) alkoxy" as used herein refers to the group having the formula,-OR68, where R68 is a (heterocyclic) alkyl group.

The term" (heterocyclic) alkyl" as used herein refers to a heterocyclic group appended to a loweralkyl radical including, but not limited to, pyrrolidinylmethyl, morpholinylmethyl and the like.

The term" (heterocyclic) alkynyl" as used herein refers to a heterocyclic group appended to a lower alkynyl radical including, but not limited to, pyrrolidinylacetylenyl, morpholinylpropynyl and the like.

The term" (heterocyclic) oxy" as used herein refers to a heterocyclic group appended to the parent molecular moiety through an oxygen atom (-O-).

The term"hydroxy protecting group","hydroxyl protecting group"or"-OH protecting group"as used herein refers to refers to groups used to hydroxy groups against undesirable reactions during synthetic procedures. Commonly used hydroxy protecting groups are disclosed in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis. 2nd edition, John Wiley & Sons, NewYork (1991).STDC0822 Such hydroxy protecting groups include: methyl ether; substituted methyl ethers, including, but not limited to, methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, tbutoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2 (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl ether and the like; substituted ethyl ethers, including, but not limited to, 1-ethoxyethyl, 1methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 2,2,2-trichloroethyl, trimethylsilylethyl, t-butyl ether and the like; benzyl ether;STDC0868 substituted benzyl ethers, including, but not limited to, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitorbenzyl, p-halobenzyl, p-cyanobenzyl, diphenylmethyl, triphenylmethyl ether and the like; silyl ethers, including, but not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, tbutyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl ether and the like; esters, including, but not limited to, formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, pivaloate, benzoate ester and the like; and the like.

Preferred hydroxy protecting groups include substituted methyl ethers, benzyl ether, substituted benzyl ethers, silyl ethers and esters.

The term"hydroxyalkyl"as used herein refers to the group having the formula,-R65-OH, where R65 is an alkylene group The term"leaving group"as used herein refers to a group which is easily displaced from the compound by a nucleophile. Examples of leaving groups include a halide (for example, Cl, Br or 1) or a sulfonate (for example, mesylate, tosylate, triflate and the like) and the like.

The term"N-protecting group"or"N-protected"as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991).STDC0413 N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like;STDC0891 carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl)-1-methylethoxycarbonyl, a, a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl,STDC0354 phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).STDC0206 The term"thioalkoxy"as used herein refers to groups having the formula -SR98 wherein R98 is an alkyl group. Preferred groups R98 are loweralkyl groups.

The term"thio-substituted alkyl"as used herein refers to an alkyl radical to which is appended a thiol group (-SH).

As used herein, the terms"S"and"R"configuration are as defined by theIUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry,Pure Appl. Chem. (1976) 45,13-30.

The compounds of the invention can comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as individual optical isomers, including, enantiomers and single diastereomers of the compounds of the invention substantially free from their enantiomers or other diastereomers.STDC0532 By"substantially free"is meant greater than about 80% free of other enantiomers or diastereomers of the compound, more preferably greater than about 90% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 95% free of other enantiomers or diastereomers of the compound, even more highly preferably greater than about 98% free of other enantiomers or diastereomers of the compound and most preferably greater than about 99% free of other enantiomers or diastereomers of the compound.

In addition, compounds comprising the possible geometric isomers of carbon-carbon double bonds and carbon-nitrogen double are also meant to be included in this invention.

Individual stereoisomers of the compounds of this invention can be prepared by any one of a number of methods which are within the knowledge of one of ordinary skill in the art. These methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers and then chromatographically separating the diastereomers and regeneration of the individual enantiomers, enzymatic resolution and the like.

Stereospecific synthesis involves the use of appropriate chiral starting materials and synthetic reactions which do not cause racemization or inversion of stereochemistry at the chiral centers.

Diastereomeric mixtures of compounds resulting from a synthetic reaction can often be separated by chromatographic techniques which are well-known to those of ordinary skill in the art.

Chromatographic resolution of enantiomers can be accomplished on chiral chromatography resins. Chromatography columns containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto the column containing the chiral stationary phase. The enantiomers are then separated by HPLC.

Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with chiral auxiliaries.

The resulting diastereomers can then be separated by column chromatography.

This technique is especially useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary. Chirally pure amino acids, organic carboxylic acids or organosulfonic acids are especially useful as chiral auxiliaries. Once the diastereomers have been separated by chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be recovered and used again.

Enzymes, such as esterases, phosphatases and lipases, can be useful for resolution of derivatives of the enantiomers in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be prepared. Certain enzymes will selectively hydrolyze only one of the enantiomers in the mixture. Then the resulting enantiomerically pure acid can be separated from the unhydrolyzed ester.

In addition, solvates and hydrates of the compounds of Formula I and 11 and III are meant to be included in this invention.

When any variable (for example R', R', R3, m, n, etc.) occurs more than one time in any substituent or in the compound of Formula I or 11 or III or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. In addition, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.

This invention is intended to encompass compounds having Formula I andII and III when prepared by synthetic processes or by metabolic processes.

Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.

Compounds of the invention can be prepared according to the methods described in Schemes 1-5 as shown below.

Throughout the schemes, methods will be illustrated wherein R'is a carboxylic acid or carboxylic acid ester substituent. It will be understood by those skilled in the art that other R'substituents can (a) be obtained either from the carboxylic acid or carboxylic acid ester group, (b) can be introduced by similar methods to those used to introduce the carboxylic acid or carboxylic acid ester group or (c) can be introduced by other methods generally known in the art.

In adddition, throughout the schemes, methods will be illustrated whereinR4, R6, R7, R8, R9 and R are hydrogen. It will be understood by those skilled in the art that compounds wherein one or more of these substituents is other than hydrogen can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.

In addition, throughout the schemes, methods will be illustrated for obtaining compounds of the invention having the preferred relative stereochemistry. It will be understood by those skilled in the art that compounds of the invention having other relative stereochemistry can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.

In addition, throughout the schemes, methods will be illustrated wherein X is-C (=O)-NH-. It will be understood by those skilled in the art that other X groups can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.

As shown in Scheme 1, reaction of acrolein with an N-protected a-amino acid ester 1 (P is an N-protecting group, preferably a benzyl group or the like and P2 is a carboxylic acid protecting group, preferably a t-butyl group or the like) in an inert solvent (for example, toluene and the like) in the presence of an acid catalyst (for example, acetic acid and the like), followed by equilibration with a base (for example, with triethylamine or the like) and separation of the isomers by chromatography, provides substituted pyrrolidine 2. Reduction of the aldehyde group to an alcohol with an aldehyde to alcohol reducing agent (for example, sodium borohydride or the like) in an inert solvent (for example, methanol or the like), followed by chromatographic separation of the isomers provides alcohol 3.

Alcohol 3 can be protected with an hydroxy protecting group P3 (preferably with a silyl protecting group, for example, t-butyldimethylsilyl or the like) using standard alcohol protection methods to provide 4. Oxidation of the vinyl group of compound 4 to an aldehyde is accomplished by reacting compound 4 with Os04 and N-methylmorpholine N-oxide to give the corresponding diol. The diol is then treated with sodium periodate to provide aldehyde 5. Substituents R3 can be introduced via reaction of aldehyde 5 with a Grignard reagent (for example, R3MgBr or the like) to give alcohol 6. Oxidation of alcohol 6 (for example, Swern oxidation or the like) provides ketone 7.STDC0618 Reductive amination of ketone 7 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 8. Amine 8 can be further functionalized to complete the introduction of the R2-X-substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 9a. The other diastereomeric amine 9b) can also be isolated and further transformed according to Scheme 1. STDCDBPG0309* Removal of hydroxy protecting group P3 (for example, by reaction with a fluoride ion source, such as tetrabutylammonium fluoride or the like, when P3 is a silyl protecting group) provides alcohol 10. Transformation of the hydroxy group of alcohol 10 allows introduction of various substituents Y.

For example, alkylation of the hydroxy group provides ethers 11. Ndeprotection (for example, where P'is a benzyl group, by hydrogenation) gives 12', followed by ester hydrolysis (for example, with acid such as HCI), provides compound 12"of the invention.

Oxidation of the hydroxy group of 10 (for example, Swern oxidation or the like) provides aldehyde 13. Oxidation of aldehyde 13 (for example, with NaCI02 or the like) provides carboxylic acid 14. The carboxylic acid substituent of 14 can be used to introduce a variety of other functional groups in substituent Y. For example, the carboxylic acid can be esterified (for example, by reaction with diazomethane or with ethanol and DCC or the like) or the carboxylic acid or an activated derivative thereof can be reacted with amines to provide 15 (wherein -C (=O)-R22 represents an ester or an amide). N-deprotection (for example, where P'is a benzyl group, by hydrogenation) gives 16', followed by ester hydrolysis (for example, with acid such as HCI), provides compound 16"of the invention.

Derivatives of the aldehyde group of 13 or the carboxylic acid group of 14 can be used to introduce substituents Y which are-CN or various heterocycles, according to methods known to those skilled in the art and according to the specific methods exemplified herein.

Reaction of aldehyde 13 with loweralkyl-or loweralkenyl-Grignard reagents, followed by oxidation (for example, Swern oxidation or the like), provides ketones 17 wherein R22 is loweralkyl or loweralkenyl. N-deprotection (for example, where P1 is a benzyl group, by hydrogenation) gives 18', followed by ester hydrolysis (for example, with acid such as HCI), provides compound 18"of the invention.

Compounds wherein substituent Y is an amino group or a derivative of an amino group can be prepared as shown in Scheme 2. Oxidation of aldehyde 2 (for example, with AgO or NaCI02 or the like) provides carboxylic acid 19.

Curtius rearrangement of carboxylic acid 19 (for example, reaction with DPPA,Et3N and benzyl alcohol or the like), followed by chromatographic separation of the diastereomers, provides amide 20 wherein P4 is an N-protecting group (for example, benzyloxycarbonyl or the like). Transformations analogous to those which converted compound 4 to compound 9a and 9b in Scheme 1, enable the conversion of 20 to 21a and 21 b, which can be separated by chromatography.

Removal of protecting group P4 (for example, by selective hydrogenation) provides 22. Further derivatization of the amino group allows for introduction of substituents Y which are amine derivatives. N-deprotection (for example, where P is a benzyl group, by hydrogenation), followed by ester hydrolysis (for example, with acid such as HCI), provides compounds of the invention wherein Y is amino or an amine derivative.

Olefination of aldehyde 13 (for example, with Ph3PCH2 or the like), followed by hydrogenation (causing N-deprotection (for example, where P'is a benzyl group) and olefin saturation, followed by ester hydrolysis (for example, with acid such as HCI), provides compounds of the invention wherein Y is loweralkyl.

As shown in Scheme 3, oxidation of the vinyl group of compound 4 to a diol (for example, with Os04 and N-methylmorpholine N-oxide or the like) gives diol 23. Removal of N-protecting group P' (for example, where P'is a benzyl group, by hydrogenation) provides pyrrolidine 24. Reprotection with an acid labile N-protecting group P5 (for example, t-butoxycarbonyl or the like) provides 25. Transformation of compound 25 to aldehyde 26a and 26b can be accomplished in a manner analogous to conversion of compound 4a to compound 10 and compound 10 to compound 13 as shown in Scheme 1.26a and 26b can be separated by chromatography.

Olefination of 26a (for example, with Ph3PCH2, or triphenylphosine/methylene chloride/n-BuLi, or I-Ph3P+CH2CH3/KOtBu, or the like) provides 27 wherein Y is an olefinic substituent. N-deprotection of the P5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 28 wherein Y is an olefinic substituent.

In yet another alternative method shown in Scheme 4, the hydroxy group of alcohol 3 is protected with a base-labile hydroxy protecting group P6 (for example, acetyl or the like) to give compound 29. Oxidation of the vinyl group of 29 with Os04 and N-methylmorpholine N-oxide provides diol 30. Removal of the P1 protecting group (for example, by hydrogenation or the like) provides pyrrolidine 31. Reprotection with an acid-labile N-protecting group P5 (for example, t-butoxycarbonyl or the like) provides 32. Selective protection of the primary alcohol of 32 with a hydroxy protecting group P7 (for example, a silyl protecting group such as triisopropylsilyl or the like) provides compound 33.

Oxidation of 33 (for example, Swern oxidation or the like) provides ketone 34.

Reductive amination of ketone 34 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 35.

Amine 35 can be further functionalized to complete the introduction of the R2-X- substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 36a. The other diastereomeric amine (36b) can also be isolated and further transformed according this scheme.

Selective removal of the P6 hydroxy protecting group in 36a (for example, with K2CO3 in methanol or the like) provides alcohol 37. Oxidation of the alcohol to an aldehyde (for example, Swern oxidation or the like) provides 38. The aldehyde can serve as a precursor for various substituents Y in the compounds of the invention. For example, olefination of 38 (for example, with Ph3PCH2, or triphenylphosine/methylene chloride/n-BuLi, or I-Ph3P'CH2CH3/KOtBu, or the like) provides 39 wherein Y is an olefinic substituent. Removal of the P7 hydroxy protecting group (for example, with a fluoride ion source such as tetrabutylammonium fluoride or the like) gives alcohol 40.

The alcohol can serve as a precursor for a variety of R3 substituents in the compounds of the invention. For example, the alcohol of 40 can be oxidized to an aldehyde (for example, by Dess-Martin oxidation or the like) to give 41.

Aldehyde 41 can be reacted with Grignard reagents (R'4MgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R'4Li or the like) to provide 42 as a mixture of alcohol diastereomers which can be separated chromatographically to provide the major isomer 42a and the other isomer 42b. Isomer 42a or the mixture of isomers 42 can be oxidized (for example, by Dess-Martin oxidation or the like) to give ketone 43. Reduction of ketone 43 (for example, with sodium borohydride in ethanol or the like) provides alcohol 42b as the major isomer, which can be isolated by chromatography.STDC0243 Ndeprotection of the P5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 44a or 44b, respectively, wherein Y is an olefinic substituent.

Alkylation of alcohol 42a or 42b provides ethers 45a or 45b, respectively.

N-deprotection of the P5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 48a or 48b, respectively, wherein Y is an olefinic substituent.

As shown in Scheme 5, reaction of ketone 43 with with Grignard reagents (R37aMgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R37aLi or the like) provides alcohols 46a and 46b as a mixture of alcohol diastereomers which can be separated chromatographically. N-deprotection of the P5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 47a or 47b, respectively, wherein Y is an olefinic substituent.

Alkylation of alcohol 46a or 46b provides ethers 49a or 49b, respectively.

N-deprotection of the P5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 50a or 50b, respectively, wherein Y is an olefinic substituent.

Esters or prodrugs of the compounds of the invention can be prepared by methods known in the art.

SCHEME 1EMI63.1 SCHEME 1 (confd. 1 EMI64.1 ester or amide SCHEME 1 (cont'd.)EMI65.1 <tb> <SEP> ruz<tb> <SEP> R22, <SEP> 1R2c <SEP> (O) <SEP> HN,, <SEP> OH<tb> 16'<tb> <SEP> I<tb> <SEP> R3 <SEP> H <SEP> O<tb> <SEP> 168'<tb> <SEP> R22l"R221l <tb> <SEP> -J <SEP> ? <SEP> R0<tb> 13 <SEP> R2C <SEP> N-''I <SEP> P <SEP> RZC <SEP> () <SEP> HN,<tb> R-r-4N<tb> <SEP> P <SEP> R <SEP> H <SEP> O<tb> <SEP> 17 <SEP> 18, <SEP> g<tb> <SEP> R22 <SEP> is <SEP> loweralkyl<tb> <SEP> or <SEP> loweralkenyl<tb> <SEP> o<tb> <SEP> R22<tb> <SEP> R2C <SEP> (O) <SEP> HN/,, <SEP> OH<tb> <SEP> 18'<tb> <SEP> I<tb> <SEP> R <SEP> H <SEP> <tb> <SEP> 18"<tb> SCHEME 2EMI66.1 SCHEME 3EMI67.1 Y is an alkene SCHEME 4EMI68.1 SCHEME 4 (cont'd.)EMI69.1 EMI69.2 <tb> <SEP> Y-1.STDC0541 <SEP> yo<tb> <SEP> R <SEP> C <SEP> (O) <SEP> HN, <SEP> < <SEP> t <SEP> oOp2<tb> /' <SEP> : <SEP> rl <SEP> N"If<tb> PO <SEP> P50 <SEP> HO<tb> <SEP> 39 <SEP> Y <SEP> is <SEP> an <SEP> alkene <SEP> 40<tb> <SEP> or <SEP> haloalkene<tb> EMI69.3 SCHEME 4 (cont'd.)EMI70.1 SCHEME 4 (cont'd.)EMI71.1 SCHEME 5EMI72.1 SCHEME 5 (cont'd.)EMI73.1 The other compounds of the invention can be readily prepared from the compounds described herein using techniques known in the chemical literature.

The methods required are known and can be readily practiced by those having ordinary skill in the art.

Key intermediates for the preparation of compounds of the invention include the following: (1)EMI74.1 wherein P'is an N-protecting group (preferably, a benzyl group or a substituted benzyl group) and P2 is a carboxylic acid protecting group (preferrably, a loweralkyl group, especially t-butyl); preferrably, P'and p2 can be selectively deprotected/removed; or a salt thereof; (2)EMI74.2 wherein P is an N-protecting group (preferably, a benzyl group or a substituted benzyl group) and P2 is a carboxylic acid protecting group (preferably, a loweralkyl group, especially t-butyl);STDC0831 and P3 is hydrogen or a hydroxy protecting group (preferably, an acyl protecting group, for example, acetyl and the like, or a silyl protecting group, for example, t-butyldimethylsilyl and the like); preferrably, p1, P2 and P3 can be selectively deprotected/removed; or a salt thereof; (3)EMI75.1 wherein P'is an N-protecting group (preferably, a benzyl group or a substituted benzyl group) and P2 is a carboxylic acid protecting group (preferably, a loweralkyl group, especially t-butyl); and P4 is hydrogen or an N-protecting group (preferably, a carbamate N-protecting group, for example, benzyloxycarbonyl and the like); preferrably, P', p2 and P4 can be selectively deprotected/removed;STDC0721 or a salt thereof; (4)EMI75.2 EMI76.1 orEMI76.2 wherein P5 is an N-protecting group (preferably, an acid labile N-protecting group, such as t-butyloxycarbonyl and the like) and P2 is a carboxylic acid protecting group (preferably, a loweralkyl group, especially t-butyl); and P6 is hydrogen or a hydroxy protecting group (preferably, a base labile hydroxy protecting group, such as acetyl and the like); and P7 is hydroxy protecting group (preferably, a silyl protecting group, such as triisopropylsilyl and the like); preferrably, P2, P5, P6 and P7 can be selectively deprotected/removed; or a salt thereof;STDC0754 and EMI77.1 wherein P5 is an N-protecting group (preferably, an acid labile N-protecting group, such as t-butyloxycarbonyl and the like) and P2 is a carboxylic acid protecting group (preferably, a loweralkyl group, especially t-butyl); and P6 is hydrogen or a hydroxy protecting group (preferably, a base labile hydroxy protecting group, such as acetyl and the like); and P7 is hydroxy protecting group (preferably, a silyl protecting group, such as triisopropylsilyl and the like); and R2 is defined as herein (preferably, loweralkyl or haloloweralkyl; most preferably, methyl or trifluoromethyl); preferrably, P2, P5, P6 and P7 can be selectively deprotected/removed; or a salt thereof.

All patents, patent applications, and literature references cited in this specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.

The reagents required for the synthesis of the compounds of the invention are readily available from a number of commercial sources such as AldrichChemical Co. (Milwaukee, Wl, USA); Sigma Chemical Co. (St. Louis, MO, USA); and Fluka Chemical Corp. (Ronkonkoma, NY, USA); Alfa Aesar (Ward Hill, MA 01835-9953); Eastman Chemical Company (Rochester, New York 14652-3512);Lancaster Synthesis Inc. (Windham, NH 03087-9977); Spectrum ChemicalManufacturing Corp. (Janssen Chemical) (New Brunswick, NJ 08901); Pfaltz andBauer (Waterbury, CT. 06708). Compounds which are not commercially available can be prepared by employing known methods from the chemical literature.

The following examples will serve to further illustrate the preparation of the compounds of the invention, without limitation.

Example1 ()- R. 3R. 5R. 1'S)-2-(1-Acetamido-3-ethvl) pentvl-3-(methoxvmethvl)-nyrrolidine- 5-carboxvlic Acid Hydrochloride.EMI79.1 STDC01811A. ()- (2S. 3R. 5R)- and ()- (2S, 3S, 5R)-1-Benzvl-2-vinvl-3-formvl-pvrrolidine- 5-carboxylic Acid t-Butvl Ester (8: 1 ratio).

Acrolein (8 mL, 120 mmole) was added to a solution of t-butyl N-benzylglycinate (4.34 g, 19.6 mmole) and acetic acid (5 drops) in toluene (100 mL). The solution was heated at reflux. After 1 hour, the reaction was cooled to about 50 C and an additional 3 mL of acrolein were added. The reaction was heated at reflux for an additional 2 hours and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% ethyl acetate/hexanes to provide a mixture of ()- (2S, 3R, 5R)- and ()- (2S, 3S, 5R)-1-benzyl-2-vinyl-3- formyl-pyrrolidine-5-carboxylic acid t-butyl esters as an oil (yield: 2.78 g, 45%).

The mixture of aldehydes was equilibrated to an 8: 1 ratio by stirring the crude product with triethylamine (0.5 mL) in ethyl acetate at room temperature followed by evaporation of the solvents.

1 H NMR (CDC13) (major isomer only): 81.45 (s, 9H), 2.26 (m, 1 H), 2.69 (m, 1 H), 3.49 (dd, J=7.8,3.0 Hz, 1H), 3.61 (d, J=13.5 Hz, 1 H), 3.93 (m, 1 H), 3.94 (d, J=13.5 Hz, 1H), 5.22-5.33 (two dd, 2H), 5.7 (ddd, J=17.7,10.2,7.8 Hz, 1H), 7. 21-7.35 (m, 5H), 9.71 (d, J=1.2 Hz, 1H).

MS (M+H) + = 316. EMI80.1 STDC0153 1 B. ()- (2S. 3R, 5R)-1-Benzyl-2-vinvl-hydroxymethvl)-pvrrolidine-5-carboxylic Acid t-Butvl Ester.

A solution of the 8: 1 mixture of ()- (2S, 3R, 5R)- and ()- (2S, 3S, 5R)-1- benzyl-2-vinyl-3-formylpyrrolidine-5-carboxylic acid t-butyl ester (6.0 g, 19.0 mmole), prepared according to the method described in Example 1A, in 100 mL of methanol was cooled to 0 C and treated with sodium borohydride (0.72 g, 19.0 mmole). The mixture was stirred for 0.5 hour, warmed to room temperature, and stirred for an additional 1 hour. The reaction was quenched with aqueous ammonium chloride, and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was dried over MgS04, filtered and concentrated in vacuo.STDC0183 The residual oil was purified by chromatography on silica gel using a gradient of 20-30% ethyl acetate/hexanes to furnish the title compound as a colorless oil (yield: 4.0 g, 66%).

1 H NMR (CDC13): 81.46 (s, 9H), 1.80 (m, 1H), 2.16 (m, 1H), 2.39 (m, 1H), 2.54 (m, 1H), 3.48-3.53 (m, 2H), 3.08 (d, 2H), 3.91 (d, 2H), 5.17-5.22 (m, 2H), 5.70 (m, 1 H), 7.23-7.34 (m, 5H).

MS (M+H) + = 318. EMI81.1 STDC0195 1C.(#)-(2S,3R,5R)-1-Benzyl-2-vinyl-3-(t-butyldimethylsilyloxymethyl)- pyrrolidine-5-carboxylic Acid t-Butvl Ester.

A solution of ()- (2S, 3R, 5R)-1-benzyl-2-vinyl-3- (hydroxymethyl)- pyrrolidine-5-carboxylic acid t-butyl ester (3.6 g, 11.4 mmole), tert-butyidimethylsilyl chloride (3.7 g, 24.5 mmole) and imidazole (2.8 g, 41.2 mmole) in 80 mL of DMF was stirred at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried over MgS04, and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% ethyl acetate/hexanes to provide the title compound, as a colorless oil (yield: 3.5 g, 71%).STDC0329 1 H NMR (CDC13): 80.02 (d, 6H), 0.86 (s, 9H), 1.43 (s, 9H), 1.67 (ddd, 1 H), 2.11 (m, 1 H), 2.28 (m, 1H), 3.40-3.70 (m, 6H), 3.90 (d, 2H), 5.11-5.19 (m, 2H), 5.69 (ddd, 1 H), 7.20-7.30 (m, 5H).

MS (M+H) + = 432.EMI81.2 STDC0143 1D.(#)-(2R,3R,5R)-1-Benzyl-2-formyl-3-(t-butyldimethylsilyloxymethyl)pyrrolidine-5-carboxylic Acid t-Butvl Ester.

Osmium tetroxide (20 mg) was added to a room temperature solution of ()- (2S, 3R, 5R)-1-benzyl-2-vinyl-3-(t-butyidimethylsilyloxymethyl)-pyrrolidine-5- carboxylic acid t-butyl ester (3.5 g, 8.12 mmole) in 60 mL of 8: 1 acetone/water and N-methylmorpholine N-oxide (3.0 g, 25.6 mmole). The reaction mixture was stirred at room temperature for 6 hours and quenched with saturated aqueousNa2S203. The mixture was stirred for an additional 10 minutes and the solvent removed. The brownish residue was partitioned between dichloromethane and water. The organic layer was dried over MgS04 and concentrated in vacuo to provide the intermediate diol as an oil (?3.8g) which was used without additional purification.

MS (crude): (M+H) + = 466 The crude diol was dissolved in 6: 1 tetrahydrofuran (THF)/water (50 mL) and treated with sodium periodate (3.0 g, 14.0 mmole). The mixture was stirred at room temperature for 1 hour and diluted with ethyl acetate, washed with water, dried over MgS04, filtered, and concentrated in vacuo. The crude aldehyde was purified by chromatography on silica gel using 3% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 1.6 g, 46%).

1 H NMR (CDC13): 80.03 (d, 6H), 0.86 (s, 9H), 1.46 (s, 9H), 1.72 (m, 1 H), 2.26-2.45 (m, 2H), 3.53-3.71 (m, 5H), 3.84 (d, 1 H), 3.93 (d, 1H), 7.27-7.31 (m, 5H), 9.32 (d, 1H).

MS (M+H) + = 434. EMI83.1 STDC0191 1 E. (i)-(2R, 3R, 5R)-1-Benzvl-2-(1-oxo-3-ethvl) nentvl-3-(t-butvidimethvisilvioxy- methvl)-pyrrolidine-5-carboxylic Acid t-Butvl Ester.

A dry flask containing magnesium (0.14 g, 5.83 mmole), under argon, was charged with 10 mL of dry THF and 3 drops of dibromoethane. This was followed by addition of 1-bromo-2-ethylbutane (0.95 g, 5.83 mmole). The reaction mixture was heated at reflux for 45 minutes, until most of the magnesium had reacted.

The reaction mixture was cooled to-30 C and ()- (2R, 3R, 5R)-1-benzyl-2-formyl- 3-(t-butyidimethylsilyloxymethyl)-pyrrolidine-5-carboxylic(t-butyidimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (0.5 g, 1.15 mmole) in of THF (6 mL) was added, dropwise. The reaction was slowly warmed to-10 C, over a period of about 2 hours, and quenched with aqueous ammonium chloride. The resultant slurry was diluted with ethyl acetate and washed with water, brine, and dried over MgS04 and concentrated. The crude alcohol product, an oil (?0.85 g), was used without further purification.

MS (M+H) + = 520.

A solution of oxalyl chloride (2.5 mL, 2M in CH2CI2) in 10 mL of anhydrous dichloromethane was prepared and maintained under a nitrogen atmosphere, at -78 C. DMSO (0.77 mL, 9.83 mmole) was added slowly to the solution. The mixture was stirred for 15 minutes and treated with the crude alcohol prepared above, about 0.85 g, in 5 mL of anhydrous dichloromethane. The solution was stirred for 1 hour and triethylamine (2.3 mL, 16.4 mmole) was added slowly to the reaction mixture. The solution was then allowed to slowly warmed to room temperature and diluted with dichloromethane. The organic layer was washed with water, dried over MgS04, and concentrated. The residue was purified by chromatography on silica gel using 3% ethyl acetate/hexanes to provide the title compound, as an oil (yield: 0.35 g, 66%).

MS (M+H) + = 518.EMI84.1 STDC0246 1 F. ()- (2R. 3R, 5R, 1'R)- and ()- (2R. 3R. 5R, 1'S)-1-Benzyl-2- (1-amino-3-ethvl)- pentyt-butrldimethvlsilyloxvmethvl)-pyrrolidine-5-carboxvlic Acid t-Butvl Ester.

A solution of ()- (2R, 3R, 5R)-1-benzyl-2- (1-oxo-3-ethyl) pentyl-3- (t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (0.20 g, 0.39 mmole), ammonium acetate (30 equiv.) and sodium cyanoborohydride (10 equiv.) in 5 mL of methanol was heated at reflux for 24 hours with occasional addition of an additional 60 equivalents of ammonium acetate and 20 equivalents of sodium cyanoborohydride. The solvent was evaporated. The resultant residue was partitioned between dichloromethane and water. The organic layer was dried over MgS04, filtered, and concentrated. The product was purified by chromatography on silica gel using 30-50% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 130 mg, 64%).

'H NMR (CDC13) 8 7.30 (m, 5H), 4.91 (s, 1H), 3.53 (m, 2H), 3.08 (m, 1H), 2.88 (m, 1H), 2.35 (m, 1H), 1.85 (m, 1H), 1.44 (s, 9H), 1.20-1.40 (m, 7H), 0.88 (s, 9H), 0.85 (m, 6H), 0.03 (s, 6H) MS (M+H) + = 519. EMI85.1 STDC01931G.($)-(2R,3R,5R,1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(t-butyldimethylsilvloxymethvl)-pvrrolidine-5-carboxylic Acid t-Butyl Ester.

A solution of ()- (2R, 3R, 5R, 1'R)- and ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1- amino-3-ethyl) pentyl-3- (t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (110 mg, 0.21 mmole) and acetic anhydride (214 mg, 2.1 mmole) in 10 mL of dichloromethane was stirred for 1 hour. The solvent and excess acetic anhydride were removed in vacuo. The residue was purified by chromatography on silica gel using 30% ethyl acetate/hexanes to provide the title compound as a white solid (yield: 85 mg, 72%).

'H NMR (CDC13) 8 7.28 (m, 5H), 5.14 (d, J=14Hz, 1H), 4.36 (m, 1H), 3.95 (m, 2H), 3.62 (m, 1 H), 3.52 (m, 1 H), 3.45 (m, 1 H), 2.98 (m, 1 H), 1.98 (s, 3H), 1.60 (m, 2H), 1.43 (s, 9H), 1.20-1.40 (m, 7H), 0.88 (s, 9H), 0.80 (m, 6H), 0.04 (s, 6H) MS (M+H) + = 561.EMI85.2 STDC0213 1H. ()- (2R, 3R. 5R, 1'S)-1-Benzvl-2-1-acetamido-3-ethvl) pentvl-3- (hydroxv- methyl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

A solution of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-amino-3-ethyl) pentyl-3- (t- butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (85 mg, 0.15 mmole) in dry THF (5 mL) was prepared and maintained at room temperature under a nitrogen atmosphere. Tetrabutylammonium fluoride (1 M in THF, 0.23 mL) was added slowly to the solution. The reaction mixture was stirred for 1 hour. The solvent was removed in vacuo and the residue purified by chromatography on silica gel using 30-50% ethyl acetate/hexanes to provide the title compound as a white foam (yield: 41 mg, 61 %).

'H NMR (CDC13) 6 7.20-7.35 (m, 5H), 5.20 (d, J=14Hz, 1H), 4.28 (m 1H), 4.93 (m, 2H), 3.65 (m, 2H), 3.50 (m, 1 H), 3.23 (m, 2H), 2.22 (m, 2H), 1.98 (s, 3H), 1.62 (m, 1H), 1.43 (s, 9H), 1.15-1.40 (m, 7H), 0.80 (m, 6H) MS (M+H) + = 447.EMI86.1 STDC0154 11.(#)-(2R,3R,5R,1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(methoxy- methvl)-pvrrolidine-5-carboxvlic Acid t-Butvl Ester.

A mixture of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3 (hydroxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (40 mg, 0.09 mmole) and silver oxide (200 mg, 0.90 mmole) in 3 mL of iodomethane was heated at reflux for three hours. The reaction was cooled, filtered, and the solvent was removed in vacuo, to provide the title product as a crude oil.

MS (M+H) + = 461. EMI87.1 STDC0196 1J.(#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(methoxymethyl)- pyrrolidine-5-carboxylic Acid t-Butvl Ester.

A mixture of the crude ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3ethyl) pentyl-3- (methoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (32 mg, 0.07 mmole), prepared according to the method described in Example 11, and ammonium formate (130 mg, 2. 1 mmole) in ethanol (5 mL) was heated at reflux in the presence of a catalytic amount of 10% palladium, on activated carbon, for 1.5 hours. The reaction was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes followed by 10% methanol/dichloromethane to provide the title compound as a colorless oil (yield: 16 mg, 47%).

MS (M+H) + = 371. EMI87.2 STDC0178 1 K. ()- (2R. 3R, 5R. 1'S)-2- (1-Acetamido-3-ethyl) pentvl-3- (methoxymethyl)- pyrrolidine-5-carboxylic Acid Hydrochloride.

A solution of the ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3 (methoxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (15 mg) was dissolved in 6 N HCI in water (1 mL) and stirred at room temperature for 3 hours. The solvent was removed under high vacuum to provide the title compound as a white solid.

'H NMR (d6-DMSO) 8 8.10 (d, J=14Hz, 1H), 4.28 (m, 1H), 4.18 (m, 1H), 3.45 (m, 1H), 3.22 (s, 3H), 2.47 (m, 1H), 2.38 (m, 1H), 1.90 (m, 1H), 1.88 (s, 3H), 1.15-1.42 (m, 7H), 0.82 (t, J=12.5Hz, 3H), 0.79 (t, J=12.5Hz, 3H) MS (M+H) + = 315, (M-H)-= 313.

Example 2 (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine- 5-carboxylic Acid Hvdrochloride. EMI88.1 STDC01772A. ()- (2R. 3R. 5R, 1'S)-1-Benzvl-2- (1-acetamido-3-ethvl) pentvl-3-formyl- pyrrolidine-5-carboxylic Acid t-Butyl Ester.

A solution of oxalyl chloride (0.11 mL, 2M in CH2CI2) in 5 mL of anhydrous dichloromethane was prepared and maintained, under a nitrogen atmosphere, at -78 C. DMSO (32 mg, 0.42 mmole) was added slowly to the solution. The mixture was stirred for 15 minutes and treated with ()- (2R, 3R, 5R, 1'S)-1-benzyl- 2- (1-acetamido-3-ethyl) pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t- butyl ester (38 mg, 0.085 mmole) in 5 mL of dichloromethane. The solution was stirred for 1 hour and triethylamine (86 mg, 0.85 mmole) was added slowly to the reaction mixture. The solution was allowed to warm to room temperature and diluted with dichloromethane. The organic layer was washed with water and brine, dried over MgS04, filtered and concentrated.STDC0160 The residue was purified by chromatography on silica gel using 3% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 39 mg, 97%).

'H NMR (CDC13) 8 9.68 (d, J=1.0Hz, 1H), 7.28 (m, 5H), 5.06 (d, J=14Hz, 1H), 4.38 (m, 1H), 4.10 (m, 1H), 3.75 (m, 2H), 3.45 (m, 1H), 2.62 (m, 1H), 2.20 (m, 2H), 1.98 (s, 3H), 1.42 (s, 9H), 1.25-1.40 (m, 7H), 0.82 (m, 6H) MS (M+H) + = 445.EMI89.1 STDC0183 2B. ()- (2R. 3R. 5R, 1'S)-1-Benzvl-2- nentvl-3-carboxyl- pyrrolidine-5-carboxvlic Acid t-Butyl Ester.

A solution of NaCI02 (0.16 g) and NaH2PO4. H20 (0.17g) in water (1 mL) was added to a solution of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3ethyl) pentyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester (35 mg, 0.079 mmole) and 2-methyl-2-butene (0.5 mL) dissolved in t-BuOH (1.5 mL) and acetonitrile (1.5 mL) at 0 C. After 1 hour the reaction was quenched with 10% aqueous Na2S203 and extracted with dichloromethane. The organic layer was washed with water and brine, dried (MgSO4) and concentrated to provide the title product (yield:-30 mg).

MS (M+H) + = 461. EMI90.1 STDC01792C. (#)-(2R,3R,5R,1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3- methoxvcarbonvl-pyrrolidine-5-carboxvlic Acid t-Butvl Ester.

A solution of Diazald" (0.5 g, 2.33 mmole) in 5 mL of ether was added slowly to a solution of aqueous KOH (0.5 g in 1 mL of water) and 1 mL of ethanol maintained at 65 C. Diazomethane was distilled into a receiving flask charged with a solution of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3- carboxyl-pyrrolidine-5-carboxylic acid t-butyl ester (30 mg, 0.065 mmole) in 3 mL of THF. The receiving flask was cooled to 0 C in an ice/water bath. The condenser was cooled with dry ice/acetone and 3 mL of ether was added the distilling flask until the distillate was colorless.STDC0479 The reaction was stirred for an additional 0.5 hours at 0 C. The yellowish reaction mixture was quenched with acetic acid (0.1 mL) and diluted with ethyl acetate. The organic layer was washed with 10% NaHC03 and brine, dried with MgS04 and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50 % ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 20 mg, 65%).

NMR (CDCIs) S 7.25 (m, 5H), 5.10 (d, J=14Hz, 1H), 4.23 (m, 1H), 4.08 (m, 1H), 3.85 (m, 1H), 3.72 (m, 1H), 3.69 (s, 3H), 3.40 (m, 1H), 2.75 (m, 1H), 2.33 (m, 1H), 2.15 (m, 1H), 1.98 (s, 3H), 1.42 (s, 9H), 1.20-1.40 (m, 7H), 0.83 (m, 6H) MS (M+H) + = 475. EMI91.1 STDC01702D. (#)-(2R.3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-methoxycarbonyl- pyrrolidine-5-carboxylic Acid t-Butyl Ester.

A mixture of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3methoxycarbonyl-pyrrolidine-5-carboxylic acid t-butyl ester (14 mg, 0.03 mmole) and ammonium formate (0.3 g) in ethanol (1.5 mL) with a catalytic amount of 10% palladium on activated carbon was heated at about 75 C, for 1 hour. After filtration to remove the catalyst, the solvent was removed in vacuo. The residue was purified by chromatography on silica gel to provide the title compound as a colorless oil (yield: 8.5 mg, 73%).

MS (M+H) + = 385.EMI91.2 STDC02002E. (i)-(2R. 3R. 5R. 1'S)-2-(1-Acetamido-3-ethyl) pentvl-3-methoxycarbonyl- prrrolidine-5-carboxvlic Acid Hvdrochloride.

A solution of ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3-methoxycarbonylpyrrolidine-5-carboxylic acid t-butyl ester (8.5 mg, 0.022 mmole) in 4 NHCI in dioxane (1 mL) was stirred at room temperature for 24 hours. The solvent was removed in vacuo to provide the title compound as an off-white solid (yield 8 mg, 100%).

'H NMR (d6-DMSO) 6 8.02 (d, J=14Hz, 1H), 4.40 (m, 1H), 4.22 (m, 1H), 3.85 (t, J=13Hz, 1H), 3.70 (m, 1H), 3.65 (s, 3H), 3.15 (m, 1H), 2.55 (m, 1H), 2.20 (m, 1H), 1.84 (s, 3H), 1.12-1.42 (m, 7H), 0.82 (t, J=12.5Hz, 3H), 0.68 (t, 3H) MS (M+H) + = 329, (M-H)-= 327.

Example 3 ()- R, 3R. 5R. 1'S)-2- (1-Acetamido-3-ethvl) Pentvl-3-cvano-pvrrolidine-5- carboxylic Acid Hvdrochloride. EMI92.1 STDC01853A. (#)-(2R,3R,5R,1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3- (hvdroxviminoformyl)-rrrolidine-5-carboxylic Acid t-Butvl Ester.

The title compound is prepared by reacting a solution of (#)- (2R, 3R, 5R, 1'S)-1-benzyl-2-(1-acetamido-3-ethyl) pentyl-3-formyi-pyrrolidine-5- carboxylic acid t-butyl ester with hydroxylamine hydrochloride and 10% aqueous potassium carbonate in methanol according to the procedure described byChelucci etal., Tetrahedron: Asymmetry 5: 1973 (1994). EMI93.1 STDC01733B. (s)-(2R. 3R. 5R, 1'S)-1-Benzyl-2-(1-acetamido-3-ethvl) nentyl-3-cvano- pvrrolidine-5-carboxylic Acid t-Butyl Ester.

The title compound is prepared by reacting a solution of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3- (hydroxyiminoformyl)- pyrrolidine-5-carboxylic acid t-butyl ester with 1,1'-carbonyldiimidazole in dichloromethane according to the procedure described by Chelucci et al., Tetrahedron: Asymmetry 5: 1973 (1994).EMI93.2 3C. (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-cyano-pyrrolidine-5- carboxylic Acid t-Butyl Ester.

The title compound is prepared according to the method described inExample 1J, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3ethyl) pentyl-3-cyano-pyrrolidine-5-carboxylic acid t-butyl ester in place of (#)- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethylpyrrolidine-5-carboxylic acid t-butyl ester. EMI94.1 STDC01393D. ()- (2R. 3R. 5R. 1'S)-2- (1-Acetamido-3-ethvl) pentvl-3-cvano-pvrrolidine-5- carboxylic Acid Hydrochloride.

The title compound is prepared according to the method described inExample 1 K, substituting ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3cyano-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2t-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid butyl ester.

Example 4 (#)-(2R,3R,5R,1'S,)-2-(1-Acetamido-3-ethyl)pentyl-3-propionyl-pyrrolidine-5- Hydrochloride.carboxylicAcidEMI94.2 4A. ()- (2R. 3R. 5R. 1'S. 1"R)-and ()- (2R. 3R. 5R. 1'S. 1"S)-1-Benzvl-2- (1- t-Butylacetamido-3-ethyl)pentyl-3-(1-hydroxy)propyl-pyrrolidine-5-carboxylicAcidEster.

Ethyl magnesium bromide (0. 070mL, 3M in ether) was added to a solution of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2-(1-acetamido-3-ethyl) pentyl-3-formyl pyrrolidine-5-carboxyiic acid t-butyl ester (18 mg, 0.041 mmole) in 3 mL of tetrahydrofuran. The reaction mixture was maintained at 0 C, and stirred for 1 hour. The reaction was quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic layer was dried over MgS04, filtered and concentrated to provide the title product (crude yield: 20mg, 100%).

MS (M+H) + = 475.EMI95.1 STDC02004B. (#)-(2R,3R,5R,1'S,)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-propionyl- pvrrolidine-5-carboxvlic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 2A, substituting ()- (2R, 3R, 5R, 1'S, 1"R)- and ()- (2R, 3R, 5R, 1'S, 1"S)-1 benzyl-2- (1-acetamido-3-ethyl) pentyl-3- (1-hydroxy) propyl-pyrrolidine-5-carboxylic acid t-butyl ester, 20 mg 0.041 mmole), in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 11 mg, 56%).

MS (M+H) + = 473. EMI96.1 STDC0171 4C. ()- (2R, 3R, 5R. 1'S,)-2- (1-Acetamido-3-ethvl) pentvl-3-propionvl-prrrolidine- 5-carboxylic Acid t-Butvl Ester.

A mixture of ()- (2R, 3R, 5R, 1'S,)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3propionyl-pyrrolidine-5-carboxylic acid t-butyl ester (11 mg, 0.023 mmole), ammonium formate (250 mg) and palladium (15 mg, 10% on carbon) in ethanol (1.5 mL) was heated at 70 C for 20 minutes. The reaction was filtered, to remove the catalyst and concentrated. The residue was purified by chromatography on silica gel using 5% methanol/chloroform to provide the title compound (yield: 8.5 mg, 95%).

MS (M+H) + = 383.EMI96.2 STDC01444D. ()- (2R. 3R. 5R. 1'S.)-2- (1-Acetamido-3-ethvl) pentvl-3-propionvl-pyrrolidine- 5-carboxylic Acid Hydrochloride.

A solution of ()- (2R, 3R, 5R, 1'S,)-2- (1-acetamido-3-ethyl) pentyl-3propionyl-pyrrolidine-5-carboxylic acid t-butyl ester (8 mg) was dissolved in 4 NHCI in dioxane (1 mL) and stirred at room temperature for 24 hours. The reaction was concentrated in vacuo to provide the title compound as an off white solid (yield: 8 mg, 100%).

'H NMR (DMSO-d6) 6 8.03 (d, J=14Hz, 1H), 4.41 (m, 1H), 4.20 (m, 1H), 3.92 (m, 1H), 3.68 (m, 1H), 3.46 (m, 1H), 2.65 (m, 2H), 2.00 (m, 1H) 1.84 (s, 3H), 1.10-1.35 (m, 9H), 0.95 (t, J=Hz, 3H), 0.81 (t, J=12.5Hz, 3H), 0.75 (t, J=12.5Hz, 3H) MS: (M-H) =325, (M+35) + = 361, (2M-H)-=651; (M+H) + = 327, (2M+1) + = 653, (2M+Na) + = 675.

Example 5 ()- (2R. 3R. 5R. 1'S)-2- (1-Acetamido-3-ethvl) pentvl-3- (N-methvlcarbamovl)- pyrrolidine-5-carboxylic Acid Hvdrochloride. EMI97.1 STDC01605A. ( (2R. 3R, 5R. 1'S)-1-Benzyl-2-1-acetamido-3-ethvl) pentvl-3- (N-methvl- carbamoyl)pyrrolidine-5-carboxylic Acid t-Butyl Ester.

A solution of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3carboxyl-pyrrolidine-5-carboxylic acid t-butyl ester (0.175 mmole) and triethylamine (18 mg, 0.175 mmole) in 10 mL THF was cooled in an ice-bath.

Isobutylchloroformate (24 mg, 0.175 mmole) was added and stirred for 30 min.

Then methylamine (2.0 M in THF, 0.35 mL, 0.70 mmole) was added. The mixture was stirred while allowed to warm up to room temperature overnight. The reaction was then diluted with ethyl acetate. The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% methanol/ methylene chloride to provide the title compound, as an oil (yield: 17.2 mg, 21%).

MS: (M+H) += 474EMI98.1 5B. (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N-methylcarbamoyl)- pvrrolidine-5-carboxylic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3ethyl) pentyl-3- (N-methylcarbamoyl) pyrrolidine-5-carboxylic acid f-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 13 mg, 94%).

MS: (M+H) += 384EMI98.2 5C. () (2R. 3R. 5R. 1'S)-2- (1-Acetamido-3-ethvl) pentvl-3- (N-methylcarbamovl)- pyrrolidine-5-carboxylic Acid Hydrochloride.

The title compound was prepared according to the method described in Example 1K, substituting ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3ethyl) pentyl-3- (N-methylcarbamoyl) pyrrolidine-5-carboxylic acid f-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3- (methoxymethyl)pyrrolidine-5-carboxylic acid ester.

'H NMR (D2O) : 6 4.43 (t, J=10Hz, 1H), 4.36 (m, 1H), 4.09 (dd, 1H), 3.08 (q, J=10Hz, 1H), 2.75 (m, 4H), 2.25 (m, 4H), 2.02 (s, 3H), 1.5-1.15 (br, 7H), 0.80 (m, 6H).

MS: (M+H)+= 328.

Example 6 (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N-aminocarbamoyl)- pyrrolidine-5-carboxvlic Acid Hvdrochloride. EMI99.1 STDC02026A. (#)-(2R,3R,5R,1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(N-(t- butoxycarbonyllaminocarbamoyl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

A solution of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3carboxyl-pyrrolidine-5-carboxylic acid t-butyl ester (60 mg, 0.13 mmole), t-butyl carbazate (21 mg, 0.16 mmole), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 31 mg, 0.16 mmole) and 1-hydroxybenzotriazole (9 mg, 0.065 mmole) in 3 mL anhydrous THF was stirred at room temperature for 6 hours. The reaction was then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 2% methanol/methylene chloride to provide the title compound, as an oil (yield: 45.6 mg, 61%).

MS: (M+H) += 575EMI100.1 6B. ()- (2R. 3R. 5R. 1'S)-2- (1-Acetamido-3-ethvl) pentvl-3- (N- (t- butoxvcarbonvl) aminocarbamovl) pvrrolidine-5-carboxvlic Acid t-Butvl Ester.

The title compound was prepared according to the method described in Example 1J, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1- acetamido-3-ethyl) pentyl-3- (N- (t-butoxycarbonyl) aminocarbamoyl) pyrrolidine-5carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S))-1-benzyl-2- (1- acetamido-3-ethyl) pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 28 mg, 75%).

MS: (M+H) += 484 EMI101.1 6C. (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N-aminocarbamoyl)- pyrrolidine-5-carboxvlic Acid Hydrochloride.STDC0469 The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3- (N (t-butoxycarbonyl) aminocarbamoyl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)pyrrolidine-5-carboxylic acid t-butyl ester.

1H NMR (D20): # 4.32 (m, 2H), 4.18 (dd, 1H), 3.14 (q, J=8.4Hz, 1H), 2.75 (m, 1H), 2.26 (m, 1H), 2.01 (s, 3H), 1.50-1.15 (m, 7H), 0.80 (q, J=7.5Hz, 6H) MS: (M+H) += 329 Example 7 ()- (2R. 3R. 5R, 1'S)-2- (1-Acetamido-3-ethvl) pentvl-3-ethoxvcarbonyl-pvrrolidine-5- carboxylic Acid Hydrochloride.EMI102.1 STDC02127A. ()- (2R, 3R. 5R, 1'S)-1-Benzyl-2- (1-acetamido-3-ethyl) pentyl-3- ethoxvcarbonvl-pyrrolidine-5-carboxylic Acid t-Butvl Ester.

A solution of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3carboxyl-pyrrolidine-5-carboxylic acid t-butyl ester (42 mg, 0.091 mmole), ethanol (0.5 mL), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 36 mg, 0.188 mmole) and 1-hydroxybenzotriazole (7 mg, 0.05 mmole) in 2 mL anhydrous THF was stirred at room temperature overnight. The reaction was then diluted with ethyl acetate. The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 2% methanol/methylene chloride to provide the title compound, as an oil (yield: 36 mg, 33%).

'H NMR (CDC13): 8 7.50-7.20 (br, 5H), 5.12 (d, J=9Hz, 1H), 4.60-4.30 (br, 2H), 4.14 (q, J=6Hz, 2H), 4.08 (m, 1H), 3.85 (br, 1H), 3.72 (m, 1H), 3.40 (m, 1H), 2.75 (m, 1 H), 2.32 (m, 1 H), 1.97 (s, 3H), 1.40 (s, 9H), 1.37 (t, J=6Hz, 3H), 1.201.50 (m, 7H), 0.83 (m, 6H).

Mass spectrum: (M+H) + = 489 EMI103.1 7B. (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-ethoxycarbonyl- pyrrofidine-5-carboxylic Acid t-Bu l Ester.

The title compound was prepared according to the method described inExample 1J, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl)pentyl-3-ethoxycarbonyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2-(1-acetamido-3-ethyl) pentyl-3-methoxymethylpyrrolidine-5-carboxylic acid t-butyl ester.

Mass spectrum: (M+H) + = 399.EMI103.2 STDC01737C. (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-ethoxycarbonyl- pvrrolidine-5-carboxylic Acid Hydrochloride.

The title compound was prepared according to the method described in Example 2E, substituting ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3ethyl) pentyl-3-ethoxycarbonyl-pyrrolidine-5-carboxylic acid t butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3-methoxycarbonyl-pyrrolidine5-carboxylic acid t-butyl ester.

'H NMR (D20): 6 4.35 (m, 1H), 4.20 (q, J=7.5Hz, 2H), 3.87-3.55 (m, 2H), 3.20 (q, J=7.5Hz, 1H), 2.67 (m, 1H), 2.42 (m, 1H), 2.02 (s, 3H), 1.24 (t, J=7.5Hz, 3H), 1.54-1.15 (m, 7H), 0.82 (m, 6 H).

Mass spectrum: (M+H) + = 343, (M-H)-= 341.

Example 8 (t)- (2R. 3R, 5R. 1'S)-2- (1-Acetamido-3-ethyl) pentvl-3-acetyl-pvrrolidine-5- carboxvlic Acid Hydrochloride.EMI104.1 STDC01578A. (#)-(2R,3R,5R,1'S,1"S)-1-Benzyl-2-(1- t-Butylacetamido-3-ethyl)pentyl-3-(1-hydroxy)ethyl-pyrrolidine-5-carboxylicAcidEster.

The title compound was prepared according to the method described inExample 4A substituting methyl magnesium bromide in place of ethyl magnesium bromide. EMI105.1 STDC01418B ()- (2R. 3R. 5R. 1'S)-1-Benzvl-2- (1-acetamido-3-ethvl) pentvl-3-acetvl- pyrrolidine-5-carboxylic Acid Ester.

The title compound was prepared according to the method described inExample 2A, substituting ()- (2R, 3R, 5R, 1'S, 1"R)-and (#)-(2R, 3R, 5R, 1'S, 1"S)-1benzyl-2- (1-acetamido-3-ethyl) pentyl-3- (1-hydroxy) ethyl-pyrrolidine-5-carboxylic acid t-butyl ester, prepared according to the procedure described in Example 8A, in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester. <RTI ID=105.5>

1H NMR (CDC13) 6 5.00 (d, J=9.7Hz, 1H), 3.94 (m, 2H), 3.68 (m, 1H), 3.55 (m, 1H),</RTI> 2.64 (m, 1H), 2.32 (m, 1H), 2.29 (s, 3H), 2.20 (m, 1H), 1.94 (s, 3H), 1.43 (s, 9H), 1.1511.35 (m, 7H), 0.80 (m, 6H).

MS: (M+H) +=459 EMI106.1 8C. (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-acetyl-pyrrolidine-5- carboxylic Acid t-Butvl Ester.

The title compound is prepared according to the method described inExample 4C, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3ethyl) pentyl-3-acetyl-pyrrolidine-5-carboxylic Acid t-butyl ester., prepared according to the procedure described in Example 8B, in place of (#)- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-propionyl-pyrrolidine-5carboxylic acid t-butyl ester.

MS: (M+H) +=369 EMI106.2 8D. (#)-(2R,3R,5R,1's)-2-(1-Acetamido-3-ethyl)pentyl-3-acetyl-pyrrolidine-5- carboxylic Acid Hydrochloride.

The title compound is prepared according to the method described inExample 1K, substituting ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3acetyl-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2- (1 acetamido-3-ethyl) pentyl-3- (methoxymethyi)-pyrrolidine-5-carboxylic acid t-butyl ester.

'H NMR (DMSO-d6) 8 8.20 (m, 1H), 4.35 (m, 1H), 4.15 (m, 1H), 4.03 (m, 1H), 2.43 (m, 1H), 2.03 (m, 1H), 1.91 (s, 3H), 1.77 (s, 3H), 1.55 (m, 1H), 1.46 (m, 1H), 1.35 (m, 2H), 1.12 (m, 4H), 0.84 (m, 3H), 0.79 (m, 3H)MS: (M+H) +=314, (M-H)-=312 Example 9 (t)- (2S, 3R, 5R, 1'S)-2-1-Acetamido-3-ethvl) pentyl-3-amino-pyrrolidine-5- carboxylic Acid Dihvdrochloride.EMI107.1 STDC0173 9A. ()- (2S. 3R. 5R)- and ()- (2S. 3S. 5R)-1-Benzvl-2-vinvl-3-carboxvl- pvrrolidine-5-carboxvlic Acid t-Butvl Ester.

A solution of ()- (2S, 3R, 5R)- and ()- (2S, 3S, 5R)-1-benzyl-2-vinyl-3-formyl- pyrrolidine-5-carboxylic acid t-butyl ester (10 g, 31.7 mmole) (8: 1 ratio), in 39 mL of ethanol was prepared. The solution was treated with a suspension of silver oxide (8.83 g, 38.1 mmole) and potassium hydroxide (10.86 g, 194 mmole) in 65 mL of water. The reaction was stirred at room temperature for 1 hour and filtered through a pad of Celte. The ethanol was removed in vacuo. The aqueous solution was acidified with acetic acid to about pH 4. The acidic solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to provide the title compound as a brownish oil (crude yield: 8.2 g, 77%).STDC0074 The crude acid was used for the next step without further purification.

MS (M+H) + = 332, (M-H)-= 330.EMI108.1 STDC01289B. () (2S, 3R, 5R)-1-Benzyl-2-vinvi-3-benzyloxycarbonvlamino-pyrrolidine-5- carboxylic acid Ester.

A mixture of ()- (2S, 3R, 5R)- and ()- (2S, 3S, 5R)-1-benzyl-2-vinyl-3- carboxyl-pyrrolidine-5-carboxylic acid t-butyl ester (1.0 g, 3.02 mmole), diphenylphosphoryl azide (0.83 g, 3.32 mmole), benzyl alcohol (0.36 g, 4.53 mmole) and triethylamine (0.32 g, 3.32 mmole) in 30 mL of toluene was heated at reflux for 16 hours. The solvent was evaporated and the residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 0.86 g, 65%).

'H NMR (CDC13) 6 7.20-7.40 (m, 10H), 5.70 (m, 2H), 5.10-5.23 (m, 3H), 4.10 (m, 1H), 3.85 (m, 1H), 3.62 (m, 1H), 3.45 (m, 2H), 2.50 (m, 1H), 1.70 (m, 1H), 1.41 (s, 9H).

MS (M+H) + = 437. EMI109.1 STDC01399C. (i)-(2R, 3R. 5R)-1-Benzvl-2-formvl-3-benzyloxvcarbonvlamino-pvrrolid ine-5- carboxylic Acid t-Butvl Ester.

Osmium tetroxide (3 crystals) was added to a stirred solution of the (i)- (2S, 3R, 5R)-1-benzyl-2-vinyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylic acid t-butyl ester (1.10 g, 2.52 mmole), N-methylmorpholine N-oxide (0.95 g, 8.07 mmole), in 27 mL of acetone/water (8: 1), maintained at room temperature. After 6 hours, 10% aqueous Na2S203 was added and stirring continued for an additional 15 minutes. The reaction was extracted with dichloromethane and the organic layer was concentrated to provide the crude diol intermediate. The diol product was used in the next step without additional purification.

MS (M+H) + = 471.

Sodium periodate (1.0 g, 4.52 mmole) was added in portions to a stirred solution of the crude diol (-1.25 g, 2.66 mmole) in 21 mL of THF/water (6: 1). The reaction was stirred for 1 hour then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over MgS04, filtered and concentrated.

The residue was purified by chromatography on silica gel using 15% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 0.66 g, 60%).

'H NMR (CDC13) 5 9.44 (d, J=1.2Hz, 1H), 7.20-7.40 (m, 10H), 5.98 (d, J=14Hz, 1H), 5.10 (m, 2H), 4.45 (m, 1H), 3.90 (m, 2H), 3.70 (m, 1H), 3.60 (m, 1H), 2.43 (m, 1 H), 1.70 (m, 1 H), 1.45 (s, 9H), MS (M+H) + = 439.

9D. (s)-(2R. 3R. 5R. 1'R)-and (i)-(2R. 3R. 5R, 1'S)-1-Benzvl-2-(1-hydroxv-3- ethyl) pentyl-3-benzyloxvcarbonvlamino-pyrrolidine-5-carboxvlic Acid t-Butyl Ester.

1-Bromo-2-ethylbutane (1.7 g, 10.3 mmole) was added a solution of dibromoethane (3 drops) in 15 mL of dry THF, under argon, in a flask charged with magnesium (0.25 g, 10.3 mmole). The reaction mixture was heated at reflux for 45 minutes, until most of the magnesium reacted. The solution was allowed to cool to room temperature and transferred via cannula to a suspension of CuBr-SMe2 (2.12 g, 10.3 mmole) in 15 mL of dry THF, maintained under argon, at-10 C. The mixture was stirred for 0.5 hours until the solution turned dark.STDC0515 A solution of ()- (2R, 3R, 5R)-1-benzyl-2-formyl-3-benzyloxycarbonylamino- pyrrolidine-5-carboxylic acid t-butyl ester (0.45 g, 1.03 mmole) in 10 mL of THF was added dropwise and stirred for 1.5 hours, while maintaining the temperature at 0 C. The reaction was quenched with aqueous ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried over MgS04, filtered and concentrated.STDC0472 The residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide alcohol adducts as a pale yellow oil (yield: 160 mg, 30%). aH NMR (CDC13) 8 7.20-7.40 (m, 10H), 6.10 (d, J=14Hz, 1H), 5.10 (m, 2H), 4.22 (m, 1 H), 4.01 (m, 1 H), 3.71 (m, 1 H), 3.65 (m, 2H), 3.55 (m, 1 H), 3.20 (m, 1 H), 2.00-2.30 (m, 2H), 1.45 (s, 9H), (m, 7H), 0.84 (m, 6H) MS (M+H) + = 525. EMI111.1 STDC02049E. (t)- (2R. 3R, 5R-1-Benzyl-2- (1-oxo-3-ethpentvl-3- benzylorcarbonylamino-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

A solution of oxalyl chloride (0.29 ml, 2 M in CH2CI2) in 5 mL of dry dichloromethane was prepared and maintained under a nitrogen atmosphere at78 C. DMSO (90 mg, 1.14 mmole) was added to the solution. The mixture was stirred for 15 minutes. The alcohol adduct, prepared above, (150 mg, 0.286 mmole), in 5 mL of dichloromethane, was added dropwise to the cold (-78 C) reaction mixture. The solution was stirred, at-78 C, for 1 hour. Triethylamine (250 mg, 2.29 mmole) was added slowly. The reaction was allowed to slowly warm to room temperature and then diluted with dichloromethane. The organic layer was washed with water and brine, dried over MgS04, filtered and concentrated.STDC0142 The residue was purified by chromatography on silica gel using 5% ethyl acetate/hexanes to provide the title compound (yield: 100 mg, 67%).

'H NMR (CDC13) 67.35 (m, 10H), 5.10 (m, 2H), 4.28 (m, 1H), 3.95 (m, 2H), 2.60 (m, 1H), 2.40 (m, 1H), 2.03 (m, 1H), 1.70 (m, 2H), 1.45 (s, 9H), (m, 7H), 0.70 (m, 6H) MS (M+H) + = 523. EMI112.1 STDC02119F. (+)-(2S. 3R. 5R. 1'R)-and (i)-(2S. 3R. 5R. 1'S)-1-Benzvl-2-(1-amino-3- ethyl) pentyl-3-benzvycarbonylamino-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

A mixture of ()- (2R, 3R, 5R)-1-benzyl-2- (1-oxo-3-ethyl) pentyl-3-benzyloxy- carbonylamino-pyrrolidine-5-carboxylic acid t-butyl ester (90 mg, 0.172 mmole), ammonium acetate (400 mg, 5.17 mmole) and sodium cyanoborohydride (65 mg, 1.03 mmole) in 5 mL in methanol was heated at reflux for 18 hours. Additional portions of ammonium acetate and sodium cyanoborohydride were added and heating continued for an additional 2 hours. The reaction was quenched with 1 N sodium hydroxide, and diluted with dichloromethane. The organic layer was washed with water and brine, dried over MgS04, filtered and concentrated. The residue was purified by chromatography on silica gel using 1: 1 ethyl acetate/hexanes followed by 5% methanol/dichloromethane to provide the title compounds.STDC0058 (yield: 58 mg, 64%) MS (M+H) + = 524. EMI113.1 STDC02199G. ()- (2S. 3R. 5R. 1'R)-and ()- (2S. 3R. 5R. 1'S)-1-Benzvl-2- (1-acetamido-3- ethvl) pentyl-3-benzvloxvcarbonylamino-pyrrolidine-5-carboxviic Acid t-Butyl Ester.

A solution of ()- (2S, 3R, 5R, 1'R)-and ()- (2S, 3R, 5R, 1'S)-1-benzyl-2- (1- amino-3-ethyl) pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylic acid tbutyl ester (50 mg, 0.096 mmole) and acetic anhydride (117 mg, 1.15 mmole) in 5 mL of dichloromethane was stirred for 1 hour at room temperature. The solvent was evaporated in vacuo and the residue purified by chromatography on silica gel using 30-50% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 51 mg, 97%).

1H NMR (CDC13) 8 7.72-7.35 (m, 10H), 5.82 (d, J=14Hz, 1H), 5.10 (m, 2H), 4.38 (m, 1 H), 4.15 (m, 2H), 3.63 (m, 1 H), 3.38 (m, 1 H), 3.10 (m, 1 H), 2.15 (m, 1 H), 2.00 (s, 3H), 1.65 (m, 1 H), 1.42 (s, 9H), 1.20-1.35 (m, 7H), 0.80 (m, 6H) MS (M+H) + = 567. EMI114.1 STDC01629H. (#)-(2S,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-amino-pyrrolidine-5- carboxylic Acid t-Butvl Ester.

A solution of ()- (2S, 3R, 5R, 1'R)- and ()- (2S, 3R, 5R, 1'S)-1-benzyl-2- (1- acetamido-3-ethyl) pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylic acid t-butyl ester (49 mg, 0.087 mmole), ammonium formate (150 mg, 0.22 mmole) and 10% palladium on activated carbon in ethanol (5 mL) was heated at 80 C for 45 minutes. After filtration to remove the catalyst, the solvent was removed. The residue was purified by chromatography on silica gel using 5-10% methanol/dichloromethane to furnish the diastereomers, ()- (2S, 3R, 5R, 1'S) (19 mg) and ()- (2S, 3R, 5R, 1'R) (8.6 mg) of 2- (1-acetamido-3-ethyl) pentyl-3-aminopyrrolidine-5-carboxylic acid t-butyl ester.

'H NMR (CDC13) 5 6.00 (d, J=14Hz, 1H), 3.90 (m, 1H), 3.73 (m, 1H), 3.49 (m, 1H), 3.10 (m, 1H), 2.48 (m, 1H), 2.03 (s, 3H), 1.82 (m, 1H), 1.48 (s, 9H), 1.151.42 (m, 7H), 0.85 (m, 6H) MS (M+H) + = 342. EMI115.1 STDC016991. ()- (2S. 3R. 5R. 1'S)-2- (1-Acetamido-3-ethvl) pentyl-3-amino-pvrrolidine-5- carboxvlic Acid Dihydrochloride.

A solution of ()- (2S, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3-aminopyrrolidine-5-carboxylic acid t-butyl ester (17 mg, 0.050 mmole) in 1 mL of 6 NHCI was stirred at room temperature for 3 hours. The solvent was removed under high vacuum to provide the title compound as a white solid (yield: 15 mg, 100%) 'H NMR (d6-DMSO) 8 8.28 (bs, 1H), 7.90 (d, J=Hz, 1H), 4.71 (d, J=14Hz, 1 H), 4.39 (m, 1 H), 4.10 (m, 1 H), 3.92 (m, 1 H), 3.08 (m, 1 H), 2.64 (m, 1 H), 2.31 (m, 1H), 1.95 (m, 1H), 1.88 (s, 3H), 1.50 (m, 1H), (m, 7H), 0.72-0.90 (m, 6H).

MS (M+H) + = 286.

Example 10 (i)-(2S, 3R, 5R. 1'S)-2-(1-Acetamido-3-ethvl) nentvl-3-acetamido-nYrrolidine-5 carboxylic Acid Hydrochloride.EMI116.1 STDC0175 10A. ()- (2S. 3R, 5R, 1'S)-1-Benzvl-21-acetamido-3-ethyl) pentvl-3-amino- Pvrrolidine-5-carboxvlic Acid t-Butyl Ester.

A solution of ()- (2S, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3benzyioxycarbonylamino-pyrrolidine-5-carboxylic acid t-butyl ester (50 mg, 0.88 mmole) was stirred with 10% palladium on carbon (5 mg) in 50 mL of ethyl acetate under 1 atmosphere of hydrogen for 45 minutes. The reaction was filtered and concentrated to provide the title compound as an oil (crude yield: 35 mg, 92%).

MS (M+H) + = 431. EMI116.2 STDC0149 10B.(#)-(2S,3R,5r,1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-acetamido- pyrrolidine-5-carboxylic Acid t-Butyl Ester.

A solution of ()- (2S, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3amino-pyrrolidine-5-carboxylic acid t-butyl ester (35 mg, 0.080 mmole) was reacted with acetic anhydride (0.05 mL) in 8 mL of dichloromethane for 1 hour.

The reaction was concentrated and the residue purified by chromatography on silica gel using 50% ethyl acetate/hexanes followed by 3% methanol/dichloromethane to provide the title compound (yield: 30 mg, 80%).

'H NMR (CDC13) 67.20-7.35 (m, 5H), 6.62 (d, J=14Hz, 1H), 5.34 (d, J=14Hz, 1 H), 4.42 (m, 2H), 4.20 (m, 1 H), 3.68 (m, 1 H), 3.42 (m, 1 H), 3.10 (m, 1 H), 2.18 (m, 2H), 2.02 (s, 3H), 1.96 (s, 3H), 1.45 (s, 9H), 1.25-1.42 (m, 7H), 0.85 (m, 6H).

MS (M + H) + = 474. EMI117.1 STDC017310C. ()- (2S. 3R. 5R. 1'S)-2- (1-Acetamido-3-ethvl) pentyl-3-acetamido-pyrrolidine- 5-carboxylic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting ()- (2S, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3 ethyl) pentyl-3-acetamido-pyrrolidine-5-carboxylic acid t-butyl ester in place of (i)- (2R, 3R, 5R, 1'S)-1-benzyl-2-(1-acetamido-3-ethyl) pentyl-3-methoxymethylpyrrolidine-5-carboxylic acid t-butyl ester. The residue was purified by chromatography on silica gel using 5% methanol/dichloromethane to provide the title compound (yield: 11.5 mg, 50%).

'H NMR (CDC13) 8 6.20 (d, J=14Hz, 1H), 5.94 (d, J=14Hz, 1H), 4.24 (m, 1H), 4.08 (m, 1H), 3.95 (m, 1H), 3.75 (m, 1H), 3.18 (m, 1H), 2.45 (m, 1H), 2.02 (s, 3H), 1.96 (s, 3H), 1.82 (m, 1 H), 1.49 (s, 9H), 1.20-1.42 (m, 7H), 0.85 (m, 6H).

MS (M + H) + = 384. EMI118.1 STDC0139 10D(#)-(2S,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-acetamido-pyrrolidine- 5-carboxylic Acid Hydrochloride.

The title compound was prepared according to the method described inExample 1K, substituting ()- (2S, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3acetamido-pyrrolidine-5-carboxylic acid t-butyl ester (11.0 mg, 0.029 mmole) in place of ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3- (methoxymethyl)- pyrrolidine-5-carboxylic acid t-butyl ester (yield: 11.0 mg, 100%).

'H NMR (d6-DMSO) 5 8.15 (d, J=14Hz, 1H), 8.05 (d, J=14Hz, 1H), 4.35 (m, 1H), 4.28 (m, 1H), 4.19 (m, 1H), 3.59 (m, 1H), 1.90 (s, 3H), 1.81 (s, 3H), 1.151.40 (m, 7H), 0.80 (m, 6H).

MS: (M-H)-= 326, (M+35) + = 362; (M+H) + = 328, (M+23) + = 350.

Example11 ()- (2S. 3R. 5R. 1'S)-2- (1-Acetamido-3-ethvl) pentvl-3-methoxycarbonviamino- pyrrolidine-5-carboxylic Acid Hydrochloride.EMI119.1 STDC0533 11A.t ? (2S. 3R. 5R. 1'S)-1-Benzvl(1-acetamido-3-ethvl) pentvl-3-methoxy- t-ButylEster.carbonylamino-pyrrolidine-5-carboxylicAcid A solution of ()- (2S, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3amino-pyrrolidine-5-carboxylic acid t-butyl ester is reacted with methyl chloroformate and triethylamine in dichloromethane. The reaction is partitioned between dichloromethane and water. The organic layer is concentrated to provide the title compound.EMI119.2 STDC0575 11B.(#)-(2S,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3- t-ButylEster.methoxycarbonylamino-pyrrolidine-5-carboxylicAcid The title compound is prepared according to the method described inExample 1J, substituting ()- (2S, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl)pentyl-3-methoxycarbonylaminopyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethylpyrrolidine-5-carboxylic acid t-butyl ester.EMI120.1 STDC0149 11C.(#)-(2S,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3methoxycarbonylamino-pyrrolidine-5-carboxyiic Acid Hvdrochloride.

The title compound is prepared according to the method described inExample 1K, substituting ()- (2S, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3methoxycarbonylamino-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3- (methoxymethyl)-pyrrolidine-5carboxylic acid t-butyl ester.

Example 12 ()- (2R, 3R, 5R, 1'S)-2-(1-Acetamido-3-ethvl) pentvi-3-(imidazoi4-yl)-5-carboxyiic Acid Dihvdrochloride.EMI121.1 STDC0172 12A. ()- (2R, 3R. 5R. 1'S)-1-Benzvl-2- (1-acetamido-3-ethyl) pentvl-3-diazoacetyl- 5-carboxylic Acid t-Butvl Ester.

A solution of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3carboxyl-pyrrolidine-5-carboxylic acid t-butyl ester (405.3 mg, 0.88 mmol) and Nmethylmorpholine (106 sll, 0.96 mmol) in THF (20 ml) was reacted with isobutyl chloroformate (96 ul, 0.93 mmole) at-10 C for 30 minutes. To the reaction flask was cannulated a distilled diazomethane solution in ether prepared from the reaction of diazald (2.4 g) in ether (60 ml) with a solution of potassium hydroxide (2.4 g) in ethanol (15 ml) and water (15 ml). The reaction was stirred for 3 hours at room temperature then diluted with ether.STDC0316 The organic layer was washed with brine, dried (Na2SO4) and concentrated to give the title compound as a thick oil (430.4 mg). EMI122.1 12B. ()- (2R. 3R. 5R. 1'S)-1-Benzvl-2- (1-Acetamido-3-ethvl) pentvl-3-bromoacetvl5-carboxylic Acid t-Butyl Ester.

A solution of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3diazoacetyl-5-carboxylic acid t-butyl ester (427.4 mg, 0.88 mmol) in dioxane (50 ml) was reacted with hydrobromic acid (0.25 ml, 2.2 mmol) at 0 C for 0.5 hours.

The reaction was quenched with saturated aqueous sodium bicarbonate (25 ml) and concentrated in vacuo. The residual aqueous layer was extracted with dichloromethane (3x50 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% methanol in dichloromethane to provide the title compound as a white foamy solid (379.3 mg, 80.2 %).

MS: (M+H) += 539. EMI123.1 STDC0200 12C. f (2R. 3R. 5R, 1'S)-1-Benzvl-2- (1-acetamido-3-ethvl) pentvl-3- (imidazol-4- yl)-5-carboxvlic Acid t-but Ester.STDCDBPG0767* ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-bromoacetyl5-carboxylic acid t-butyl ester (60 mg, 0.112 mmol) was treated with formamidine acetate (120 mg, 1.15 mmol) in liquid ammonia and heated at 45 C in a sealed tube for 20 h. The reaction was concentrated in vacuo. The residue was treated with aqueous NaHCO3 and extracted with dichloromethane (5x20 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% methanol in dichloromethane to provide the title compound as a white solid (21.2 mg, 39.4 %).STDC0035 MS: (M+H) += 483.EMI123.2 STDC0168 12D. ()- (2R, 3R, 5R, 1'S)-2- (1-Acetamido-3-ethvl) pentvl-3- (imidazol-4-yl)-5- carboxylic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 1J, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3- (imidazol-4-yl)-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-methoxy-methylpyrrolidine-5-carboxylic acid t-butyl ester (yield: 12.9 mg, 66.2%).

'H NMR (CDC13): â (m, 6H), 1.17-1. 42 (m, 7H), 1.47 (s, 9H), 2.03 (s, 3H), 2.66 (m, 1 H), 3.50 (m, 1H), 3.73 (m, 1 H), 3.86 (m, 1 H), 4.06 (m, 1H), 7.04 (br s, 1 H), 7.86 (br s, 1 H).

MS: (M+H) += 393.EMI124.1 STDC0136 12E.(#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(imidazol-4-yl)-5- carboxylic Acid Dihvdrochloride.

The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3(imidazol-4-yl)-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2- (1acetamido-3-ethyl) pentyl-3- (methoxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester to provide the title compound solid (yield: 12.0 mg, 96.0%).

'H NMR (DMSO-d6): 8 0.67 (t, J = 7 Hz, 3H), 0.75 (t, J = 7 Hz, 3H), 1.11 (m, 3H), 1.23 (m, 4H), 1.78 (s, 3H), 2.33 (m, 1H), 2.70 (m, 1H), 3.69 (dt, 1H), 3.95 (dd, 1H), 4.29 (m, 1H), 4.48 (dd, 1 H), 7.63 (s, 1 H), 8.28 (d, J = 9 Hz, 1 H), 9.06 (s, 1H).

MS: (M+H) += 337.

Example13 (#)-(2R, 3R, 5R, 1'S)-2-{1-Acetamido-3-ethvl)pentvl-3-(oxazol-2-vl)-pvrrolidine-5- carboxvlic Acid Dihvdrochloride.EMI125.1 STDC0176 13A. ()- (2R. 3R. 5R. 1'S)-1-Benzvl-2- (1-acetamido-3-ethvl) pentvl-3- (N- (2hydroxvethvl) carbamoyl)-pvrrolidine-5-carboxvlic Acid t-Butyl Ester.

The title compound is prepared according to the method described inExample 5A, substituting ethanolamine for N-methylamine hydrochloride.EMI125.2 STDC0189 13B. ()- (2R, 3R. 5R. 1'S)-1-Benzvl-2- (1-acetamido-3-ethvl) pentyl-3- (oxazolin-2- vl)-pvrrolidine-5-carboxvlic Acid t-Butyl Ester.

A solution of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2-(1-acetamido-3-ethyl) pentyl-3(N- (2-hydroxyethyl) carbamoyl)-pyrrolidine-5-carboxylic acid t-butyl ester, triethylamine (4 eq.), carbon tetrachloride (3.5 eq.) in acetonitrile is reacted with triphenylphosphine (3.15 eq.) for 16h at room temperature. The reaction is concentrated in vacuo. The residue is partitioned between ethyl acetate and water. The organic layer is washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel using ethyl acetate/hexanes to provide the title compound.EMI126.1 13C.(#)-(2R,3R,5R,1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(oxazol-2-yl)pvrrolidine-5-carboxvlic Acid f-Butvl Ester.

A solution of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3(oxazolin-2-yl)-pyrrolidine-5-carboxylic acid t-butyl ester is reacted with nickel peroxide in cyclohexane according to the method described by Meyer in J. Org.

Chem. 1979,497-501 to provide the title compound.EMI126.2 STDC0149 13D. ()- (2R. 3R. 5R. 1'S)-2- (1-Acetamido-3-ethvl) pentvl-3- (oxazol-2-vl)pyrrolidine-5-carboxylic Acid t Butvl Ester.

The title compound is prepared according to the method described inExample 1J, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl)- pentyl-3- (oxazol-2-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethylpyrrolidine-5-carboxylic acid t-butyl ester.EMI127.1 STDC0173 13E.(#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(oxazol-2-yl)- pyrrolidine-5-carboxylic Acid Dihydrochloride.

The title compound is prepared according to the method described inExample 1K, substituting ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3 (oxazol-2-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethyl-pyrrolidine-5- carboxylic acid t-butyl ester.

Example14 (t)- (2S. 3R, 5R, 1'S)-2- (1-Acetamido-3-methvi) butyl-3- (N-methylamino) pvrrolidine- 5-carboxylic Acid Dihydrochloride.EMI128.1 STDC017814A. ()- (2S. 3R, 5R)-1-Benzyl-2-vinyl-3- (N-methvl-N-benzyloxvcarbonylamino)- pvrrolidine-5-carboxvlic Acid t-Bu l Ester.

A solution of ()- (2S, 3R, 5R)-1-benzyl-2-vinyl-3-benzyloxycarbonylamino- pyrrolidine-5-carboxylic acid t-butyl ester (2.08 g, 4.77 mmole) was dissolved in 50 mL of anhydrous DMF and maintained under a nitrogen atmosphere. The solution was treated with sodium hydride (0.32 g, 8 mmole), and stirred at room temperature for 30 minutes. The solution was treated with iodomethane (0.8 ml, 12.85 mmole) and stirred for an additional 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were concentrated to provide the crude product which was purified by chromatography on silica gel to provide the title compound as an oil (yield: 1.75 g, 81 %).

'H NMR (CDC13) b 7.36-7.20 (m, 10H), 5.75-5.50 (br, 1H), 5.25-5.07 (m, 4H), (br, 1H), 3.97 (d, J=13.5Hz, 1H), 3.75 (m, 1H), 3.61 (d, J=13.5Hz, 1 H), 3.50 (m, 1 H), 2.93 (s, 3H), 2.45 (m, 1 H), 1.75 (m, 1 H), 1.46 (s, 9H).

MS (M+H) + = 451. EMI129.1 STDC0209 14B. ()- (2R. 3R. 5R)-1-Benzvl-2-formvl-3- (N-methvl-N-benzvloxvcarbonvl- amino) pyrrolidine-5-carboxvlic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 9C, substituting ()- (2S, 3R, 5R)-1-benzyl-2-vinyl-3- (N-methyl-N-benzyloxycarbonylamino) pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2S, 3R, 5R)-1-benzyl-2-vinyl-3-benzyioxycarbonylamino-pyrrolidine-5-carboxylic acid t-butyl ester. (Yield: 747 mg, 42%.) MS (M+H) + = 453.EMI129.2 STDC0193 14C.(#)-(2R,3R,5R)-1-Benzyl-2-(1-oxo-3-methyl)butyl-3-(N-methyl-N- benzvloxvcarbonylamino) pvrrolidine-5-carboxvlic Acid t-Butvl Ester.

Isobutyl magnesium chloride (2.0 M in ether, 0.68 ml) was added dropwise over about 12 minutes to a solution of ()- (2R, 3R, 5R)-1-benzyl-2-formyl-3- (Nmethyl-N-benzyloxycarbonylamino) pyrrolidine-5-carboxylic acid t-butyl ester (196 mg, 0.43 mmole) in 5 mL of anhydrous THF, maintained at-78 C. The resulting yellow solution was stirred at-78 C for 1 hour. The solution was quenched with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was concentrated and the crude product was oxidized according to the procedure described in Example 9D. Purification by column chromatography on silica gel, with 10-25% ethyl acetate/hexanes, provided the title compound (yield: 78 mg, 36%).

'H NMR (CDC13) 6 7.46-7.25 (m, 10H), 5.09 (br, 2H), (m, 1H), 3.97-3.65 (m, 4H), 3.00 (s, 3H), 2.60 (br, 1 H), 2.20-1.80 (m, 3H), 1.46 (s, 9H), 0.80-0.67 (m, 7H).

MS (M+H) + = 509.EMI130.1 STDC022714D. ()- (2S, 3R. 5R. 1'R)- and ()- (2S. 3R, 5R, 1'S)-1-Benzvl-2- 1-amino-3- methyl)butvl-3- (N-methvl-N-benzyloxvcarvlamino) pvrrolidine-5-carboxvlic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 9F, substituting ()- (2R, 3R, 5R)-1-benzyl-2- (1-oxo-3-methyl) butyl-3- (Nmethyl-N-benzyloxycarbonylamino) pyrrolidine-5-carboxylic acid t butyl ester in place of ()- (2R, 3R, 5R)-1-benzyl-2-formyl-3-benzyloxycarbonylamino-pyrrolidine- 5-carboxylic acid t-butyl ester. (Yield: 97 mg, 65%.) MS (M+H) + = 510. EMI131.1 STDC022714E. (i)-(2S, 3R. 5R. 1'R)-and (i)-(2S. 3R. 5R. 1'S)-1-Benzvl-2-(1-acetamido-3- methvl) buty(N-methvl-N-benzvloxvcarbonylamino) pyrrolidine-5-carboxylic Acid t-ButylEster.

A solution of ()- (2S, 3R, 5R, 1'R)- and ()- (2S, 3R, 5R, 1'S)-1-benzyl-2- (1- amino-3-methyl) butyl-3- (N-methyl-N-benzyloxycarbonylamino) pyrrolidine-5carboxylic acid t-butyl ester (47 mg, 0.094 mmole) was reacted with acetic anhydride (0.15 mL) in 4 mL of dichloromethane at room temperature for 2 hours.

The reaction was concentrated in vacuo to provide the title compound.

MS (M+H) + = 552.EMI131.2 STDC0144 14F.(#)-(2S,3r,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(N-methylamino)pyrrolidine-5-carboxvlic Acid t-Butvl Ester.

A solution of ()- (2S, 3R, 5R, 1'R)- and ()- (2S, 3R, 5R, 1'S)-1-benzyl-2- (1- acetamido-3-methyl) butyl-3- (N-methyl-N-benzyloxycarbonylamino) pyrrolidine-5carboxylic acid t-butyl ester (0.094 mmole), palladium (40 mg, 10% on carbon) and ammonium formate (160 mg) in 3 mL of ethanol was heated at reflux for 30 minutes. Additional palladium on carbon (15 mg) and ammonium formate (50 mg) were added. The solution was stirred for an additional 15 minutes and the mixture was then filtered to remove the solids and catalyst.STDC0524 The filtrate was evaporated and the residue purified by chromatography on silica gel 5% methanol/dichloromethane and 1% NH40H to provide ()- (2S, 3R, 5R, 1'S) (15.4 mg, lower Rf) and ()- (2S, 3R, 5R, 1'R) (5.4 mg, higher Rf)-2- (1-acetamido-3- methyl) butyl-3- (N-methylamino) pyrrolidine-5-carboxylic acid t-butyl esters (yield: 20.8 mg, 68%).EMI132.1 STDC0148 14G.(#)-(2S,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(N-methylamino)- pvrrolidine-5-carboxvlic Acid Dihvdrochloride.

A solution of ()- (2S, 3R, 5R, 1'S)-2- (1-Acetamido-3-methyl) butyl-3- (Nmethylamino) pyrrolidine-5-carboxylic acid t-butyl ester (9.4 mg) was stirred with 4N aqueous HCI (?1.5 mL) for 2 hours. The reaction was concentrated in vacuo to provide the title compound (yield: 10 mg, 100%).

1H NMR (major peaks) (DMSO-d6) 52.57 (s, 3H), 1.90 (s, 3H), 1.47 (m, 3H), 0.91 (d, J=7.5Hz, 3H), 0.83 (d, J=7.5Hz, 3H) MS : (M+H) + = 272.

Example15 ()- (2R, 3R, 5R. 1'S)-2- pentvl-3-(imidazol-2-yl !-pvrrolid ine-5- Carboxylic Acid Dihydrochloride.EMI133.1 STDC021515A. ()- (2R. 3R. 5R. 1'S)-1-Benzvl-2- (1-acetamido-3-ethvl) pentvl-3- (imidazol-2- yl)-pvrrolidine-5-carboxvlic Acid t Butyl Ester.

Ammonia gas was bubbled slowly through a solution of (t)- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-formyl-pyrrolidine-5carboxylic acid t-butyl ester (20 mg, 0.045 mmole) and glyoxal (6.2 uL, 0.054 mmole, 1.2 equiv.) in 5 mL of methanol, maintained at 0 C, for 5 minutes. After 7 hours at 0 C, additional glyoxal (10 uL) was added and ammonia was bubbled through the solution for 5 minutes. The reaction was allowed to stir at room temperature for 16 hours. A final addition of glyoxal (10 uL) and ammonia as, described above, followed by reaction at room temperature for an additional 4 hours effected a complete reaction.STDC0220 The reaction was concentrated in vacuo and purified by chromatography on silica gel using 50% ethyl acetate/hexanes, followed by 10% methanol/chloroform to provide the title compound as a solid (yield: 19.9 mg, 91 %).

1H NMR (CDCI3): d 0.67 (t, J=7.2 Hz, 3H), 0.73 (t, J=7.2 Hz, 3H), 1.091.32 (m, 7H), 1.41 (s, 9H), 2.00 (m, 1 H), 2.09 (s, 3H), 2.79 (m, 1 H), 3.29 (m, 1H), 3.66 (dd, J=9.6,2.7 Hz, 1 H), 3.77 (m, 1H), 3.92 (d, J=13.4 Hz, 1 H), 4.04 (d, J=13.4 Hz, 1H), 4.22 (dd, 1H), 4.49 (m, 1H), 6.08 (brs, 1H), 7.00 (s, 2H), 7.217.34 (m, 5H).

MS (M+H) + = 483.EMI134.1 STDC0745 15B. ()- (2R. 3R, 5R, 1'S)-2- (1-Acetamido-3-ethvl) pentyl-3- (imidazol-2-yl)- pyrrolidine-5-carboxylic Acid t-Butvl Ester A mixture of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3(imidazol-2-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (17 mg, 0.035 mmole), ammonium formate (250 mg) and 10% palladium on carbon (20 mg), in 5 mL of ethanol, was heated at reflux for 15 minutes The reaction was concentrated in vacuo and the residue was purified by chromatography on silica gel using 5% methanol/dichlormethane and 0.25% ammonium hydroxide to provide the title compound as a white solid (yield: 11.3mg, 81.9%).

MS (M+H) + = 393. EMI135.1 STDC018115C. ()- (2R. 3R. 5R. 1'S)-2- (1-Acetamido-3-ethyl) pentyl-3- (imidazol-2-vl)- pvrrolidine-5-Carboxylic Acid Dihydrochloride.

()- (2R, 3R, 5R, 1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(imidazol-2-yl)pyrrolidine-5-carboxylic acid t-butyl ester (11 mg, 0.028 mmole) was dissolved in 2 mL of 6N HCI and stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to provide the title compound, as an off white solid (yield: 11.3 mg, 100%).

1 H NMR (DMSO-d6): d 0.71 (t, J=7 Hz, 3H), 0.75 (t, J=7 Hz, 3H), 1.091.28 (m, 7H), 1.74 (s, 3H), 2.43 (m, 1 H), 2.80 (m, 1 H), 3.85 (m, 1 H), 4.04 (m, 1 H), 4.29 (m, 1H), 4.52 (m, 1H), 7.64 (s, 2H), 8.07 (br d, J=9 Hz, 1H).

MS (M+H) + = 337 and (M-H)-= 335.

Example 16 (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N,N-dimethylcarbamoyl)- pyrrolidine-5-carboxylic Acid Hydrochloride.EMI136.1 STDC0261 16A. ()- (2R. 3R. 5R. 1'S)-1-Benzvl-2- (1-acetamido-3-ethvQpentvl-3- (N.- (2R. 3R. 5R. 1'S)-1-Benzvl-2- (1-acetamido-3-ethvQpentvl-3- (N. N- dimethylcarbamovl) pvrrolidine-5-carboxvlic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 5A substituting N, N-dimethylamine in place of N-methylamine (yield: 10 mg, 23%).

Mass spectrum: (M+H) + = 488.EMI136.2 16B. ()- (2R. 3R. 5R. 1'S)-2- (1-Acetamido-3-ethvl) tvl-3- (N-methylcarbamovl)- nyrrolidine-5-carboxylic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 1J, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3ethyl) pentyl-3- (N, N-dimethylcarbamoyl) pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester to provide the title compound (yield: 5.5 mg, 67%).

Mass spectrum: (M+H) + = 398.EMI137.1 STDC0564 16C. ()- (2R. 3R. 5R. 1'S)-2- (1-Acetamido-3-ethvl) pentvl-3- (N. N-dimethvl- Hydrochloride.carbamoyl)pyrrolidine-5-carboxylicAcid The title compound was prepared according to the method described inExample 1 K, substituting ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3 (N, N-dimethylcarbamoyl) pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3- (methoxymethyl)-pyrrolidine5-carboxylic acid f-butyl ester.

'H NMR (major peaks) (D20) d 3.15 (s, 3H), 2.94 (s, 3H), 1.98 (s, 3H), 0.80 (m, 6H) MS (M+H) + = 342, (M-H)-= 340.

Example 17 ()- 3R, 3R. 1'S)-2- (1-Acetamido-3-Ethvl) pentvl-3-cvano-pyrrolidine-5- carboxylic Acid Hydrochloride.EMI138.1 STDC0119 17A. () (2S, 3R. 5R)-1-Benzvl-2-vinvl-3-cvano-pyrrolidine-5-carboxylic Acid t-Buty Ester.

A solution of ()- (2S, 3S, 5R)-1-benzyl-2-vinyl-3-formyl-pyrrolidine-5- carboxylic acid t-butyl ester (8: 1 ratio) (5g, 15.9 mmole) with hydroxylamine hydrochloride (1.28g, 18.5 mmole) and 10% aqueous potassium carbonate (8 mL) in 20 mL of methanol, according to the procedure described by Chelucci et aL, Tetrahedron: Asymmetry 5: 1973 (1994) provided an the intermediate oxime product.

The crude oxime, prepared above, was reacted with 1,1'carbonyidiimidazole (3.9,23.9 mmole) in 50 mL of dichloromethane for 3 hours, at room temperature. The reaction was concentrated in vacuo and chromatographed on silica gel with 2-10% ethyl acetate/hexanes to provide the title compound (yield: 2.5g, 50%).

MS (M+H) += 313 EMI139.1 17B. ()- (2R. 3R. 5R)-1-Benzvl-2-formvl-3-cvano-pvrrolidine-5-carboxvlicAcid t- Butyl Ester.

The title compound is prepared according to the method described inExample 1 D, substituting () (2S, 3R, 5R)-1-benzyl-2-vinyl-3-cyano-pyrrolidine-5- carboxylic acid t-butyl ester in place of ()- (2S, 3R, 5R)-1-benzyl-2-vinyl-3-(t- butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 2.2 g, 80%).

MS (M+H) += 315EMI139.2 17C.(#)-(2R,3R,5R)-1-Benzyl-2-(1-oxo-3-ethyl)pentyl-3-cyano-pyrrolidine-5- carboxylic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 1 E, substituting () (2S, 3R, 5R)-1-benzyl-2-formyl-3-cyano-pyrrolidine-5- carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R)-1-benzyl-2-formyl-3- (t butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield 0.4 g , 27%).

MS (M+H) += 399 EMI140.1 17D. ()- (2R. 3R, 5R. 1'S)-1-Benzvl-2- (1-amino-3-ethyl) pentyl-3-cyano-pvrrolidine- 5-carboxylic Acid t Butyl Ester.

The title compound was prepared according to the method described inExample 1F, substituting ()- (2R, 3R, 5R)-1-benzyl-2- (1-oxo-3-ethyl) pentyl-3cyano-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R)-1- benzyl-2- (1-oxo-3-ethyl) pentyl-3- (t-butyldimethylsilyloxymethyl)-pyrrolidine-5- carboxylic acid t-butyl ester (yield 0.215 g, 50%).

MS (M+H) += 400EMI140.2 17E.(#)-(2R,3R,5R,1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-cyano- pyrrolidine-5-carboxvlic Acid t Butyl Ester.

The title compound is prepared according to the method described inExample 1G, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-amino-3-ethyl) pentyl3-cyano-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'R)and ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-amino-3-ethyl) pentyl-3- (t butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield 0.210 g, 90%).

'H NMR (CDC13) # 7.25 (m, 5H), 5.08 (m, 1H), 4.40 (m, 1H), 4.15 (m, 1H), 3.78 (m, 1H), 3.48 (m, 1H), 2.93 (m, 1H), 2.32 (m, 1H), 2.12 (m, 1H), 2.02 (s, 3H), 1.52 (s, 9H), 1.35 (m, 7H), 0.85 (m, 6H) MS: (M+H) + = 442.EMI141.1 STDC0137 17F.(#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-cyano-pyrrolidine-5- carboxylic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample (#)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-substituting ethyl) pentyl-3-cyano-pyrrolidine-5-carboxylic acid t-butyl ester in place of (fui)- (2R, 3R, 5R, 1'S)-1-benzyl-2-(1-acetamido-3-ethyl) pentyl-3-methoxymethylpyrrolidine-5-carboxylic acid t-butyl ester.

1H NMR (CDC13) # 5.35 (bs, 1H), 4.00 (m, 1H), 3.83 (m, 1H), 3.39 (m, 1H), 3.08 (m, 1 H), 2.63 (m, 1 H), 2.15 (m, 1 H), 2.05 (s, 3H), 1.48 (s, 9H), 1.20-1.45 (m, 7H), 0.85 (m, 6H) MS: (M+H) +=352 EMI142.1 17G. ()- (2R, 3R. 5R, 1'S)-2- (1-Acetamido-3-ethyl) pentvl-3-cyano-pvrrolidine-5carboxylic Acid Hydrochioride.

The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3cyano-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2 (1-acetamido-3-ethyl) pentyl-3- (methoxymethyl)-pyrrolidine-5-carboxylic acid tbutyl ester.

1H NMR (d6-DMSO) 8 9.12 (bs, 1H), 8.05 (m, 1H), 4.38 (m, 1H), 4.23 (m, 1 H), 3.88 (m, 1 H), 3.68 (m, 1 H), 3.00 (m, 1 H), 2.55 (m, 1 H), 2.05 (m, 1 H), 1.88 (s, 3H), 1.10-1.40 (m, 7H), 0.80 (m, 6H) MS: (M+H) += 296, (M-H)-= 294, Example 18 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-ethyl-pyrrolidine-5-carboxylic Acid Hvdrochloride. EMI143.1 STDC014518A. (#)-(2R,3S,5R,1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-vinyl- pyrrolidine-5-carboxylic Acid t-Butyl Ester.

To an ice-cold suspension of methyl triphenylphosphonium bromide (240 mg, 0.67 mmol) in 5 mL THF was added potassium t-butoxide (60 mg, 0.54 mmol) under nitrogen. The color changed immediately to bright yellow. After stirring at room temperature for 1 h, ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido3-ethyl) pentyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester (100 mg, 0.225 mmol) in 5 mL THF was added and stirred at room temperature overnight.

Reaction was then quenched with saturated ammonium chloride and extracted with ethyl acetate to give the crude product which was purified by chromatography on silica gel using 30% ethyl acetate/hexanes to provide the title compound, as an oil (yield: 55 mg, 55%).

'H NMR (CDC13): 6 7.45-7.20 (m, 5H), 5.94 (ddd, 1H), 5.24 (d, J=12Hz, 1H), 4.98 (d, J=18Hz, 1H), 4.93 (d, J=10.5HZ, 1H), 4.37 (m, 1H), 4.06 (d, J=13.5Hz, 1H), 3.80 (d, J=13.5Hz, 1H), 3.41 (dd, J=9 Hz, J=3Hz, 1H), 3.31 (q, J=13.5Hz, 1H), 2.60 (m, 1H), 2.26 (m, 1H), 2.00 (s, 3H), 1.45 (s, 9H), 1.40-1.25 (m, 7H), 0.82 (m, 6H).

MS: (M+H) += 443 EMI144.1 18B. ()- (2R. 3S. 5R. 1'S)-2- (1-acetamido-3-ethvl) pentvl-3-ethvl-pyrrolidine-5- carboxylic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting ()- (2R, 3S, 5R, 1'S)-1-benzyl-2- (1-acetamido-3ethyl) pentyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethylpyrrolidine-5-carboxylic acid t-butyl ester.

'H NMR (CDC13): 8 5.71 (br, 1H), 4.00 (br, 1H), 3.68 (t, J=8Hz, 1H), 3.10 (m, 1H), 2.38 (m, 1H), 1.98 (s, 3H), 1.87 (m, 1H), 1.47 (s, 9H), 1.55-1.20 (m, 10H), 0.93 (t, J=7.5Hz, 3H), 0.83 (m, 6H).

MS: (M+H) += 355EMI144.2 %18C.(#)-(2R,3S,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-ethyl-pyrrolidine-5- carboxylic Acid Hydrochloride The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3S, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3ethyl-pyrrolidine-5-carboxyiic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2 (1-acetamido-3-ethyl) pentyl-3- (methoxymethyl)-pyrrolidine-5-carboxylic acid tbutyl ester.

'H NMR (D20): 6 4.30 (br, 1H), 4.25 (t, J=7.5Hz, 2H), 3.58 (br, 1H), 2.61 (m, 1 H), 2.23 (br, 1 H), 2.05 (s, 3H), 1.90 (m, 1H), 1.70-1.20 (m, 9H), 0.92 (t,J=7.5Hz, 3H), 0.81 (m, 6H).

MS: (M+H)+= 299 Example 19 ()- (2R, 3S. 5R. 1'S)-2- (1-Acetamido-3-ethvl) pentyl-3-propvl-pvrrolidine-5- carboxylic Acid Hydrochloride.EMI145.1 STDC0340 19A.(#)-(2R,3S,5R,1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(cis-propen- 1-vl)-pvrrolidine-5-carboxylic Acid t-Butyl Ester and (#)-(2R,3S,5R,1'S)-1-Benzyl- 2-(1-acetamido-3-ethyl)pentyl-3-(trans-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.STDC0685 The title compound was prepared according the method described inExample 18A substituting ethyl triphenylphosphonium bromide for methyl triphenylphosphonium bromide. aH NMR (CDC13) 6 7.24 (m, 5H), 5.59 (m, 1H), 5.36 (dd, J= 11,7Hz, 1H), 5.28 (bs, 1H), 4.32 (m, 1H), 4.06 (d, J= 12.9Hz, 1H), 3.80 (d, J= 12.9Hz, 1H), 3.42 (dd, J= 8.5,2. OHz, 1H), 3.30 (dd, J= 6.1,3.1Hz, 1H), 2.88 (m, 1H), 2.29 (m, 2H), 2.01 (s, 3H), 1.64 (dd, J= 6.8,1.7Hz, 3H), 1.44 (s, 9H), 1.30 (m, 7H), 0.81 (m, 6H).

-145- MS: (M+H) += 457, (M+Na) += 479, (M-H)-= 455. EMI146.1 STDC0135 19B.(#)-(2R.3S,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-propyl-pyrrolidine-5carboxylic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting ()- (2R, 3S, 5R, 1'S)-1-benzyl-2-(1-acetamido-3ethyl) pentyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester and(#)- (2R, 3S, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3- (trans-propen-1-yl)pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl- 2- (1-acetamido-3-ethyl) pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid t- butyl ester (yield: 3.5 mg, 54%).

MS: (M+H) += 369, (M+Na) += 391, (M-H)-= 367. EMI146.2 STDC0576 19C. ()- (2R. 3S, 5R. 1'S)-2- (1-acetamido-3-ethyl) pentyl-3-propyl-pvrrolidine-5- carboxylic Acid Hydrochloride The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3S, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3ethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2 t-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid butyl ester (yield: 3.5 mg, 100%).

1H NMR (DMSO-d6) 5 8.10 (d, J= 8.3Hz, 1H), 4.24 (m, 1H), 4.17 (m, 1H), 2.43 (m, 1H), 2.19 (m, 1H), 1.89 (s, 3H), 1.70 (m, 1H), 1.50-1.20 (m, 12H), 0.87 (t, J= 6.8Hz, 3H), 0.84 (t, J= 7. OHz, 3H), 0.79 (t, J= 7.3Hz, 3H).

MS: (M+H) + = 313, (M+Na) + = 335, (M-H)-= 311.

Example 20 (t)- (2R. 3S. 5R. 1'S)-2- (1-Acetamido-3-methyl) butvl-3-vinvl-pyrrolidine-5-carboxylic AcidHydrochloride.EMI147.1 STDC019220A. (#)-(2R,3R,5R,1'RS)-1-Benzyl-2-(1,2-dihydroxy)ethyl-3-(t- bu Idimethylsilyloxvmethvl)-pvrrolidine-5-carboxviic Acid t-Bu l Ester.

Osmium tetroxide was added to a room temperature solution of ()- (2S, 3R, 5R)-1-benzyl-2-vinyl-3-(t-butyidimethylsilyloxymethyl)-pyrrolidine-5- carboxylic acid t-butyl ester (3.5 g, 8.12 mmol) in 60 mL of 8: 1 acetone/water and N-methylmorpholine N-oxide (3.0 g, 25.6 mmol). The reaction mixture was stirred at room temperature for 6 hours and quenched with saturated aqueous Na2S203.

The mixture was stirred for an additional 10 minutes and the solvent removed.

The brownish residue was partitioned between dichloromethane and water. The organic layer was dried over MgS04 and concentrated in vacuo to provide the intermediate diol as an oil (?3.8g) which was used without additional purification.

MS: (M+H) + = 466.EMI148.1 STDC018020B. (#)-(2R,3R,5R,1'RS)-2-(1,2-Dihydroxy)ethyl-3-(t butvldimethvlsilvloxvmethvl)-pvrrolidine-5-carboxylic Acid-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting ()- (2R, 3R, 5R, 1'RS)-1-benzyl-2- (1,2-dihydroxy) ethyl-3(t-butyidimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (21.5g, 46.2 mmol). in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3ethyl) pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.

MS: (M+H) += 367.EMI148.2 STDC076720C. (#)-(2R,3R,5R,1'RS)-1-t-Butoxycarbonyl-2-(1,2-dihydroxy)-ethyl-3-(t- t-ButylEster.butyldimethylsilyloxymethyl)-pyrrolidie-5-carboxylicAcid ()- (2R, 3R, 5R, 1'RS)-2- (1, 2-Dihydroxy) ethyl-3- (t- butyidimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (crude from previous step) was dissolved in 160 mL of 3: 1 methanol/water and di-tert-butyldicarbonate (14.0 g, 64 mmol) was added. The mixture was stirred at room temperature for 72 h. Then solvent was removed and the residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound as light yellow solid (yield: 15.4 g, 70 %).

'H NMR (CDC13): 8 0.03 (s, 3H), 0.05 (s, 3H), 1.37 (s, 9H),. 42 (s, 9H), 1.47 (s, 9H), 1.93 (d, 1 H), 2.30-2.50 (m, 2H), 3.28 (d, 1 H), 3.66-3.43 (m, 4H), 3.85 (dd, 1H), (m, 1H).

MS: (M+H) += 476.EMI149.1 STDC020820D. (i)-(2R 3R, 5R)-1-t-Butoxycarbonvl-2-formvl-3-(t- buWdimethylsilyloxymethyl)-pyrrolidine-5-carboxVlic Acid t-Bu l Ester.

A solution of ()- (2R, 3R, 5R, 1'RS)-1-t-butoxycarbonyl-2- (1,2 dihydroxy) ethyl-3- (t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t- butyl ester (6.0 g, 12.6 mmol) was dissolved in 6: 1 tetrahydrofuran (THF)/water (110 mL) and treated with sodium periodate (4.4 g, 20.6 mmol). The mixture was stirred at room temperature for 3 hour and diluted with ethyl acetate, washed with water, dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel using 20% ethyl acetate/hexanes to provide the title compound as a white waxy solid (yield: 4.4 g, 78.6%).

'H NMR (CDC13) (mixture of two rotamers): 5 0.05 and 0.06 (two s, 6H), 0.88 and 0.90 (two s, 9H), 1.42 and 1.44 (two s, 9H), 1.47 and 1.48 (two s, 9H), 1.89-1. 99 (m, 1 H), (m, 2H), (m, 2H), (m, 2H), 9.43 and 9.53 (two d, 1 H).

MS: (M+H) += 444. EMI150.1 STDC0211 20E.()- (2R. 3R, 5R. 1'RS)-1-t-Butoxycarbonvi-2- (1-hydroxv-3-methyl) butvl-3-ft- butldimethvlsilyloxymethvl)-pvrrolidine-5-carboxylic Acid t-Butyl Ester.

A solution of ()- (2R, 3R, 5R)-1-t-butoxycarbonyl-2-formyl-3-(t- butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (7.1 g, 16.03 mmol) in diethyl ether (75 mL) was reacted with isobutyl magnesium chloride (24 mL, 2.0 M in ether, 48 mmol) at 0 C for 2.5 hours. The reaction was quenched with saturated ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was used in next step without further purification.

MS: (M+H) += 502EMI150.2 20F. 1-t-Butoxycarbonyl-2-(1-oxo-3-methyl)butyl-3-(tbutyldimethsilyloxvmethyl)-pvrrolidine-5-carboxvlic Acid t-Butvl Ester.

A solution of oxalyl chloride (16 mL, 2M in CH2CI2) in 100 mL of anhydrous dichloromethane was prepared and maintained under a nitrogen atmosphere, at -78 C. DMSO (4.26 mL, 64.1 mmol) was added slowly to the solution. The mixture was stirred for 15 minutes and reacted with ()- (2R, 3R, 5R, 1'RS)-1-tbutoxycarbonyl-2- (1-hydroxy-3-methyl) butyl-3- (t-butyldimethylsilyloxymethyl)- pyrrolidine-5-carboxylic acid t-butyl in 30 mL of anhydrous dichloromethane. The solution was stirred for 1 hour and triethylamine (17 mL, 128 mmol) was added slowly to the reaction mixture. The solution was allowed to warm slowly to room temperature, quenched with saturated sodium bicarbonate and diluted with dichloromethane.STDC0279 The organic layer was washed with water and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5-10% ethyl acetate/hexanes to provide the title compound (yield: 6.3 g, 78.8 %).

'H NMR (CDC13): 8 0.07 (m, 6H), (m, 15H), 1.40 and 1.42 (two s, 9H), 1.46 and 1.47 (two s, 9H), 1.72-1.82 (m, 1 H), 2.15-2.45 (m, 4H), 3.473.69 (m, 1 H), (m, 2H).

MS: (M+H) += 500EMI151.1 20G. ()- (2R, 3R, 5R. 1'RS)-1-t-Butoxycarbonyl-2-(1-amino-3-methy)butyl-3-(tbutyidimethylsilyloxvmethyl)-pvrrolidine-5-carboXviic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 1 F, substituting ()- (2R, 3R, 5R) 1-t-butoxycarbonyl-2- (1-oxo-3- methyl) butyl-3- (t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R)-1-benzyl-2- (1-oxo-3-ethyl) pentyl-3- (t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.54 g, 34.1%).

MS : (M+H) += 501. EMI152.1 STDC078020H. (#)-(2R,3R,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methy)butyl-3-(t- t-ButylEster.butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicAcid The title compound was prepared according to the method described inExample 1G, substituting ()- (2R, 3R, 5R, 1'RS)-1-t-butoxycarbonyl-2-(1-amino-3- t-bytylmethyl)butyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid ester in place of ()- (2R, 3R, 5R, 1'R)- and ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1- amino-3-ethyl)pentyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 462 mg, 79.0 %).

()- (2R, 3R, 5R, 1'S) 1H NMR (CDCL3) : 5 0.03 and 0.04 (two s, 6H), 0.86 (s, 9H), 0.89 and 0.95 (two d, 6H), 1.04 (m, 1H), 1.17-1. 25 (m, 2H), 1.44 (s, 9H), 1.46 (s, 9H), 1.86 (m, 1H), 1.99 (s, 3H), 2.07 (m, 1H), 2.30 (m, 1H), 3.48 (m, 1H), 3.61 (m, 1H), 3.67 (m, 1H), 4.16 (m, 1H), 4.27 (m, 1H), 7.35 (brd, 1H).

MS: (M+H) += 543.EMI152.2 STDC0724201. (#)-(2R,3R,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methy)butyl-3- t-ButylEster.(hydroxymethyl)-pyrrolidine-5-carboxylicAcid The title compound was prepared according to the method described inExample 1H, substituting ()- (2R, 3R, 5R, 1'S)-1-t butoxycarbonyl-2- (1-acetamido- 3-methy) butyl-3- (t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t- butyl ester in place ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) butyl-3-tbutyidimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.

MS: (M+H)+= 429.EMI153.1 STDC018220J. (#)-(2R,3R,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methy)butyl-3- formyl-pvrrolidine-5-carboxylic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 2A, substituting ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido3-methy) butyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-hydroxymethylpyrrolidine-5-carboxylic acid t-butyl ester (yield: 1.5 g, 91 %).

1H NMR (CDC13): 5 0.92 and 0.94 (two d, 6H), 1.07 (m, 1 H), 1.23-1.33 (m, 2H), 1.43 (s, 9H), 1.44 (s, 9H), 1.64 (m, 1 H), 2.03 (s, 3H), 2.39 (m, 1 H), 2.46 (m, 1H), 3.18 (m, 1H), 4.19 (m, 1H), 4.32 (m, 1H), 4.39 (m, 1H), 7.12 (br d, 1H).

MS: (M+H) += 427 EMI154.1 20K. ()- (2R, 3S. 5R. 1'S)-1-t-Butoxvcarbonyl-2- (1-acetamido-3-methy) butyl-3vinvl-pyrrolidine-5-carboxviic Acid t-Butvl Ester.

To a suspension of methyl triphenylphosphonium bromide (125.6 mg, 0.35 mmol) in 3 ml of anhydrous toluene was added potassium t-butoxide (1.0 M in THF, 0.31 mmol) dropwise at room temperature. After stirring for 16 hours, (i)- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido-3-methyl) butyl-3-formylpyrrolidine-5-carboxylic acid t-butyl ester (30 mg, 0.070 mmol) in 3 ml of toluene was added dropwise and stirred for 0.5 hour. The reaction was quenched with saturated ammonium chloride and diluted with methylene chloride. The organic layer was washed with water and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate to provide the title compound, as an white foamy solid (yield: 23.7 mg, 79.4%).

'H NMR (CDC13): 0.92 (m, 6H), 1.26 (m, 2H), 1.44 (s, 9H), 1.47 (s, 9H), 1.65 (m, 1H), 1.97 (s, 3H), 2.43 (m, 2H), 3.56 (m, 1H), 4.15 (m, 2H), 4.32 (m, 1H), 5.11 (m, 1H), 5.15 (m, 1H), 5.75 (m, 1H), 7.35 (br, 1H).

MS: (M+H) += 425. EMI155.1 STDC0136 20L.(#)-(2R,3S,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-vinyl-pyrrolidine-5- carboxvlic Acid Hydrochloride.

The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido3-methy) butyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (#)- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3- (methoxymethyl)-pyrrolidine-5- carboxylic acid t-butyl ester (yield: 16.0 mg, 99.1%).

'H NMR (DMSO-d6) : # 0.82 (d, 3H), 0.88 (d, 3H), 1.29 (m, 1H), 1.42 (m, 1H), 1.57 (m, 1H), 1.87 (s, 3H), 1.91 (m, 1H), 2.40 (m, 1H), 2.90 (m, 1H), 4.20 (m, 1H), 4.32 (m, 1H), 5.08 (dd, 1H), 5.17 (dd, 1H), 5.72 (ddd, 1H), 8.09 (d, 1H), 9.16 (br s, 1 H), 9.28 (br s, 1 H).

MS: (M+H)+= 269.

Example 21 (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-hydroxymethyl-pyrrolidine-5- carboxylic Acid Hydrochloride.EMI156.1 STDC0169 21A.(#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-hydroxymethyl- pvrrotidine-5-carbolic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3ethyl) pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethylpyrrolidine-5-carboxylic acid t-butyl ester.

MS: (M+H)+= 471EMI156.2 21B.(#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-hydroxymethyl- pyrrolidine-5-carboxvlic Acid Hydrochloride.

The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethyl-pyrrolidine-5carboxylic acid t-butyl ester 'H NMR (DMSO-d6): b 8.15 (d, J=9Hz, 1H), 4.28-4.15 (m, 2H), 3.95-3.45 (m, 4H), 2.35 (m, 1 H), 1.98 (m, 1 H), 1.89 (s, 3H), 1.50-1.45 (m, 7H), 0.81 (t,J=7.4Hz, 3H), 0.77 (t, J=7.5Hz, 3H).

MS: (M+H) += 301, (M-H)-= 299 Example 22 ()- 3R. 5R. 1'S)-2- (1-Acetamido-3-ethvl) pentvl-3- (pyrrol-1-yl)-pvrrolidine-5- carboxylic Acid Hydrochloride.EMI157.1 STDC023122A. (#)-(2S,3R,5R,1'S)-1-Benzyl-2-(1-Acetamido-3-ethyl)pentyl-3-(2- trimethylsilvlethoxvcarbonvlamino)-pyrrolidine-5-carboxvlic Acid t-Butyl Ester.

()- (2R, 3R, 5R, 1'S)-1-Benzyl-2-(1-acetamido-3-ethyl) pentyl-3-carboxylpyrrolidine-5-carboxylic acid t-butyl ester (80 mg, 0.18 mmol) prepared according to the procedure of Example 2B was reacted with diphenylphosphoryl azide (0.047 mL, 0.216 mmol), 2-trimethylsilylethanol (0.034 mL, 0.234 mmol), and triethylamine (0.030 mL, 0.216 mmol) in toluene (2 mL) at 75 C for 15 hours. The reaction was concentrated in vacuo and the resulting residue purified by chromatography on silica gel using 25% ethyl acetate/hexanes to provide the title compound, as a light yellow oil (yield: 46 mg, 45%).

MS: (M+H) += 576, (M+Na) + = 598, (M-H)-= 574. EMI158.1 STDC017222B. (#)-(2S,3R,5R,1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-amino- pvrrolidine-5-carboxvlic Acid t-Butvl Ester.

The title compound is prepared according to the method described inExample 1H, substituting ()- (2S, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3ethyl) pentyl-3-(2-trimethylsilylethoxycarbonylamino)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3- (t butyldimethylsilyloxmethyl)-pyrrolidine-5-carboxylic acid t-butyl ester.

MS: (M+H) += 432, (M-H)-= 430.EMI158.2 22C. ()- (2S. 3R. 5R. 1'S)-1-Benzvl-2- (1-Acetamido-3-ethvl) pentvl-3- (pvrrol-1-vl)- pvrrolidine-5-carboxylic Acid t-Butyl Ester.

()- (2S, 3R, 5R, 1'S)-1-Benzyl-2- (1-acetamido-3-ethyl) pentyl-3-aminopyrrolidine-5-carboxylic acid t-butyl ester (34 mg, 0.078 mmol) was reacted with 40% succinic dialdehyde in water (50 mg, 0.234 mmol), acetic acid (0.00044 mL, 0.0078 mmol), and 4A molecular sieves (200 mg) in toluene (2 mL) at RT for 3 hours. The reaction was concentrated in vacuo and the resulting residue purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound, as an oil (yield: 7.1 mg, 19%).

MS: (M+H) += 482, (M+Na) + = 504, (M-H)-= 480.EMI159.1 STDC017022D. (#)-(2S,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)penty-3-(pyrrol-1-yl)- pyrrolidine-5-carboxylic Acid t-Butyl ester.

The title compound is prepared according to the method described inExample 1J, substituting ()- (2S, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3ethyl) pentyl-3- (pyrrol-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethylpyrrolidine-5-carboxylic acid t-butyl ester (yield: 3.5 mg, 61%).

MS: (M+H) += 392, (M-H)-= 390. EMI160.1 STDC014422E. (#)-(2S,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(pyrrol-1-yl)- pyrrolidine-5-carboxylic Acid Hydrochloride.

The title compound was prepared according to the method described inExample 1K, substituting ()- (2S, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3(pyrrol-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (#)- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethyl-pyrrolidine-5carboxylic acid f-butyl ester (yield: 3.5 mg, 100%).

'H NMR (D20) 5 7.48 (bs, 1H), 6.77 (bs, 2H), 5.97 (bs, 2H), 4.33 (m, 1H), 3.70 (m, 1H), 3.07 (m, 1H), 2.43 (m, 1H), 1.92 (m, 1H), 1.75 (s, 3H), 1.55 (m, 1H), 1.35-1.10 (m, 7H), 0.81 (m, 3H), 0.75 (m, 3H).

MS: (M+H) += 336, (M-H)-= 334.

Example 23 ()- 3R, 5R. 1'S)-2-(1-Acetamido-3-ethvl) pentvl-3-(1-cis-N-hvd roxyimino) ethyl- pyrrolidine-5-carboxylic Acid Hydrochloride.EMI161.1 STDC019823A. (#)-(2R,3R,5R,1'S)-1-Benzyl-2-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(1-cis-N- hydroxyimino) pyrrolidine-5-carboxvlic Acid t-Butyl Ester.

()- (2R, 3R, 5R, 1'S) 1-Benzyl-2- (1-acetamido-3-ethyl) pentyl-3-acetylpyrrolidine-5-carboxylic acid t-butyl ester (45 mg, 0.1 mmol) prepared according to the method of Example 8B in methanol/methylene chloride (3/1) was reacted with a solution of hydroxylamine hydrochloride (21 mg, 0.3 mmol) and sodium hydroxide (12 mg, 0.3 mmol) in methanol (2 mL) for 2h. The reaction was diluted with ethyl acetate. The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 40% ethyl acetate/hexanes to provide the cisoxime title compound (lower Rf spot on TLC), as an oil (yield: 35 mg, 75%), as well as the trans-oxime title compound (higher Rf spot on TLC), as an oil (yield: 13 mg, 25%).

MS: (M+H) += 474 EMI162.1 23B (#)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3(1-cis-N- Acidt-ButylEster.hydroxyimino)ethylpyrrolidine-5-carboxylic The title compound is prepared according to the method described inExample 1J, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3ethyl) pentyl-3- (1-cis-N-hydroxyimino) ethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3methoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.

'H NMR (CDC13): 8 3.92 (br, 1H), 3.70 (m, 2H), 2.82 (m, 1H), 2.38 (m, 1H), 1.88 (s, 3H), 1.78 (s, 3H), 1.39 (s, 9H), 1.40-1.20 (m, 7H), 0.76 (m, 6H).

MS: (M+H) += 384EMI162.2 23C. (#)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(1-cis-N- Hydrochloridehydroxyimino)ethyl-pyrrolidine-5-carboxylicAcid The title compound is prepared according to the method described inExample 1K, substituting ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3- (1cis-N-hydroxyimino) ethyl-5-carboxyiic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3- (methoxymethyl)-pyrrolidine-5- carboxylic acid t-butyl ester.

'H NMR (D20): #4. 35 (m, 1H), 4.00 (m, 1H), 3.80 (m, 1H), 3.71 (m, 1H), 3.63 (m, 1H), 3.13 (q, J=8.4Hz"1H), 2.64 (m, 1H), 2.18 (m, 1H), 1.97 (s, 3H), 1.85 (s, 3H), 1.50-1.10 (m, 7H), 0.77 (m, 6H).

MS: (M+H) += 328 Example 24 ()- (2R. 3R. 5R. 1'S-2- (1-Acetamido-3-ethvlDentvl-3- (N-hvdroxvimino) methvl- Hydrochloride.pyrrolidine-5-carboxylicAcidEMI163.1 24A. ()- (2R. 3R. 5R. 1'S)-2- (1-Acetamido-3-ethvl) pentvl-3- (N- hvdroxyimino methyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

()- (2R, 3R, 5R, 1'S)-1-Benzyl-2- (1-acetamido-3-ethyl) pentyl-3-formylpyrrolidine-5-carboxylic acid t-butyl ester (18 mg, 0.051 mmol) prepared according to the method of Example 2A was reacted with hydroxylamine hydrochloride (7 mg, 0.11 mmol) in 1 N NaOH in methanol (3 mL) at 25 C for 1.5 hours. The reaction was quenched with aqueous ammonium chlororide (3ml) and water (3ml) and taken by dichloromethane (2x 10 ml). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% methanol in dichloromethane to provide the title compound, as an oil (yield: 6 mg, 32%).

MS: (M+H) +=370EMI164.1 24B ()- (2R. 3R. 5R. 1'S)-2- (1-Acetamido-3-ethvnpentvl-3- (N- hydroxyimino) methyl-pyrrolidine-5-carboxylic Acid Hvdrochloride The title compound is prepared according to the method described inExample 1K, substituting ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3- (Nhydroxyimino) methyl-5-carboxylic acid t-butyl ester in place of (#)- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3- (methoxymethyl)-pyrrolidine-5carboxylic acid t-butyl ester.

Example 25 (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(methoxyimino)methyl- pyrrolidine-5-carboxylic Acid.EMI164.2 STDC0740 25A. (W2R. 3R. 5R. 1'S) 1-Benzvl-2- (1-acetamido-3-ethvl) pentvl-3- (methoxyimino) methyl-pvrrolidine-5-carboxvlic Acid ()- (2R, 3R, 5R, 1'S) 1-Benzyl-2- (1-acetamido-3-ethyl) pentyl-3-cyanopyrrolidine-5-carboxylic acid t-butyl ester (20 mg, 0.045 mmol) prepared according to the method of Example 17E was reacted with hydrogen chloride (0.45 mmol) in ether (2 mL) and methanol (0.1 mL) at 0 C for 5 hours. The reaction was neutralized with aqueous ammonium hydroxide and purified on silica gel with 3% methanol in dichloromethane to provide the title compound, as a white solid (yield: 5 mg, 26%).

MS:(M+H)+=418EMI165.1 25B. ()- (2R, 3R. 5R, 1'S)-2-(1-Acetamido-3-ethyl)pentyl-3 (methoxyimino)methyl-pyrrolidine-5-carboxylicAcid.

The title compound is prepared according to the method described inExample 1J, substituting ()- (2R, 3R, 5R, 1'S) 1-Benzyl-2- (1-acetamido-3ethyl) pentyl-3-(imino-methoxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester, in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3methoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 3.9 mg, 96%).STDC0717 1H NMR (DMSO D6)# 7.52 (d, J=8.7 HZ, 1H), 7.15 (s, 1H), 6.77 (s, 1H), 3.68 (m, 1H), 3.61 (s, 3H), 3.22 (m, 1H), 2.51 (m, 1H), 2.23 (m, 1H), 1.82 (m, 1H), 1.78 (s, 3H), 1.40 (m, 1H), 1.26 (m, 3H), 1.13 (m, 3H), 0.78 (t, J=6.5HZ, 3H), 0.72 (t Example 26 (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(hydroxyacetyl)-pyrrolidine- 5-carboxylic Acid Hydrochloride.EMI166.1 STDC020826A. ()- (2R, 3R. 5R, 1'S. 1"RS)-1-t-Butoxvcarbonvl-2-l-acetamido-3- methv) butvl-3- (1, 2-dihvdroxv) ethvl-pyrrolidine-5-carboxvlic Acid t-Butyl Ester.

The title compound is prepared according to the method described inExample 20A substituting ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido3-methy) butyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester for ()- (2S, 3R, 5R)1-benzyl-2-vinyl-3-(t-butyldimethylsilyloxymethyl)-pyrrollidine-5-carboxylicacid t-butyl ester.EMI166.2 STDC019526B. (i)-(2R, 3R, 5R, 1'S)-1-t-Butoxvcarbonyl-2-(1-acetamido-3-methy) butyl-3- (hydroxyacetvl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

()- (2R, 3R, 5R, 1'S, 1"RS)-1-t-Butoxycarbonyl-2-(1-acetamido-3methy) butyl-3- (1,2-dihydroxy) ethyl-pyrrolidine-5-carboxylic acid t-butyl ester is reacted with dibutyltin oxide in methanol according to the procedure of Kong in J.

Carbohydrate Chem. 1993, p. 557. The reaction is concentrated and the residue is redissolved in dichloromethane and reacted with bromine as described in the above reference to give the title compound.EMI167.1 STDC014626C. (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(hydroxyacetyl)- pvrrolidine-5-carboxvlic Acid Hydrochloride.

The title compound is prepared according to the method described inExample 1K, substituting ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido- 3-methy) butyl-3-hydroxyacetyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3- (methoxymethyl)pyrrolidine-5-carboxylic acid t-butyl ester.

Example 27 (#)-(2S,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-amino-pyrrolidine-5- carboxylic Acid Dihydrochloride.EMI168.1 STDC021527A. (#)-(2S,3R,5R,1'RS)-1-Benzyl-2-(1-hydroxy-3-methyl)butyl-3- benzvloxvcarbonvlamino-pvrrolidine-5-carboxvlic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 9D, substituting isobutylmagnesium bromide in place of 3pentylmagnesium bromide.EMI168.2 STDC019227B. ()- (2S. 3R. 5R. 1'SL1-Benzvl-2- (1-acetamido-3-methyllbutvi-3- benzvloxvcarbonylamino-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExamples 9E-H substituting ()- (2R, 3R, 5R, 1'RS)-1-benzyl-2- (1-hydroxy-3methyl) butyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylic acid t-butyl ester for ()- (2R, 3R, 5R, 1'RS)-1-benzyl-2- (1-hydroxy-3-ethyl) pentyl-3benzyloxycarbonylamino-pyrrolidine-5-carboxylic acid t-butyl ester as the starting material of the sequence in Example 9E. EMI169.1 STDC054627C. (#)-(2S,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-amino-pyrrolidine-5- carboxylic Acid Dihvdrochloride The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-methyl) butyl-3amino-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2 (1-acetamido-3-ethyl) pentyl-3- (methoxymethyl)-pyrrolidine-5-carboxylic acid tbutyl ester.

'H NMR (d6-DMSO) â 8.64 ( bs, 1 H), 8.32 (bs, 1H), 8.23 (bs, 1H), 8.18 (d,J=6Hz, 1 H), 4.79 (d, J=7Hz, 1 H), 4.42 (m, 1 H), 4.33 (m, 1 H), 4.21 (m, 1 H), 4.07 (m, 1 H), 3.76 (m, 2H), 2.73 (m, 2H), 1.92 (m, 3H), 0.80-0.97 (m, 7H).

MS (M+H) + = 258 Example 28 (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-methoxycarbonyl- pyrrolidine-5-carboxylic Acid Hydrochloride.EMI170.1 STDC018728A. (i)-(2R. 3R. 5R. 1'S)-1-t-Butoxvcarbonvi-2-(1-acetamido-3-methylbutvl-3- carboxvl-pyrrolidine-5-carboxvlic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 2B, substituting ()- (2R, 3R, 5R, 1'S)-1-t butoxycarbonyl-2- (1-acetamido- 3-methyl) butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2-(1-acetamido-3-ethyl) pentyl-3-formyl-pyrrolidine-5- carboxylic acid t-butyl ester.EMI170.2 STDC0594 28B. (i)-(2R, 3R, 5R. 1'S)-1-t-Butoxvcarbonvl-2-(1-acetamido-3-methvl) butvl-3methoxycarbonyl-nvrrolidine-5-carboxviic Acid t-Butvl Ester The title compound was prepared according to the method described inExample 2C, substituting ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido3-methyl) butyl-3-carboxyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (#)- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-carboxyl-pyrrolidine-5carboxylic acid t-butyl ester. EMI171.1 STDC061128C. (#)-(2R,3R,5R,1'S)L-2-(1-Acetamido-3-methyl)butyl-3-methoxycarbonyl- Hydrochloride.pyrrolidine-5-carboxylicAcid The title compound was prepared according to the method described inExample 2E, substituting ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido- 3-methyl) butyl-3-methoxycarbonyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3-methoxycarbonylpyrrolidine-5-carboxylic acid t-butyl ester.

1H NMR (DMSO-d6): 8 8.24,8.08 (d, J=9Hz, 1H), 4.44,4.36 (m, 1H), 4.25, 4.15 (m, 1H), 3.98,3.88 (m, 1H), 3.65,3.64 (s, 3H), 3.18,3.10 (m, 1H), 2.57,2.20 (m, 2H), 1.87,1.83 (s, 3H), 1.57 (m, 2H), 1.36 (m, 1H), 0.88 (d, J=7.5Hz, 3H), 0.82 (d, J=7.5Hz, 3H).

MS: (M+H) += 301 Example 29 (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-5- Carboxylic Acid Dihydrochloride.EMI172.1 STDC018229A. (#)-(2R,3R,5R,1'S)-1-Benzyl-2-(1-acetamido-3-methyl)butyl-3-(imidazol-2- yl)-pyrrolidine-5-carboxvlic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 15A, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3methyl) butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-formyl-pyrrolidine-5carboxylic acid t-butyl ester (yield: 27.4 mg, 83. %).

MS: (M+H) += 455.EMI172.2 STDC018029B. ()- (2R. 3R. 5R. 1'S)-2- (1-Acetamido-3-methvl) butvl-3- (imidazol-2-vl)- pvrrolidine-5-carboxvlic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 15B, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3methyl) butyl-3- (imidazol-2-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2-(1-acetamido-3-ethyl) pentyl-3-(imidazol-2-yl)- pyrrolidine-5-carboxylic acid t-butyl ester (yield: 19.1 mg, 95.5%).

MS: (M+H) += 365.EMI173.1 STDC058429C (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3(imidazol-2-yl)- Dihydrochloride.pyrrolidine-5-CarboxylicAcid The title compound was prepared according to the method described inExample 15B, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3methyl) butyl-3- (imidazol-2-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3- (imidazol-2-yl)pyrrolidine-5-carboxylic acid t-butyl ester.

1 NMR (DMSO-d6): 8 0.76 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H), 1.18 (t, 2H), 1.44 (m, 1H), 1.71 (s, 3H), 2.43-2.47 (m, 1H), 2.80 (m, 1H), 3.83 (m, 1 H), 4.05 (m, 1 H), 4.28 (m, 1 H), 4.55 (t, 1 H), 7.65 (s, 2H), 8.03 (d, J = 8.4 Hz, 1H).

MS: (M+H) += 326.

Example 30 ()- 3R, 5R. 1'S)-2- (1-Acetamido-3-methyl) butv(imidazol-4-vl)-pyrrolidine-5- carboxvlic Acid Dihvdrochloride.

30A. ()- (2R, 3R. 5R, 1'S)-1-t-Butoxvcarbonvl-2- (1-acetamido-3-methv) butyl-3- carboxvl-pvrrolidine-5-carboxvlic Acid t-Butyl Ester.EMI174.1 STDC0620 The title compound was prepared according to the method described inExample 2B, substituting ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido- 3-methy) butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester prepared according to the method described in Example 20J in place ()- (2R, 3R, 5R, 1'S)-1- t-butylbenzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylicacid ester (yield: 129.5 mg, > 100 %).

MS: (M+H) += 443.EMI174.2 STDC0152 30B.(#)-(2R,3R,5R,1'S)-1-Benzyl-2-(1-acetamido-3-methyl)butyl-3-diazoacetyl- pvrrolidine-5-carboxvlic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 12A, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3 methyl) butyl-3-carboxyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (#)- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-carboxyl-pyrrolidine-5- carboxylic acid t-butyl ester (yield: 218.8 mg, 100%).

MS: (M+H) += 458.EMI175.1 STDC021030C. ()- (2R. 3R. 5R. 1'S)-1-Benzvl-2- (1-acetamido-3-methvl) butvl-3- bromoacetvl-pvrrolidine-5-carboxvlic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 12B, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3methyl) butyl-3-diazoacetyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2-(1-acetamido-3-ethyl) pentyl-3-diazoacetyl- pyrrolidine-5-carboxylic acid t-butyl ester (yield: 107.2 mg, 45.5 %). aH NMR (CDC13): # 0.90 (d, 6H), 1.26-1. 35 (m, 3H), 1.42 (s, 9H), 1.95 (s, 3H), 2.25 (m, 2H), 3.11 (m, 1H), 3.54 (dd, 1H), 3.69 (m, 1H), 3.93 (dd, 2H), 4.11 (d, 1 H), 4.27 (m, 1 H), 4.35 (d, 1 H), 5.05 (br d, 1 H), 7.25-7.32 (m, 5H).

MS: (M+H) += 509. EMI176.1 STDC0208 30D.(#)-(2R,3R,5R,1'S)-1-Benzyl-2-(1-acetamido-3-methyl)butyl-3-(imidazol-4- vl)-pyrrolidine-5-carboxvlic Acid t-Bu l Ester.

The title compound was prepared according to the method described inExample 12C, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3methyl) butyl-3-bromoacetyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2-(1-acetamido-3-ethyl) pentyl-3-bromoacetyl- pyrrolidine-5-carboxylic acid t-butyl ester (yield: 32.3 mg, 60.4%).

MS: (M+H) += 455.EMI176.2 STDCDBPG0202*30E. (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-4-yl)- pvrrolidine-5-carboxylic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 1J, substituting ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3methyl) butyl-3- (imidazol-4-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethylpyrrolidine-5-carboxylic acid t-butyl ester (yield: 23.9 mg, 96.2%).

'H NMR (CDC13): 8 0.87 (d, 3H), 0.89 (d, 3H), 1.26 (m, 1H), 1.41 (m, 2H), 1.46 (s, 9H), 1.59 (m, 1H), 1.93 (s, 3H), 2.62 (m, 1H), 3.30 (m, 1 H), 3.54 (m, 1H), 3.79 (m, 1H), 4.01 (m, 1H), 6.11 (brd, 1H), 6.89 (s, 1H), 7.63 (s, 1H).

MS: (M+H) += 365.EMI177.1 STDC014930F. (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-4-yl)- pyrrolidine-5-carboxylic Acid Dihvdrochloride.

The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-methyl) butyl-3 (imidazol-4-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2-(1-acetamido-3-ethyl) pentyl-3-(methoxymethyl)-pyrrolidine-5- carboxylic acid f-butyl ester to provide the title compound solid (yield: 24.4mg, <RTI ID=177.16> 100%).

1 NMR (DMSO-d6): # 0.76 (d, J = 3.6 Hz, 3H), 0.88 (d, J = 3.6 Hz, 3H),</RTI> 1.22 (m, 1 H), 1.28 (m, 1 H), 1.48 (m, 1 H), 1.79 (s, 3H), 2.32 (dt, 1 H), 2.71 (dt, 1 H), 3.68 (m, 1 H), 3.96 (m, 1 H), 4.28 (m, 1 H), 4.51 (t, 1 H), 7.63 (s, 1 H), 8.23 (d, J = 5.1 Hz, 1H), 9.10 (s, 1H), 9.67 (brs, 1H), 14.51 (br s, 1H).

MS: (M+H) += 309.

Example 31 ()-!-(2R, 3R. 5R. 1'S)-2-(1-Acetamido-3-methvl) butvl-3-(th iazol4-vl)-pvrrolidine-5- carboxylic Acid Dihydrochloride.EMI178.1 STDC0197 31A. ()- (2R. 3R. 5R. 1'S)-1-t-Butoxvcarbonyl-2- (1-acetamido-3-methyl) butyl-3- (thiazol-4-vl)-pvrrolidine-5-carboxvlic Acid t-Butyl Ester.

()- (2R, 3R, 5R, 1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3bromoacetyl-pyrrolidine-5-carboxylic acid t-butyl ester (36.5 mg, 0.07 mmol) was reacted with thioformamide (21.4 mg, 0.35 mmol) in ethanol (5 ml) at reflux for 4 hours. The reaction was concentrated in vacuo. The residue was treated with 5 ml of aqueous NaHCO3 and extracted with dichloromethane (4 x 5 ml). The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate to provide the title compound, as a white solid (yield: 23.8 mg, 70.4%).

MS: (M+H) += 482. EMI179.1 STDC0174 31B.(#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(thiazol-4-yl)- pyrrolidine-5-carboxvlic Acid Dihvdrochloride.

The title compound was prepared according to the method described inExample 1 K, substituting ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido3-methyl) butyl-3- (thiazol-4-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethyl-pyrrolidine-5carboxylic acid t-bytyl ester (yield: 18.5 mg, 100%).

1 NMR (DMSO-d6): 5 0.62 (d, J = 4.2 Hz, 3H), 0.72 (d, J = 4.2 Hz, 3H), 1.05 (m, 1H), 1.12 (m, 1H), 1.30 (m, 1H), 1.72 (s, 3H), 2.14 (dt, 1H), 2.59 (dt, 1H), 3.69 (m, 1 H), 3.92 (br m, 1 H), 4.21 (m, 1 H), 4.38 (br m, 1 H), 7.46 (d, J = 1.2 Hz, 1 H), 8.02 (d, J = 5.1 Hz, 1 H), 9.04 (d, J = 1.2 Hz, 1 H), 9.39 (br s, 1 H), 9.48 (br s, 1H).

. MS: (M+H)+= 326.

Example 32 ()- 3R. 5R. 1'S)-2- (1-Acetamido-3-methvl) buty(thiazol-2-vl)-yrrolidine-5- carboxylic Acid Dihvdrochloride.EMI180.1 STDC018532A. (#)-(2R,3R,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3 carbamovl-pvrrolidine-5-carboxylic Acid t-Butyl Ester.

()- (2R, 3R, 5R, 1'S)-1-f-Butoxycarbonyl-2- (1-acetamido-3-methyl) butyl-3carboxyl-pyrrolidine-5-carboxylic acid f-butyl ester (0.258g, 0.584 mmol) was reacted with isobutyl chloroformate (80 mg, 0.84 mmol) and N-methylmorpholine (59 mg, 0.584 mmol) in THF (10 mL) at 0 C for 0.25 hours. Aqueous ammonium hydroxide (. 39 mL) was added and the reaction was stirred at 0 C for 0.5 hours.

The reaction was diluted with ethyl acetate. The organic layer was washed with water, and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 100% ethyl acetate to 5 % methanol-ethyl acetate to provide the title compound, as a glass (yield: 182 mg, 70.7 %).

(CD3OD)#4.70(m,1H),4.36(q,J=3Hz,1H),4.05(m,1H),2.87(q1HNMR oft, J=9 and 3 Hz, 1H), 2.52 (m, 1H), 2.36 (m, 1H) 1.94 (d, 3H), 1.63 (m, 1H), 1.41-1.53 (m, 18H), 1.3 (m, 2H), 0.9-0.18 (m, 6H) MS: (M+H) += 442 EMI181.1 32B. (#)-(2R,3R,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3- thiocarbamovl-nvrrolidine-5-carboxviic Acid t-Butyl Ester.

()- (2R, 3R, 5R, 1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methy) butyl-3- carbamoyl-pyrrolidine-5-carboxylic acid t-butyl ester (70 mg, 0.159 mmol) was reacted with P2S, (8.5 mg, 0.019 mmol) in 4 ml tetrahydrofuran and 1 ml of methylene chloride at room temperature. After 1.25 hrs, 9.6 mg of P2S10 was added. The starting material had been consumed after 2 hrs. The mixture was diluted with ethyl acetate, washed with water and brine, dried over Mgs04, filtered and concentrated. Tic analysis showed two spots and the mass spectrum indicated it was a mixture of mono-thio and di-thio compounds. The material was used in the next reaction without further purification.

MS: (M+H) += 458,474EMI181.2 32C. (t)-(2R, 3R, 5R, 1'S)-1-t-Butoxvcarbonyl-2-(1-acetamido-3-methvl) butvl-3- (thiazol-2-v0-pyrrolidine-5-carboxylic Acid f-Butvl Ester.

()- (2R, 3R, 5R, 1'S)-1-t-Butoxycarbonyl-2- (1-acetamido-3-methy) butyl-3thiocarbamoyl-pyrrolidine-5-carboxylic acid f-butyl ester (73 mg, o. 16 mmol) was reacted with chloroacetaldehyde (50% in water) (0.02 ml, 0.16 mmol) in 5 ml of acetone at 75 C. Magnesium sulfate (0.9 g) and additional chloroacetaldehyde was added at intervals over the next 5 hr when till complete conversion of starting material. The reaction was diluted with ethyl acetate, washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo.STDC0151 The residue was purified by chromatography on silica gel using 100% ethyl acetate to provide the title compound, as a glass (yield: 12.6 mg, 16.3%).

'H NMR (CDC13) 7.69 (m, 1H), 7.45 (m, 1H), 4.44 (m, 1H), 4.28 (m, 2H), 3.52 (m,! H), 2.7 (m, 1 H), 2.5 (m, 1 H), 1.99 (s, 3H), 1.44 (s, 9H), 1.37 (s, 9H), 1.27 (m, 3 H), 0.95 (m, 6 H).

MS: (M+H) += 482EMI182.1 32D. (i)-(2R, 3R, 5R. 1'S)-1-t-Butoxvcarbonvl-2-(1-acetamido-3-methvlAbutvl-3- (thiazol-2-vl)-pyrrolidine-5-carboxrlic Acid Dihvdrochloride The title compound was prepared according to the method described inExample 1K, substituting (#)-(2R,3R,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido- 3-methyl) butyl-3- (thiazol-2-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5carboxylic acid t-butyl ester (yield: 10.1 mg, 82%).

1 H NMR (DMSO-d6) 8 8.1 (d, J=10Hz, 1H), 7.79 (d, J=4Hz, 1H), 7.69 (d=4 Hz, 1H), 4.49 (t, J=7.5,1H), 4.22 (m, 1H), 4.14 (t, J=9Hz, 1H), 4.01 (q, J=10Hz, 1 H), 2.80 (m, 1 H), 2.25 (m, 1 H), 1.78 (s, 3H), 1.47 (m, 1 H), 1.25 (m, 2H), 0.83 (d,J=6.2Hz, 3H), 0.75 (d, J=6.2Hz, 3H) MS:STDC0662 (M-H)-= 324, (2M-1) = 649, (M+350)?= 360 Example 33 (#)-(2R,3S,5R,1'S)--2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)- pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI183.1 33A. ()- (2R. 3S, 5R. 1'S)-1-t-Butoxvcarbonyl-2- (1-acetamido-3-methvl) butyl-3- (cis-2-chloro-vin-1-yl)-pyrrolicine-5-carboxylic Acid t-Butyl Ester and ()- (2R, 3S. 5R. 1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(trans-2chloro-vin-1-yl)-prrrolidine-5-carboxvlic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 20K substituting (chloromethyl) triphenylphosphonium chloride in place of methyltriphenylphosphonium bromide. The higher Rf 0.73 (ethyl acetate) new spot was identified to be the cis-isomer (yield: 38.4 mg, 40 %) and the lower Rf 0.57 (ethyl acetate) spot trans-isomer (yield: 42 mg, 43 %). cis-isomer 1H NMR (CDCI3): 87.44 (br, 1H), 6.13 (d, J=7.5Hz, 1H), 5.32 (dd, J=9Hz, J=7.5Hz, 1H), (m, 2H), 3.65 (m, 1H), 3.12 (m, 1H), 2.50 (m, 1H), 1.98 (s, 3H), 1.62 (m, 1H), 1.47 (s, 9H), 1.45 (s, 9H), 1.30-1.07 (m, 2H), 0.82 (m, 6H) MS:STDC0231 (M+H) += 459 trans-isomer'H NMR (CDC13): 6 6.12-5.90 (m, 2H), 4.30-4.07 (m, 2H), 3.64 (m, 1 H), 2.62-2.37 (m, 2H), 1.98 (s, 3H), 1.69 (m, 1 H), 1.48 (s, 9H), 1.45 (s, 9H), 1.26 (m, 2H), 0.91 (m, 6H).

MS: (M+H) += 459EMI184.1 33B. (#)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)- Qyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.

()- (2R, 3S, 5R, 1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3 (cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (10 mg, 0.022 mmol) was reacted with trifluoroacetic acid (1.8 mL) in dichloromethane (0.4 mL) at room temperature for 7 hours. The reaction was concentrated in vacuo. The residue was dried on high vacuum to provide the title compound.

'H NMR (DMSO-d6): 5 8.015 (d, J=7.63Hz, 1H), 6.42 (d, J=7.02Hz, 1H), 5.89 (dd, J=7.02Hz, J=8.7Hz, 1H), 4.42 (m, 1H), 4.17 (m, 1H), 3.59 (m, 1H), 3.31 (m, 1 H), 2.47 (m, 1 H), 1.88 (s, 3H), 1.84 (m, 1 H), 1.58 (m, 1 H), 1.39 (m, 1 H), 1.29 (m, 2H), 0.885 (d, J=6. 71Hz, 3H), 0.83 (d, J=6.41,3H).

MS: (M+H) += 303 Example34 (#)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(trans-2-chloro-vin-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI185.1 34B, (#)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(trans-2-chloro-vinyl)- pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 33B, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido- 3-methyl) butyl-3- (trans-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'S)-1-f-butoxycarbonyl-2- (1-acetamido-3-methyl) butyl3- (cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.

1H NMR (DMSO-d6): # 8.04 (d, J=7.93Hz, 1H), 6.355 (d, J=13.1 Hz, 1H), 5.93 (dd, J=13.1 Hz, J=9.32 Hz, 1 H), 4.33 (m, 1 H), 4.19 (m, 1 H), 2.95 (m, 1 H), 2.40 (m, 1H), 1.94 (m, 1H), 1.88 (s, 3H), 1.58 (m, 1H), 1.39 (m, 1H), 1.29 (m, 1H), 0.89 (d, J=6. 7 Hz, 3H), 0.825 (d, J=6.7 Hz, 3H).

MS: (M+H) += 303 Example 35 (#)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine- 5-carboxylic Acid Trifluoroacetic Acid Salt EMI186.1 35A. (i)-(2R. 3R. 5R. 1'S)-1-t-Butoxvcarbonvl-2-(1-acetamido-3-methyl) butyl-3-( cis-propen-1-yl)-pvrrolidine-5-carboxylic Acid t-Butvl Ester.

To a suspension of ethyl triphenylphosphonium bromide (479 mg, 1.29 mmol) in 3 mL anhydrous toluene was added potassium t-butoxide (1.0 M in THF, 0.94 mmol) dropwise at room temperature. After stirring for 2.5 hours, () (2R, 3R, 5R, 1'S)-1-t-Butoxycarbonyl-2- (1-acetamido-3-methyl) butyl-3-formylpyrrolidine-5-carboxylic acid t-butyl ester (90 mg, 0.211 mmol) in 5 mL toluene was added dropwise and stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound, as an oil (yield: 70.6 mg, 76%).STDC0225 MS: (M+H) += 439EMI186.2 35B. ()- (2R. 3S, 5R. 1'S)-2- (1-acetamido-3-methvi butvl-3- (cis-propen-1-vl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 33B, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido- 3-methyl) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3 (cis-2-chloro-vinyl)-pyrrolidine-5-carboxylic acid t-butyl ester.

'H NMR (DMSO-d6): 6 8.04 (d, J=7.5Hz, 1H), 5.51 (m, 1H), 5.26 (m, 1H), 4.32 (m, 1H), 4.18 (m, 1H), 3.45 (m, 1H), 3.18 (m, 1H), 2.39 (m, 1H), 1.88 (s, 3H), 1.73 (m, 1H), 1.63 (dd, 3H), 1.58 (m, 1H), 1.38 (m, 1H), 1.28 (m, 1H), 0.88 (d,J=6Hz, 3H), 0.81 (dd, J=6Hz, 3H).

MS: (M+H)+= 283 Example 36 (#)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-dimethyl-vin-1-yl)pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt EMI187.1 36A. (#)-(2R,3R,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3- t-ButylEster.(2,2-dimethyl-vin-1-yl)-pyrrolidine-5-carboxylicAcid The title compound was prepared according to the method described inExample 20K substituting isopropyl triphenylphosphonium iodide in place of methyltriphenylphosphonium bromide (yield: 22.6 mg, 33 %).

'H NMR (CDC13): # 7.77 (d, 1H), 5.06 (d, J=10Hz, 1H), 4.18 (m, 2H), 3.50 (m, 1 H), 2.69 (m, 1 H), 2.32 (m, 1H), 1.97 (s, 3H), 1.70 (s, 3H), 1.64 (s, 3H), 1.65 (m, 1 H), 1.47 (s, 9H), 1.44 (s, 9H), 1.30-1.00 (m, 3H), 0.93 (d, J=6Hz, 3H), 0.88 (d, J=6Hz, 3H).

MS: (M+H)+= 453EMI188.1 36B. ()- (2R. 3S, 5R. 1'S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-dimethyl-vin-1- vl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 33B, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido3-methyl) butyl-3- (2,2-dimethyl-vin-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.

1H NMR (DMSO-d6): 5 8.01 (d, J=7.5HZ, 1H), 4.99 (d, J=10Hz, 1H), 4.30 (m, 1H), 4.14 (m, 1H), 3.40 (m, 1H), 3.06 (m, 1H), 2.36 (m, 1H), 1.86 (s, 3H), 1.66 (s, 3H), 1.63 (s, 3H), 1.57 (m, 1H), 1.39-1.20 (m, 3H), 0.88 (d, J=6Hz, 3H), 0.81 (d, J=6Hz, 3H).

MS: (M+H) += 297 Example 37 (#)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-difluoro-vin-1- pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt EMI189.1 37A. (s)-(2R, 3S. 5R. 1'S)-1-t-Butoxycarbonvl-2-(1-acetamido-3-methvl) butvl-3- (2,2-difluoro-vin-1-vl)-pvrrolidine-5-carboxvlic Acid t-Butvl Ester. n-Butyllithium (1.6M in hexanes, 0.61 mL, 0.97 mmol) was added to diisopropylamine (136 pL, 0.97 mmol) in 4 mL THF at-78 C and stirred for 30 min. diethyl difluoromethylphosphonate (182 mg, 0.97 mmol) was added, the colorless solution changed slowly to yellow after stirring at-78 C for 2 hours.

()- (2R, 3R, 5R, 1'S)-1-t-Butoxycarbonyl-2- (1-acetamido-3-methyl) butyl-3-formyl- pyrrolidine-5-carboxylic acid t-butyl ester (59 mg, 0.138 mmol) in 3 mL THF was added, stirred at-78 C for 30 min, then warm up to room temperature. The mixture was then heated at reflux for 1.5 hour, and stirred at room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride, and diluted with ethyl acetate. The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound, as a light yellow oil (23.4 mg, 37%).

'H NMR (CDC13): 8 7.44 (d, 1H), 5.92 (ddd, 1H), (m, 2H), 3.55 (m, 1H), 2.69 (m, 1H), 2.45 (m, 1H), 2.00 (s, 3H), 1.47 (s, 9H), 1.43 (s, 9H), 1.451.00 (m, 4H), 0.91 (m, 6H).

MS: (M+H) += 461 EMI190.1 37B. (#)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-difluoro-vin-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 33B, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido3-methyl) butyl-3- (2,2-difluoro-vin-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3 (cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.

'H NMR (DMSO-d6): # 8.04 (d, J=7.5Hz, 1H), 4.59 (ddd, 1H), 4.23 (m, 1H), 4.14 (m, 1H), 3.48 (m, 1H), 3.39 (m, 1H), 2.91 (m, 1H), 2.43 (m, 1H), 1.85 (s, 3H), 1.58 (m, 1H), 1.40 (m, 1H), 1.31 (m, 1H), 1.22 (m, 1H), 0.89 (d, J=7.5Hz, 3H), 0.83 (d, J=7.5Hz, 3H).

MS: (M+H)+= 305 Example 38 (#)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt EMI191.1 38A. (i)-(2R, 3R, 5R, 1'S, 1"RS)-1-t-Butoxvcarbonyl-2-(1-acetamido-3- methyl)butyl-3- ('I-hydroxv-2-propyn-1-vl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 4A substituting 2-propynyl magnesium bromide in place of ethyl magnesium bromide and substituting ()- (2R, 3R, 5R, 1'S)-1-t-Butoxycarbonyl-2-(1acetamido-3-methyl) butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester (250 mg, 0.587 mmol) in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3ethyl) pentyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester the crude product was used directly in the next reaction.

MS: (M+H) +=453EMI191.2 38B. (#)-(2R,3R,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1- oxo-2-propyn-1-rLl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

(i)-(2R, 3R, 5R, 1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(1- hydroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester was reacted withJones reagent (3.0 M in acetone, 0.33 mL) in acetone (90 mL) at 0 C to room temperature for 1 hour. The reaction was diluted with ethyl acetate. The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound, as a white solid (yield: 143 mg, 54%).

MS: (M+H) += 451EMI192.1 38C.()- (2R, 3R, 5R. 1'S)-1-t-Butoxvcarbonvl-2- (1-acetamido-3-methvl) butvl-3 (pyrazol-3-vi)-pvrrolidine-5-carboxylic Acid t-Butvl Ester.

()- (2R, 3R, 5R, 1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(1- oxo-1-ethynyl) methyl-pyrrolidine-5-carboxylic acid t-butyl ester (140 mg, 0.311 mmol) was reacted with hydrazine monohydrate (0.24 mL, 4.944 mmol) in ethanol (12 mL) at room temperature for 4 hours. The reaction was concentrated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate to provide the title compound, as a white solid (yield: 131 mg, 91%).

MS: (M+H) += 465 EMI193.1 38D. (#)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)- pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 33B, substituting ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido3-methyl) butyl-3- (pyrazol-3-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido-3-methyl) butyl-3- (cis-2chloro-vinyl)-pyrrolidine-5-carboxylic acid t-butyl ester.

'H NMR (DMSO-d6): #8. 13 (d, J=7.5Hz, 1H), 7.65 (d, J=2.2Hz, 1H), 6.20 (d, J=2.2Hz, 1H), 4.39 (m, 1H), 4.25 (m, 1H), 3.94 (m, 1H), 3.56 (q, J=7.5Hz, 1H), 2.62 (m, 1H), 2.17 (m, 1H), 1.87 (s, 3H), 1.42 (m, 1H), 1.21 (m, 1H), 1.11 (m, 1H), 0.80 (d, J=6.6Hz, 3H), 0.71 (d, J=6.6Hz, 3H).

MS: (M+H) +=309 Example 39 ()- 3R, 5R, 1'S)-2-(1-acetamido-3-methvl) butvl-3-(isoxazol-3-vl)-pvrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt and ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido- 3-methyl) butyl-3- (isoxazol-5-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic AcidSalt.EMI194.1 STDC078439A. ()- (2R, 3R, 5R, 1'S)-l-t-Butoxycarbonyl-2- (l-acetamido-3-methvl) bulyl-3- (isoxazol-3-yi)-pyrrolidine-5-carboxylic Acid t-Butyl Ester and (i)-(2R3R, 5R, 1'S)- 1-t-Butoxycarbonyl-2-(1-acetamido-3-methvl) butvl-3-(isoxazol-5-vl)-pvrrolidine-5- carboxylic Acid t-Butvl Ester ()- (2R, 3R, 5R, 1'S)-1-t-Butoxycarbonyl-2- (1-acetamido-3-methyl) butyl-3- (1oxo-1-ethynyl) methyl-pyrrolidine-5-carboxyiic acid t-butyl ester (31 mg, 0.07 mmol) was reacted with hydroxyamine hydrochloride (4.9 mg, 0.07 mmol) and sodium carbonate (3.7 mg, 0.035 mmol) in ethanol (3 mL) at reflux for 30 hours.

The reaction was concentrated in vacuo. The residue was purified by chromatography on silica gel using 3% methanol/dichloromethane to provide the title compound, as an oil (yield: 11.5 mg, 36%).

MS: (M+H) += 466 EMI195.1 39B.()- (2R. 3R, 5R, 1'S)-2- (1-acetamido-3-methyl) butvl-3- (isoxazol-3-vl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt and ()- (2R. 3R. 5R. 1'S)-2- (1-acetamido-3-methvl) butvl-3- (isoxazol-5-vl)-pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 33B, substituting ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido3-methyl) butyl-3- (isoxazol-3-yl)-pyrrolidine-5-carboxylic acid t-butyl ester and (#)- (2R, 3R, 5R, 1'S)-1-t-butoxywarbonyl-2-(1-acetamido-3-methyl) butyl-3-(isoxazol-5- yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-tbutoxycarbonyl-2- (1-acetamido-3-methyl) butyl-3- (cis-2-ch loro-vi nyl)-pyrrolid ine-5carboxylic acid t-butyl ester.

1H NMR (DMSO-d6): s 8.91,8.54 (d, 1H), 8.12,8.05 (d, J=7.5Hz, 1H), 6.64,6.43 (d, 1 H), 4.48,4.51 (m, 1 H), 4.28 (m, 1 H), 3.97,3.89 (m, 1 H), 3.70,3.81 (m, 1H), 2.72 (m, 1H), 25 (m, 1H), 1.83,1.80 (s, 3H), 1.48 (m, 1H), 1.341.10 (m, 2H), 0.83,0.84 (d, J=6Hz, 3H), 0.77,0.78 (d, J=6Hz, 3H).

MS: (M+H) +=310Example 40 (i)-(2R 3S. 5R. 1'R)-2-(1-Acetamido-2-hvd roxv) ethvl-3-(cis-pronen-1-vl)- pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI196.1 40A. (t)- (ZR. 3R. 5R)-1-Benzvl-2-viny(acetoxymethvl)-pyrrolidine-5-carboxylic Acid t-Butvl Ester.

()- (2R, 3R, 5R)-1-Benzyl-2-vinyl-3- (hydroxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (54.2 g, 0.17 mol) and 4- (dimethylamino) pyridine (0.5 g, 4.1 mmol), in anhydrous pyridine (400 mL) was reacted with acetic anhydride (30 mL, 0.32 mol) at 0 C for 1 hour then allowed to warm to room temperature. The reaction was stirred an additional 16 hours. The pyridine was removed in vacuo at 30 C. The residue was partitioned between ethyl acetate (100 mL) and of water (400 mL). The aqueous layer was extracted with ethyl acetate (3 x 100 mL) and the combined ethyl acetate layers were washed with brine, dried with MgS04, filtered, and concentrated.STDC0168 The crude product was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 49.6 g, 81%).

'H NMR (CDC13) 8 7.28 (m, 4H), 7.21 (m, 1H), 5.68 (m, 1H), 5.21 (m, 2H), 4.16 (dd, J=6.3,10.7 Hz, 1H), 4.10 (dd, J=7.3,10.7 Hz, 1H), 3.92 (d, J=13.7 Hz, 1H), 3.64 (d, J=13.7 Hz, 1H), 3.52 (m, 1H), 3.50 (m, 1H), 2.33 (m, 1H), 2.26 (m, 1H), 2.02 (s, 3H), 1.62 (m, 1H), 1.45 (s, 9H).

MS 360.= EMI197.1 40B. (#)-(2R,3R,5R,1'S)-1-Benzyl-2-(1,2- dihvdroxy) ethyl-3- (acetoxvmethvl)-pvrrolidine-5-carboXvlic Acid t-Butvl Ester.

()- (2R, 3R, 5R)-1-benzyl-2-vinyl-3- (acetoxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester. (52.5 g, 0.15 mol) and 4-methylmorpholine N-oxide (54.7 g, 0.47 mol) in acetone (540 mL) and water (60 mL) was reacted with osmium tetroxide (200 mg, 0.8 mmol). After 24 hours, the reaction was quenched with 10% sodium thiosulfate (250 mL) concentrated in vacuo. The aqueous layer was extracted with ethyl acetate (3 x 300 mL) and the combined organic layers were washed with brine, dried over MgS04, filtered and concentrated. The residue was purified by chromatography on silica gel using a gradient elution of ethyl acetate and dichloromethane to provide the title compound as a viscous oil (yield: 41.2 g, 72%).

'H NMR (DMSO) 8 7.32 (m, 3H), 7.30 (m, 1H), 7.22 (m, 1H), 4.48 (t, J=5.4Hz, 1 H), 4.42 (d, J=5.4 Hz, 1 H), 4.04 (m, 1 H), 4.01 (m, 1 H), 3.97 (m, 1 H), 3.80 (d, J=13.2 Hz, 1H), 3.78 (m, 1H), 3.43 (m, 1H), 3.39 (m, 1H), 3.32 (m, 1H), 3.07 (t,J=4.9 Hz, 1H), 2.48 (m, 1H), 2.19 (m, 1H), 1.99 (s, 3H), 1.57 (dt, J=13.7,2.0 Hz, 1H), 1.38 (s, 9H).

MS (M+H) + = 394. EMI198.1 STDC0214 (#)-(2R,3R,5R,1'S)-2-(1,2-Dihydroxy)ethyl-3-40C.(#)-(2R,3R,5R,1'R)and (acetoxvmethyl)-pyrrolidine-5-carboxvlic Acid t Butyl Ester.

()- (2R, 3R, 5R, 1'R) and ()- (2R, 3R, 5R, 1'S)-1-Benzyl-2- (1,2- dihydroxy) ethyl-3- (acetoxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (24 g, 61 mmol) in ethanol (300 mL) was reacted with ammonium formate (38.5 g, 0.61 mol) and 10% Pd/C (2g) for 2 hours at reflux. The reaction was cooled and the catalyst removed by filtration through Celite. The filtrate was concentrated in vacuo to provide the title compound (yield: 16.7 g, 90%).

'H NMR (DMSO) 8 4.56 (m, 1H), 4.30 (m, 1H), 4.06 (dd, J=5.8,10.9 Hz, 2H), 3.79 (dd, J=8.8,10.5 Hz, 2H), 3.49 (m, 4H), 3.00 (m, 1H), 2.35 (m, 1H), 2.16 (dt, J=12.6,8.5 Hz, 1H), 2.01 (s, 3H), 1.52 (m, 1H), 1.40 (s, 9H).

MS (M+H) + = 304.EMI198.2 STDC020440D. ()- (2R. 3R. 5R. 1'R) and (#)-(2R,3R,5R,1'S)-1-t-Butoxycarbonyl 2-(1, 2dihydroxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylic Acid Ester.

()- (2R, 3R, 5R, 1'R) and ()- (2R, 3R, 5R, 1'S)-2-(1,2-Dihydroxy) ethyl-3(acetoxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (33.4 g, 0.11 mol) in methanol (250 mL) and water (50 mL) was reacted with di-t-butyl dicarbonate (33.6 g, 0.15 mol) for 48 hours at room temperature. The methanol was removed in vacuo and the residue diluted with water (500 mL), and extracted with ethyl acetate (3 x 200 mL). The combined ethyl acetate layers were washed with brine, dried with MgS04, filtered and concentrated.STDC0406 The residue was chromatographed on silica gel using methanol/dichloromethane to provide the title compound as a white solid (yield: 32.8 g, 78%) 'H NMR (DMSO) # 4. 80 (m, 1 H), 4.45 (m, 1 H), 4.08 (m, 1 H), 3.91 (m, 2H), 3.82 (m, 1 H), 3.71 (m, 1 H), 3.28 (m, 2H), 2.48 (m, 1 H), 2.07 (m, 2H), 2.01 (m, 3H), 1.39 (m, 18H).

MS (M+H) + = 404.EMI199.1 STDC0195 40E (#)-(2R,3R,5R, 1'R) and ()- (2R. 3R. 5R, 1'S)-1-t-Butoxvcarbonvl 2-(1hydroXv-2-triisopropylsilvloXv)ethyl-3- (acetoxvmethyl)pPvrrolidine-5-carboxylic Acid Ester.

()- (2R, 3R, 5R, 1'R) and ()- (2R, 3R, 5R, 1'S)-1-t-Butoxycarbonyl 2-(1, 2dihydroxy) ethyl-3- (acetoxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester. (26.5 g, 66 mmol) in anhydrous dimethylformamide (200 mL) was reacted with imidazole (8.9 g, 0.13 mol) and triisopropylsilyl chloride (19.0 g, 99 mmol) for 4 hours at room temperature. The solvent was removed under vacuum and the residue partitioned between 300 mL of water and 150 mL of ethyl acetate. The aqueous layer was extracted with ethyl acetate (2 x 100 mL), and the combined ethyl acetate layers extracted with brine, dried with MgS04, filtered and concentrated.STDC0164 The residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 28.9 g, 79%).

1H NMR (CDCI3) 6 4.22 (m, 1H), 4.04 (m, 3H), 3.87 (t, J=2.0 Hz, 1H), 3.74 (dd, J=4.9,9.8 Hz, 1H), 3.58 (dd, J=7.8,10.2 Hz, 1H), 3.39 (bs, 1H), 2.61 (m, 2H). 2.03 (s, 3H), 1.75 (m, 1H), 1.46 (m, 18H), 1.07 (m, 18H).

MS (M+H) + = 560.EMI200.1 STDC0227 40F (*)-(2R. 3R, 5R)-1-t-Butoxvcarbonvl-2-(1-oxo-2-triisopropylsilvioxv ! ethyl-3- (acetoxymethyl)-pyrrolidine-5-carboxylic Acid t-Butvl Ester.

Dimethylsulfoxide (6 mL, 85 mmol) was added slowly to a solution of oxalyl chloride (2 M) (19.3 mL, 38.6 mmol) in dry dichloromethane (70 mL) at-78 C.

After 10 minutes, a solution of ()- (2R, 3R, 5R, 1'R) and ()- (2R, 3R, 5R, 1'S)-1-t- butoxycarbonyl2-(1-hydroxy-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)pyrrolidine-5-carboxylic acid f-butyl ester (14.4 g, 26 mmol) in dry dichloromethane (75 mL) was added at a rate such that the temperature did not exceed-70 C. After 1.5 hours, triethylamine (18 mL, 0.13 mol) was added and the temperature allowed to rise to 0 C. The reaction was quenched with a solution of ammonium chloride, diluted with water, and extracted with dichloromethane (3 x 100 mL). The combined dichloromethane layers were extracted with brine, dried with MgSO4, filtered and concentrated.STDC0334 The residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound as a colorless oil: (yield: 11 g, 77%). aH NMR (CDC13) 8 4.32 (m, 6H), 2.43 (m, 2H), 2.04 (s. 3H), 1.78 (m, 1H), 1.48 (s, 9H), 1.41 (s, 9H), 1.1 (m, 21 H).

MS (M+H) + = 558. EMI201.1 40G (#)-(2R,3R,5R,1'R and (i)-(2R, 3R, 5R, 1'S)-1-t-Butoxvcarbonyl 2-(1-amino- 2-triisopropvlsilvloxy) ethyl-3- (acetoxymethylyrrolidine-5-carboxvlic Acid t-Butyl Ester.

()- (2R, 3R, 5R)-1-t-Butoxycarbonyl 2-(1-oxo-2-triisopropylsilyloxy) ethyl-3 (acetoxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester. (22 g, 39 mmol) in methanol (1 L) was reacted with ammonium acetate (77 g, 1.0 mol) and sodium cyanoborohydride (24.8 g, 0.39 mol) at reflux for 2 hours. The solvent was removed under in vacuo, and the residue was partitioned between water (300 mL) and dichloromethane (300 mL). The aqueous layer was extracted with dichloromethane (2 x 100 mL) and the combined organic layers were washed with brine, dried with MgS04, filtered and concentrated to provide the title compound (crude yield: 22. Og, 100%).EMI201.2 STDC0208 40H (i)-(2R. 3R, 5R, 1'R) and ()- (2R. 3R. 5R. 1'S)-1-t-Butoxycarbonvl-2- (1acetamido-2-triisopropvlsilvloxy ethyl-3- (acetoxymethyl)-pyrrolidine-5-carboxvlicAcid t-Butvl Ester.

()- (2R, 3R, 5R, 1'R) and ()- (2R, 3R, 5R, 1'S)-1-t-Butoxycarbonyl-2-(1-amino- 2-triisopropylsilyloxy) ethyl-3- (acetoxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (approx 39 mmol) in dichloromethane (500 mL) was reacted with acetic anhydride (18 mL, 0.19 mol), triethylamine (27.5 mL, 0.20 mol) and dimethylaminopyridine (50 mg, 0.39 mmol) for 18 hours at room temperature.

The reaction was quenched with a solution of ammonium chloride. The aqueous layer was extracted with dichloromethane (3 x 100 mL) and the combined organic layers extracted with brine, dried with MgS04, filtered, and concentrated. The residue was chromatographed on silica gel using ethyl acetate/hexanes to provide the title compound ()- (2R, 3R, 5R, 1'R)-1-t-butoxycarbonyl 2-(1- acetamido-2-triisopropylsilyloxy) ethyl-3- (acetoxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (9.14 g, 39%) and ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl 2-(1acetamido-2-triisopropylsilyloxy) ethyl-3- (acetoxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (9.75 g, 41 %) as white solids.

()- (2R, 3R, 5R, 1'R)'H NMR (CDC13) 8 7.38 (d, J=8.3 Hz, 1H), 4.34 (m, 1H), 4.20 (dd, J=2.4,10.3 Hz, 1H), 4.09 (dd, J=8.8,10.2 Hz. 1H), 4.02 (dd, J=7.3, 10.1 Hz, 1H), 3.88 (m, 1H), 3.71 (dd, J=4.4,10.3 Hz, 1H), 3.65 (dd, J=7.9,10,3Hz, 1H), 2.74 (m, 1H), 2.60 (m, 1H), 2.04 (s, 3H), 1.98 (s, 3H), 1.69 (dt, J=14.1, 2.5 Hz, 1 H), 1.46 (s, 9H), 1.42 (s, 9H), 1.07 (m, 21 H).

MS (M+H) + = 601 ()- (2R, 3R, 5R, 1'S)'H NMR (CDCI3) 6.82 (d, 1H), 4.10 (m, 4H), 3.81 (m, 3H), 2.55 (m, 2H), 1.98 (m, 7H), 1.46 (s, 9H), 1.42 (s, 9H), 1.07 (m, 21 H).

MS (M+H) + = 601. EMI203.1 STDC0178 401 ()- (2R. 3R. 5R. 1'R)-1-t-Butoxvcarbonvl 2-(1-acetamido-2triisopropvlsilyloxv ethvl-3-hydroxymethyl-pyrrolidine-5-carboxylic Acid t-Butvl Ester.

()- (2R, 3R, 5R, 1'R)-1-t-Butoxycarbonyl 2- (1-acetamido-2triisopropylsilyloxy) ethyl-3- (acetoxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester. (8.2 g, 13.66 mmol) in methanol (200 mL) and water (50 mL) was reacted with potassium carbonate (19 g, 136 mmol) at room temperature for 2 hr. The solvent was then removed in vacuo and the residue was partitioned between water (100 mL) and dichloromethane (3 x 100 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound as a colorless oil.EMI203.2 STDC020040J (s)-(2R, 3R, 5R, 1'R)-1-t-Butoxvcarbonvl 2-(1-acetamido-2- triisopropvlsilvloxv) ethvl-3-formyl-pyrrolidine-5-carboxylic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 2A substituting ()- (2R, 3R, 5R, 1'R)-1-t-butoxycarbonyl 2-(1-acetamido(2-triisopropylsilyloxy) ethyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 5.9 g, 78%).

1H NMR (CDCL3) # 1.04 - 1.07 (m, 21H), 1.42 (s, 9H), 1.43 (s, 9H), 1.99 (s, 3H), 2.42 (m, 1 H), 2.62 (m, 1 H), 3.04 (m, 1 H), 3.69 (m, 1 H), 3.82 (m, 1 H), 4.08 (m, 1 H), 4.38 (m, 1 H), 4.57 (t, 1 H), 7.33 (br d, 1 H), 9.65 (s, 1 H).

MS: (M+H) += 557.EMI204.1 STDC018240K (i)-(2R, 3S. 5R, 1'R)-1-t-Butoxvcarbonvl 2-(1-acetamido-2- triisopropylsiyloxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-ButylEster.

The title compound was prepared according to the method described inExample 35A substituting ()- (2R, 3R, 5R, 1'R)-1-t-butoxycarbonyl 2- (1-acetamido2-triisopropylsilyloxy-) ethyl-3-formyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido-3-methyl) butyl-3formyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 5.9 g, 78%).

1H NMR (CDC13) 61. 03-1. 10 (m, 21 H), 1.44 (s, 9H), 1.47 (s, 9H), 1.55 (m, 1H), 1.64 (dd, 3H), 1.96 (s, 3H), 2.55 (m, 1H), 3.42 (m, 1H), 3.62-3.71 (m, 3H), 4.20 (dd, 1 H), 4.30 (m, 1 H), 5.39 (m, 1 H), 5.48 (m, 1 H), 7.73 (br d, 1 H).STDC0233 MS: (M+H)+= 569 EMI205.1 40L (s)-(2R. 3S. 5R. 1'R)-1-t-Butoxvcarbonvl 2-(1-acetamido-2-hydroxy-) ethyS-3- (cis-propen-1-vi)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl 2- (1-acetamido-2- triisopropylsilyloxy) ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxyiic acid t-butyl ester (4.85 g, 8.54 mmol) in THF (100 mL) was reacted with tetrabutyl ammonium fluoride (1M in THF) (12.8 mL, 12.8 mmol) for 30 minutes at room temperature. 2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3 (trans-2-chloro-vinyl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 18.0 mg, 100%).

1H NMR (DMSO-d6) : d 1.66 (dd, 3H), 1.71 (dt, 1H), 1.87 (s, 3H), 2.41 (dt, 1H), 3.18 (m, 1H), 3.43 (dd, 1H), 3.61 (m, 1H), 4.13 (m, 1H), 4.35 (m, 1H), 5.25 (m, 1H), 5.51 (m, 1H), 8.05 (d, 1H), 9.16 (br s, 2H).

MS: (M+H)+= 257.

Example 41 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)- pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI206.1 41A ()- (2R. 3S. 5R. 1'R)-1-t-Butoxycarbonyl 2- (1-acetamido-1-formvl) methvl-3- (cis-propen-1-vl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl 2-(1-acetamido-2-hydroxy) ethyl-3(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. (600 mg, 1.46 mmol) in dichloromethane (50 mL) was reacted with Dess-Martin Periodinane (928 mg, 2.18 mmol) for 1 hour at room temperature. The reaction was quenched with 1 M aqueous sodium thiosulfate (50 mL), stirred for 20 minutes then extracted with dichloromethane (3 x 100 mL). The organic layer was dried over magnesium sulfate, concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2/1: ethyl acetate/hexane to provide the title compound (yield: 547 mg, 92%).

'H NMR (CDC13) d 9.40 (d, J= 1 Hz, 1H), 7.88 (bd), 5.69 (m, 1H), 5.27 (m, 1H), 4.78 (dd, J= 9.5,1. Hz, 1H), 4.21 (t, J= 8. Hz, 1H), 3.45 (m, 2H), 2.41 (m, 1 H), 2.09 (s, 3H), 1.69 (dd, J= 7.0,1. Hz, 3H), 1.55 (m, 1 H), 1.46 (s, 9H), 1.40 (s, 9H).

MS: (M+H) += 411, (M-H)-= 409. EMI207.1 STDC0209 41B ()- (2R, 3S, 5R, 1'R, 2'R) and (i !-(2R, 3S, 5R, 1'R. 2'S)-1-t-Butoxvcarbonyl-2 (1-acetamido-2-hydroxy) butyl-3- (cis-propen-1-vlLpyrrolidine-5-carboxvlic Acid t- Butyl Ester.

()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl 2-(1-acetamido-1-formyl) methyl-3 (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (780 mg, 1.90 mmol) inTHF (20 mL) was added dropwise to a solution of ethylmagnesium bromide (3M in ether) (3.17 mL, 9.51 mmol) in THF (15 mL) at room temperature and reacted for 40 minutes. The reaction was quenched with water (20 mL) and saturated aqueous ammonium chloride (20 mL) followed by extraction using dichloromethane (3 x 50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.STDC0566 The residue was purified by column chromatography on silica gel using 2/1: ethyl acetate/hexane to provide the title compounds ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl 2-(1-acetamído-2- hydroxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 472 mg, 56%) and ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl 2- (1-acetamido-2 hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 82 mg, 10%) as a colorless oils.

()- (2R, 3S, 5R, 1'R, 2'R) = MS: (M+H) += 441, (M+Na) += 463, (M-H)-= 439.

()- (2R, 3S, 5R, 1'R, 2'S) = MS: (M+H) += 441, (M+Na) += 463, (M-H)-= 439.EMI208.1 STDC0599 41C(#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1- L)-pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-Butoxycarbonyl-2- (1-acetamido-2hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (300 mg, 0.68 mmol) was reacted with trifluoroacetic acid (8 mL) in dichloromethane (2 mL) at room temperature for 6 hrs. The reaction was concentrated in vacuo overnight to provide the title compound (yield: 311 mg) as a colorless solid.

'H NMR (500 MHz, DMSO-d6) 6: 7.89 (d, J = 8.7 Hz, 1 H), 5.48 (m, 1 H), 5.29 (m, 1H), 4.30 (m, 1H), 4.02 (m, 1H), 3.73 (m, 1H), 3.43 (m, 1H), 3.15 (m, 1 H), 2.41 (m, 1 H), 1.82 (s, 3H), 1.63 (m, 1 H), 1.59 (dd, J = 6.8,1.9 Hz, 3H), 1.55 (m, 1 H), 1.27 (m, 1 H), 0.85 (t, J = 7.3 Hz, 3H).

MS: (M+H)+= 285, (M+Na) += 307, (M-H)-= 283.

Example 42 ()- (2R. 3S. 5R, 1'R, 2'S)-2- (1-Acetamido-2-hvdroxv) butycis-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.EMI209.1 STDC0194 42A(+)-(2R, 3S, 5R, 1'R)-1-t-Butoxvcarbonyl-2-(1-acetamido-2-oxo) buh !-3-(cis- propen-1-yl)-pvrrolidine-5-carboxvlic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'R, 2'R)-1-t Butoxycarbonyl-2- (1-acetamido-2- hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. (460 mg, 1.05 mmol) was reacted with Dess-Martin Periodinane (666 mg, 1.57 mmol) in dichloromethane (30 mL) at room temperature for 17 hours. The reaction was quenched with 1 M aqueous sodium thiosulfate (50 mL and stirred for 20 minutes.

The reaction was was extracted with dichloromethane (3 x 100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2: 1: ethyl acetate/hexane to provide the title compound as a colorless semi-solid (yield: 440 mg, 96%).

MS: (M+H) += 439, (M+Na) += 461, (M-H)-= 437. EMI210.1 STDC028242B (#)-(2R,3S,5R,1'R,2'R) and (#)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2- (1-acetamido-2-hvdroxv) buty. l-3- (cis-propen-1-yl)-pyrrolidine-5-carboxvlic Acid tButylEster.

()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl-2- (1-acetamido-2-oxo) butyl-3- (cispropen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (435 mg, 0.99 mmol) in methanol (30 mL) was reacted with sodium borohydride (188 mg, 4.97 mmol) at room temperature for 0.5 hours. The solvent was removed in vacuo and water (30 mL) was added. The aqueous layer was extracted with dichloromethane (3 x 50 mL). This organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2: 1 ethyl acetate/hexane to provide the title compounds ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido-2-hydroxy) butyl-3- (cispropen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.STDC0299 (yield: 305 mg, 70%) and compounds ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2- (1-acetamido-2hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 17 mg, 4%). EMI211.1 STDC066042C (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2hyd roxy) butyl-3-(cis-propen-1-yl)-pyrrolid ine-5-carboxylic(cis-propen-1-yl)-pyrrolid ine-5-carboxylic acid t-butyl ester (300 mg, 0.68 mmol) was reacted with trifluoroacetic acid (8 mL) in dichloromethane (2 mL) at room temperature for 6 hrs. The reaction was concentrated in vacuo overnight and triturated with acetonitrile (2 x 5 mL) to provide the title compound (yield: 311 mg) as a colorless solid.

1H NMR (500 MHz, DMSO-d6) 8: 7.89 (d, J = 8.7 Hz, 1H), 5.48 (m, 1H), 5.29 (m, 1H), 4.30 (m, 1H), 4.02 (m, 1H), 3.73 (m, 1H), 3.43 (m, 1H), 3.15 (m, 1H), 2.41 (m, 1H), 1.82 (s, 3H), 1.63 (m, 1H), 1.59 (dd, J = 6.8,1.9 Hz, 3H), 1.55 (m, 1 H), 1.27 (m, 1 H), 0.85 (t, J = 7.3 Hz, 3H).

MS: (M+H) += 285, (M+Na) += 307, (M-H)-= 283.

Example 43 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI212.1 The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2- (1- t-butylacetamindo-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido-2hydroxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxlic acid t-butyl ester (yield: . 0065 g, 100%).

1H NMR (DMSO-d6) 8 7.90 (d, J=8.8Hz, 1H), 5.47 (m, 1H), 5.29 (t, J=9.8 Hz, 1H), 4.29 (t, J=8.8Hz, 1H), 4.02 (q, J=6.8Hz, 1H), 3.71 (bt, J=8Hz, 1H), 3.43 (m, 1H), 3.15 (quint., J=8.8Hz, 1H), 2.41 (dt, J=12.7,7.8Hz, 1H), 1.82 (s, 3H), 1.64 (m, 1H), 1.58 (dd, J=6.8,1.5Hz, 3H), 1.53 (m, 1H), 0.85 (t, J=7.3Hz, 3H).

MS: (M+H) + = 285, (M+Na) + = 307, (M-H)-= 283, (M+CF3COOH)-= 397, 563(2M-1)= Example 44 ()- (2R. 3S, 5R. 1'R. 2'S)-2- (1-Acetamido-2-hvdroxv-3-cvano) propyl-3- (cis-propen- 1-vl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI213.1 44A (t)- (2R. 3S. 5R, 1'R. 2'R) and (i)-(2R. 3S. 5R. 1'R, 2'S)-1-t-Butoxycarbonyl-2- (1-acetamido-2-hydroxv-3-cyano) propyl-3- (cis-propen-1-yl)-pyrrolidine-5carboxylic Acid t-Butvl Ester.

()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl 2-(1-acetamido-1-formyl) methyl-3(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (150 mg, 0.37 mmol) inTHF (10 mL) was added dropwise to a solution of the lithium enolate of acetonitrile (1.83 mmol, 5 equivalents) in THF (15 mL) at-78 C and reacted for 15 minutes. The reaction was quenched with saturated aqueous ammonium chloride (10 mL) and water (10mL) followed by extraction using dichloromethane (2 X 50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.STDC0579 The residue was purified by column chromatography on silica gel using 2/1: ethyl acetate/hexane to provide the title compounds (#)- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-cyano)propyl3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 95mg, 58%) and ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl 2-(1-tacetamido-2-hydroxy-3cyano) propyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 30 mg, 18%) as a colorless oils.

()- (2R, 3S, 5R, 1'R, 2'R) = MS: (M+H) +=452, (M-H)-=450 ()- (2R, 3S, 5R, 1'R, 2'S) =1H NMR (CDC13) 8 8.14 (d, J=8.9Hz, 1H), 5.51 (m, 1H), 5.38 (m, 1H), 4.25 (m, 1H), 4.19 (m, 1H), 3.94 (m, 1H), 3.74 (m, 1H), 3.22 (m, 1H), 2.54 (m, 1H), 2.47 (m, 2H), 2.04 (s, 3H), 1.69 (m, 1H), 1.65 (dd, J=6.5, 1.8Hz, 3H), 1.47 (s, 9H), 1.45 (s, 9H) MS:STDC0744 (M+H) +=452, (M-H)-=450EMI214.1 44B (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-cyano)pyropyl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting (#)-(2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (#)-(2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4.5 mg, 95% %).

1H NMR (DMSO-d6) 8 7.98 (d, J=10.0 Hz, 1H), 5.49 (m, 1H), 5.27 (m, 1H), 4.30 (m, 1H), 4.15 (m, 1H), 3.75 (m, 1H), 3.18 (m, 1H), 2.72-2.58 (m, 2H), 2.41 (m, 1H), 1.85 (s, 3H), 1.65 (m, 1H), 1.61 (dd, J=6.70,1.80 Hz, 3H) MS:STDC0773 (M+H) + =296, (M-H)-=294 Example 45 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen- TrifluoroaceticAcidSalt1-yl)-pyrrolidine-5-carboxylicAcidEMI215.1 The title compound was prepared according to the method described in Example 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1 acetamido-2-hydroxy-3-cyano) propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- t-butylacetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ester (yield: 8 mg, 95%).

H NMR (DMSO-d6) 8 7.75 (d, J=9.0 Hz, 1H), 5.47 (m, 1H), 5.25 (m, 1H), 4.46 (m, 1H), 4.20 (m, 1H), 4.13 (m, 1H), 3.56 (m, 1H), 3.15 (m, 1H), 2.55 (m, 2H), 2.42 (m, 1H), 1.82 (s, 3H), 1.72 (m, 1H), 1.55 (dd, J=6.71,1.83,3H) MS:STDC0685 (M+H) + =296, (M+23) + =318, (M-H)-=294 Example 46 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-3-ethoxycarbonyl)propyl-3-(cis- propen-1-vl)-pvrrolidine-5-carboxviic Acid Trifluoroacetic Acid SaltEMI216.1 46A (#)-(2R,3S,5R,1'R,2'R) and ()- (2R, 3S. 5R. 1'R. 2'S)-1-t-Butoxvcarbonyl-2- (1-acetamido-2-hydroxv-3-ethoxvcarbonvl) propvl-3- (cis-propen-1-vl)-pyrrolidine- 5-carboxylic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl-2- (1-acetamido-1-formyl) methyl-3(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (900 mg, 2.187 mmol) in THF (40 mL) was added dropwise to a solution of the lithium enolate of ethyl acetate (8.75 mmol, 4 equivalents) in THF (40 mL) at-78 C and reacted for 15 minutes. The reaction was quenched with saturated aqueous ammonium chloride followed by extraction using dichloromethane (3 X). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.STDC0582 The residue was purified by column chromatography on silica gel using 1: 1 ethyl acetate/hexane to provide the title compounds ()- (2R, 3S, 5R, 1'R, 2'R)-1-tbutoxycarbonyl-2- (1-acetamido-2-hydroxy-3-ethoxycarbonyl) propyl-3- (cis-propen1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 690 mg, 63%) and(#)- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido-2-hydroxy-3ethoxycarbonyl) propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 246 mg, 22.5%).

()- (2R, 3S, 5R, 1'R, 2'R)'H NMR (CDCI3): 5 5.99 (d, 1H), 5.60 (m, 1H), 5.36 (m, 1H), 4.81 (m, 1H), 4.15 (m, 4H), 3.74 (m, 1H), 3.07 (m, 1H), 2.68 (m, 1 H), 2.48 (m 1 H), 2.33 (m, 1 H), 2.03 (s, 3H), 1.54 (dd, 3H), 1.47 (s, 9H), 1.46 (s, 9H), 1.24 (t, J=7.5Hz, 3H).

MS: (M+H)+=499 ()- (2R, 3S, 5R, 1'R, 2'S) 1H NMR (CDCl3) : b 7.93 (d, 1H), 5.44 (m, 2H), 4.19 (m, 4H), 4.03 (m, 1H), 3.72 (m, 1H), 3.37 (m, 1H), 2.63 (m. 1H), 2.48 (m, 2H), 2.01 (s, 3H), 1.65 (dd, 3H), 1.48 (s, 9H), 1.46 (s, 9H), 1.26 (t, J=7.5Hz, 3H).

MS: (M+H) +=499 EMI217.1 46B(#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-3- ethoxycarbonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxlyciAcidTrifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting (#)-(2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-ethoxycarbonyl)-propyl-3-(cis-propen-1-yl)-pyrrolidine-5carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonylt-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid butyl ester.

1H NMR (DMSO-d6): 8 7.74 (d, J=9Hz, 1H), 5.48 (m, 1H), 5.25 (m, 1H), 4.43 (m, 1H), 4.24 (m, 1H), 4.14 (m, 1H), 4.06 (q, J=7.5Hz, 2H), 3.54 (m, 1H), 3.16 (m, 1H), 2.41 (m, 1H), 2.36 (m, 2H), 1.82 (s, 3H), 1.77 (m, 1H), 1.56 (dd, 3H), 1.18 (t, J=7.5Hz, 3H).

MS: (M+H)+= 343 Example 47EMI218.1 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-ethoxycarbonyl)-propyl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound is prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t butoxycarbonyl-2- (1- acetamido-2-hydroxy-3-ethoxycarbonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonylt-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid butyl ester.

1H NMR (DMSO-d6): # 7.93 (d, J=9Hz, 1H), 5.48 (m, 1H), 5.30 (m, 1H), 4.19 (m, 1H), 4.09 (m, 1H), 4.06 (q, J=7.5Hz, 2H), 3.94 (m, 1H), 3.73 (m, 1H), 3.18 (m, 1H), 2.54 (dd, 1H), 2.40 (m, 1H), 2.27 (m, 1H), 1.82 (s, 3H), 1.65 (m, 1H), 1.60 (dd, 3H), 1.19 (t, J=7. 5Hz, 3H).

MS: (M+H) +=343 Example 48EMI219.1 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)propyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1t-acetamido-2-hydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido2-hydroxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0030 g, 100%).

1H NMR (DMSO-d6) d 8.97 (bs, 1H), 7.88 (d, J=8.5 Hz, 1H), 5.45 (m, 1H), 5.28 (t, J = 9. 1Hz, 1H), 4.30 (t, J=8.6Hz, 1H), 3.94 (q, J=7.3Hz, 1H), 3.71 (t,J=8. 0Hz, 1H), 3.62 (m, 1H), 3.15 (quint., J=9. OHz, 1H), 2.40 (dt, J=12.8,7.6Hz, 1H), 1.83 (s, 3H), 1.65 (m, 1H), 1.59 (dd, J=7.0,1.5Hz, 3H), 1.08 (d, J=5.5Hz, 3H).

MS: (M+H) + = 271, (M+Na) + = 293, (M-H)-= 269.

Example 49EMI220.1 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy)propyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-f-butoxycarbonyl-2- (1-acetamido-2- hydroxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0143 g, 100%).

'H NMR (DMSO-d6) 5 7.70 (d, J=9.1 Hz, 1H), 5.49 (m, 1H), 5.25 (t, J = 9. 1Hz, 1H), 4.43 (t, J=8.6Hz, 1H), 4.03 (m, 1H), 3.92 (m, 1H), 3.55 (t, J=8.5Hz, 1H), 3.17 (quint., J=8.5Hz, 1H), 2.42 (dt, J=12.8,7.3Hz, 1H), 1.85 (s, 3H), 1.72 (dt, J=12.8, 10.0Hz, 1H), 1.57 (dd, J=6.7,1.8Hz, 3H), 1.04 (d, J=6. 1Hz, 3H).

MS: (M+H)+=271, (M+Na) + = 293, (M-H)-= 269 Example 50 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-vinyl)ethyl-3-(cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.EMI221.1 STDC0212 50A (t)-(2R. 3S. 5R. 1'R, 2'S) and (#)-(2R,3S,5R,1'R,2'R)-1-t-Butoxycarbonyl-2 (1-acetamido-2-hydroxy-2-vinvl) ethyl-3- (cis-propen-1-vl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41 B, substituting vinyl magnesium bromide for ethyl magnesium bromide to provide ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2 hydroxy-2-vinyl) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 6.5 mg, 18%) and ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 22 mg, 59%).

()- (2R, 3S, 5R, 1'R, 2'S) MS: (M+H) +=439, (M-H)-= 437 ()- (2R, 3S, 5R, 1'R, 2'R) MS: (M+H)+=439, (M-H)-=437 EMI222.1 50B(#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-vinyl)ethyl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting (#)-(2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (#)-(2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)STDC0075-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 5 mg, 96%).

1H NMR (DMSO-d6) #7. 85 (d, J=9.1Hz, 1H), 5.76 (m, 1H), 5.47 (m, 1H), 5.25 (m, 2H), 5.14 (m, 1H), 4.29 (m, 1H), 4.05 (m, 1H), 3.96 (m, 1H), 3.71 (m, 1H), 3.18 (m, 1H), 2.41 (m, 1H), 1.78 (s, 3H), 1.64 (m, 1H), 1.21 Hz, 3H) MS:STDC0819 (M+H) + =283, (M+23) + =305, (M-H)-=281 Example 51EMI223.1 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-2-vinyl)ethyl-3-(cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 6 mg, 95%).

1H NMR (DMSO-d6) # 7.84 (d, J=9.7Hz, 1H), 5.78 (m, 1H), 5.48 (m, 1H), 5.23 (m, 34.43 (m, 1H), 4.26 (m, 1H), 4.20 (m, 1H), 3.55 (m, 1H), 3.18 (m, 1H), 2.43 (m, 1H), 1.81 (s, 3H), 1.73 (m, 1H), 1.57 (dd, J=6.72,1.83 HZ, 3H) MS: (M+H) + =283, (M+23)-=305, (M-H)-=281, (2M-H)-=563 Example 52 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-vinyl)propyl-3-(cis-propen-1- vl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.EMI224.1 STDC027252A ()- (2R. 3S. 5R. 1'R. 2'S) and (t)- (2R. 3S. 5R, 1'R. 2'R)-1-t-Butoxycarbonvl-2- (1-acetamido-2-hvd roxv-3-vinyl) propy(cis-p ropen-1-vl)-pyrrolid i ne-5-carboxylicAcid t-Butvl Ester.

The title compounds were prepared according to the method described inExample 41 B, substituting allyl magnesium bromide for ethyl magnesium bromide to provide ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido-2-hydroxy2-vinyl) propyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 2.0 mg, 5%) and ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2- (1-acetamido-2hydroxy) propyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 9.0 mg, 22%).STDC0142 ()- (2R, 3S, 5R, 1'R, 2'S) MS: (M+H)+=453 ; (M-H)-=451.

()- (2R, 3S, 5R, 1'R, 2'R)'H NMR (DMSO-d6) 6 7.70 (d, J=9.3Hz, 1H), 5.80 (m, 1 H), 5.51 (m, 1 H), 5.30 (m, 1 H), 5.00 (m, 2H), 4.58 (br d, 1 H), 3.93 (m, 2H), 3.50 (m, 1 H), 3.22 (br t, 1 H), 2.02 (m, 3H), 1.88 (s, 3H), 1.56 (m, 4H), EMI225.1 STDC072852B (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-vinyl)propyl-3-(cis- propen-1-vl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy-2-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 2 mg, 100%).

1H NMR (DMSO-d6) # 7.85 (d, J=9.3Hz, 1H), 5.81 (m, 1H), 5.42 (m, 1H), 5.28 (t, J=7.3Hz, 1H), 5.01 (br d, 2H), 3.99 (m, 2H), 3.57 (m, 2H), 3.08 (m, 1H), 2.33 (m, 1H), 2.26 (m, 1H), 2.07 (m, 1H), 1.81 (s, 3H), 1.57 (dd, J=1.4,5.4Hz, 4H) MS: (M-H)-= 295; (M+H)+=297, (M+Na)+= 319.

Example 53EMI226.1 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-vinyl)propyl-3-(cis-propen-1- vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting (#)-(2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2- (1- acetamido-2-hydroxy-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 6 mg, 100%).

1H NMR (DMSO-d6) # 7.68 (d, J=9.2Hz, 1H), 5.78 (m, 1H), 5.48 (m, 1H), 5.24 (t, J=7.8Hz, 1H), 5.04 (m, 2H), 4.38 (t, J=7.0,1 H), 4.09 (t, J=7.0,1 H), 3.81 (t, J=4.7,1 H), 3.53 (t, J=8.5,1H), 3.16 (m, 1H), 2.40 (m, 1H), 2.11 (m, 2H), 1.83 (s, 3H), 1.70 (m, 1 H), 1.55 (dd, J=5.4,1.4Hz, 3H) MS: (M-H)-= 295; (M+H) + = 297, (M+Na) + = 319.

Example 54 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.EMI227.1 STDC017254A (#)-(2R,3S,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-and t-(1-acetamido-2hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcidButylEster.

The title compounds were prepared according to the method described inExample 41 B, substituting propyl magnesium bromide for ethyl magnesium bromide to provide ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido-2hydroxy) pentyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 1 mg, 1%) and ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1-acetamido- 2-hydroxy) pentyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 32 mg, 39%).

()- (2R, 3S, 5R, 1'R, 2'S) 1HNMR (CDCl3) # 7. 51 (d, J=8.2Hz, 1H), 5.46 (m, 2H), 4.17 (dd, J=3.1,6.8Hz, 1H), 4.05 (m, 1H) 3.81 (t, J=3.4Hz, 1H), 3.54 (m, 1H), 3.21 (m, 1H), 2.60 (m, 1H), 2.02 (s, 3H), 1.70 (dt, J=3.0,7.4Hz, 1H), 1.61 (d,J=5.4Hz, 3H), 1.54 (m, 1 H), 1.47 (s, 9H), 1.44 (s, 9H), 1.32 (m, 4H), 0.90 (t,J=7.1Hz,3H) MS: (M+H) + = 455, (M+Na) + = 477; (M-H)-= 453.

()- (2R, 3S, 5R, 1'R, 2'R) 1H NMR (CDCl3) # 5.98 (d, J=9.5Hz, 1H), 5.60 (t, J=9.8Hz, 1H), 5.36 (m, 1H), 4.16 (m, 1H), 3.75 (d, J=10.1Hz,1H), 3.64 (m, 1H), 3.51 (m, 1H), 3.09 (brt, 1H), 2.68 (m, 1H), 2.02 (s, 3H), 1.81 (d, J=13.9Hz, 1H), 1.57 (m, 4H), 1.54 (dd, J=1.7,5.1 Hz, 3H), 1.46 (s, 9H), 1.45 (s, 9H), 0.88 (t, J=6.8Hz, 3H) MS: (M-H)-= 453; (M+H) + = 455.EMI228.1 STDC0719 54B ()- (2R, 3S, 5R, 1'R2'S)-2-(1-Acetamido-2-hvdroxv) nentvl-3-(cis-propen-1- vl)-Dvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t- butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 1 mg, 100%).

1H NMR (DMSO-d6) 8 7.83 (d, J=9.2Hz, 1H), 5.43 (m, 1H), 5.23 (m, 1H), 3.98 (m, 1 H), 3.56 (br t, 1 H), 3.46 (m, 1 H), 3.08 (m, 2H), 2.32 (m, 1 H), 1.80 (s, 3H), 1.57 (dd, J=1.4,5.4Hz, 4H), 1.43 (m, 2H), 1.23 (m, 2H), 0.85 (br t, 3H) MS: (M+H) + = 299, (M+Na) + = 321.

Example 55EMI229.1 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) pentyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t- butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0190 g, 100%).

'H NMR (DMSO-d6) 5 7.64 (d, J=9.3Hz, 1H), 5.48 (m, 1H), 5.24 (m, 1H), 4.38 (t, J=8.8Hz, 1H), 4.06 (m, 1H), 3.75 (m, 1H), 3.53 (t, J=8.5Hz, 1H), 3.16 (quint., J=8.5Hz, 1H), 2.41 (dt, J=12.8,7.3Hz, 1H), 1.82 (s, 3H), 1.70 (dt, 12.8,9.9Hz, 1 H), 1.55 (dd, J=7.0,1.6Hz, 3H), 1.35 (m, 2H), 1.26 (m 2H), 0.86 (t,J=6.7Hz, 3H).

MS: (M+H)+= 299, (M+Na) + = 321, (M-H)-= 297.

Example 56 ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-hvdroy-3-methyl) butvl-3- (cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.EMI230.1 STDC0218 56A (t)-(2R. 3S. 5R. 1'R. 2'S) and (i)-(2R. 3S. 5R. 1'R. 2'R)-1-t-Butoxycarbonvl-2 (1-acetamido-2-hydroxv-3-methyl) butyl-3- (cis-propen-1-vl)-pyrrolidine-5- carboxylic Acid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41 B, substituting isopropyl magnesium bromide for ethyl magnesium bromide to provide ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido-2hydroxy-3-methyl) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0092 g, 10%) and ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxywarbonyl-2-(1- acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0385 g, 40%).

()- (2R, 3S, 5R, 1'R, 2'S) MS: (M+H) += 455, (M+Na)+= 477, (2M+Na) +=931, (M-H)-=453.

()- (2R, 3S, 5R, 1'R, 2'R) MS: (M+H) += 455, (M+Na) += 477, (2M+Na) += 931, (M-H)-= 453. EMI231.1 STDC070556B %(#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-methyl)butyl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- t-butylacetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ester (yield: 0.010 g, 100%).

1H NMR (DMSO-d6) d 7.63 (d, J=9.2Hz, 1H), 5.48 (m, 1H), 5.23 (m, 1H), 4.44 (m, 1H), 4.24 (m, 1H), 3.57 (t, J=8.7Hz, 1H), 3.33 (dd, J=8.5,2.5Hz, 1H), 3.21 (quint., J=9.1Hz, 1H), 2.43 (dt, J=12.8,7.6Hz, 1H), 1.81 (s, 3H), 1.73 (dt, J=12.8,10.4Hz, 1H), 1.56 (dd, J=6.7,1.9Hz, 3H), 1.55 (m, 1H), 0.94 (d, J=6.7Hz, 3H), 0.78 (d, J=6.7Hz, 3H).

MS: (M+H) + = 299, (M+Na) + = 321, (M-H)-= 297, (M+CF3COOH)-= 411, (2M-H)-= 595.

Example 57EMI232.1 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting (#)-(2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-methyl) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- t-butylacetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ester (yield: 0.0433 g, 100%).

1H NMR (DMSO-d6) d 7.88 (d, J=9.2Hz, 1H), 5.46 (m, 1H), 5.29 (m, 1H), 4.26 (t, J=8.5Hz, 1H), 4.11 (m, 1H), 3.67 (m, 1H), 3.39 (dd, J=9.8,1.8Hz, 1H), 3.15 (quint., J=9.1Hz, 1H), 2.42 (dt, J=12.8,7.9Hz, 1H), 1.81 (s, 3H), 1.73 (m, 1H), 1.62 (m, 1H), 1.57 (dd, J=7.0,1.6Hz, 3H), 0.88 (d, J=6.7Hz, 3H), 0.75 (d,J=6.7Hz, 3H).

MS: (M+H) + = 299, (M+Na) + = 321, (M-H2O)+=281, (M-H)-=297, (M+CF3COOH)-= 411, (2M-H)-= 595.

Example 58 ()- (2R. 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-hvdroxv) hexyl-3- (cis-propen-1-v pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.EMI233.1 STDC023458A ()- (2R. 3S. 5R. 1'R. 2'S) and ()- (2R, 3S. 5R. 1'R. 2'R)-1-t-Butoxvcarbonyl-2- (1-acetamido-2-hydroxv) hexyl-3- (cis-propen-1-yl)-pvrrolidine-5-carboxylic Acid tButylEster.

The title compounds were prepared according to the method described inExample 41 B, substituting butyl magnesium bromide for ethyl magnesium bromide to provide ()- (2R, 3S, 5R, 1'R, 2'S)-1-t butoxycarbonyl-2- (1-acetamido-2- hydroxy) hexyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 2.0 mg, 8%) and ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2- (1-acetamido-2hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield:STDC0813 6.0 mg, 24%).EMI233.2 58B()- (2R. 3S. 5R, 1'R, 2'S)-2- (1-Acetamido-2-hydroxv) hexyl-3- (cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) heXyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t- butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 2.0 mg, 100%).

1H NMR (DMSO-d6) # 8.34 (d, J=9.3Hz, 1H), 5.24 (m, 1H), 5.12 (m, 1H), 3.90 (m, 1H), 3.78 (m, 1H), 3.23 (m, 1H), 2.90 (m, 1H), 2.14 (m, 1H), 1.80 (m, 1 H), 1.75 (s, 3H), 1.52 (m, 3H), 1.45 (m, 1 H), 1.08 (br s, 6H), 0.83 (br t, 3H).

MS: (M-H)-= 311; (M+H) + = 313.

Example 59EMI234.1 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t butoxycarbonyl-2- (1- acetamido-2-hydroxy) hexyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t- butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido2-hydroxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 6.0 mg, 100%).

1H NMR (DMSO-d6) # 7.60 (d, J=9.3 Hz, 1H), 5.46 (m, 1H), 5.24 (t, J=9.2Hz, 1 H), 4.21 (t, J=8.3 Hz, 1 H), 4.02 (t, J=7.9Hz, 1 H), 3.74 (m, 1 H), 3.47 (t, J=8.8, 1H), 3.12 (m, 1H), 2.37 (m, 1H), 1.81 (s, 3H), 1.64 (m, 1H), 1.55 (dd, J=1.5,5.4Hz, 3H), 1.29 (m, 6H), 0.86 (t, J=6.9,3H) -234 MS: (M-H)-= 311; (M+H)+= 313, (M+Na) + = 335.

Example 60 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-4-methyl)pentyl-3-(cis-propen- 1-yl)-pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt.EMI235.1 STDC023760A (#)-(2R,3S,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-4- methyl) pentyl-3- (cis-propen-1-vl)-pvrrolidine-5-carboxylic Acid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41 B, substituting isobutyl magnesium bromide for ethyl magnesium bromide to provide ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2- (1-acetamido-2 hydroxy-4-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 31 mg, 51%).

()- (2R, 3S, 5R, 1'R, 2'R)'H NMR (CDC13) 8 5.98 (d, J=9.5Hz, 1H), 5.61 (t, J=8.2Hz, 1H), 5.35 (m, 1H), 4.51 (dd, 1Hz, 1H), 4.15 (m, 1H), 3.74 (d, J=10.5Hz, 1H), 3.61 (m, 2H), 3.09 (t, J=7.5Hz, 1H), 2.71 (m, 1H), 2.02 (s, 3H), 1.81 (d, J=13.9Hz, 1H), 1.58 (brs, 1H), 1.54 (dd, J=1.7,5. 1Hz, 3H), 1.47 (s, 9H), 1.45 (s, 9H), 1.42 (m, 1 H), 0.87 (dd, J=2.4,6.7Hz, 6H) MS: (M-H)-= 467; (M+H) + = 469, (M+Na) + = 491. EMI236.1 STDC0204 60B ()- (2R, 3S, 5R, 1'R)-1-t-Butoxvcarbonvl-2-(1-acetamido4-methvl-2- oxo) pentyl-3 (cis-propen-1-vl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'R, 2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-4methyl) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (8.0 mg, 0.02 mmol) was reacted with Dess-Martin Periodinane (10 mg, 0.03 mmol) in dichloromethane (0.1 mL) at room temperature for 1 hour. The reaction was quenched with 1 M aqueous sodium thiosulfate 1 mL and stirred for 20 minutes.

The reaction was extracted with dichloromethane (3 x 1 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1: 1: ethyl acetate/hexane to provide the title compound as a colorless semi-solid (yield: 4.8 mg, 61%).EMI236.2 STDC023760C (#)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-4- methvl) pentyl-3- (cis-nronen-1-vl)-nyrrolidine-5-carboxylic Acid t-Butvi Ester.

()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl-2-(1-acetamido-4-methyl-2oxo) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (4.8 mg, 0.01 mmol) in methanol (0.1 mL) was reacted with sodium borohydride (2.0 mg, 0.05 mmol) at room temperature for 0.5 hours. The solvent was removed in vacuo and water (1 mL) was added. The aqueous layer was extracted with dichloromethane (3 x 1 mL). This organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.STDC0399 The residue was purified by column chromatography on silica gel using 1: 1 ethyl acetate/hexane to provide the title compound ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido-hydroxy4-methyl) pentyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield : 2. 4 mg, 51 %). EMI237.1 STDC0736 60B(#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-4-methyl)pentyl-3-(cis- sropen-1-vl)-Pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-4-methyl) pentyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4.4 mg, 100%).

'H NMR (D20) 6 5.45 (m, 1H), 5.15 (t, J=11. 0Hz, 1H), 3.88 (m, 1H), 3.62 (t, J=8. 0Hz, 1 H), 3.43 (br t, 1 H), 2.98 (m, 1 H), 2.36 (m, 1 H), 1.81 (s, 3H), 1.60 (m, 1H), 1.51 (m, 1H), 1.45 (dd, J=1.3,5.4Hz, 3H), 1.17 (m, 3H), 0.74 (dd, J=6.7, 14Hz, 6H) MS: (M-H)-= 311; (M+H) + = 313, (M+Na) + = 335.

Example 61EMI238.1 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-4-methyl)pentyl-3-(cis-propen- 1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t butoxycarbonyl-2- (1- acetamido-2-hydroxy-4-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 1.7 mg, 85%).

1 H NMR (DMSO-d6) 8 7.61 (d, J=9.8Hz, 1H), 5.45 (m, 1H), 5.24 (t, J=7.4Hz, 1 H), 4.29 (br t, 1 H), 4.0 (br t, 1 H), 3.83 (m, 1 H), 3.49 (t, J=8.8Hz, 1 H), 3.13 (m, 1H), 2.39 (m, 1H), 1.82 (s, 3H), 1.68 (m, 2H), 1.55 (dd, J=1.4,5.4Hz, 3H), 1.31 (m, 1H), 1.04 (m, 1H), 0.86 (dd, J=6.4,8.3Hz, 6H) MS: (M-H)-= 311; (M+H) + = 313, (M+Na) + = 335.

Example 62 (i)-(2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-hydroxy) pent-3-vnyl)-3-(cis-propen-1- vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.EMI239.1 STDCDBPG0205*62A ()- (2R. 3S. 5R. 1'R. 2'S) and (i)-(2R, S, 5R, 1'R. 2'R)-1-t-Butoxycarbonyl-2-(1- Acetamido-2-hydroxy)pent-3-ynyl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboyxlicAcid Ester.

The title compounds were prepared according to the method described inExample 41 B, substituting propyn-1-yl zinc for ethyl magnesium bromide to provide ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido-2hydroxy) pent-3-ynyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0073 g, 16%) and ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy)pent-3-ynyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0349 g, 77%).

()- (2R, 3S, 5R, 1'R, 2'S) MS: (M+H) +=451, (M+Na) +=473, (2M+Na) +=923,. (M-H)-=449.

()- (2R, 3S, 5R, 1'R, 2'R) MS: (M+H) += 451, (M+Na) +=473, (2M+Na) +=923, (M-H)-=449. EMI240.1 STDC0706 62B()- (2R, 3S, 5R. 1'R. 2'S)-2- (1-Acetamido-2-hvdroxy) pent-3-ynvl)-3- (cis- propen-1-vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy)pent-3-ynyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl)-2-(1acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0052 g, 100%).

'H NMR (DMSO-d6) d 7.97 (d, J=8.3 Hz, 1H), 5.48 (m, 1H), 5.25 (m, 1H), (m, 3H), 3.67 (m, 1H), 3.18 (quint., 8.8Hz, 1H), 2.41 (dt, J=12.7,7.8Hz, 1H), 1.84 (s, 3H), 1.81 (d, J=1.9Hz, 3H), 1.63 (m, 1H), 1.59 (dd, J=6.9,2. 0Hz, 3H).

MS: (M-H)-=293,(M+CF3COO-)-=407,(2M-(M+Na)+=317, H)-=587.

Example 63EMI241.1 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy)pent-3-ynyl)-3-(cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) pent-3-ynyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0540 g, 100%).

1H NMR (DMSO-d6) d 7.90 (d, J=8.8 Hz, 1H), 5.50 (m, 1H), 5.25 (m, 1H), 4.40-4.35 (m, 2H), 4.28 (m, 1H), 3.71 (t, J=8.0 Hz, 1H), 3.18 (quint., 8.3Hz, 1H), 2.42 (dt, J=13.2,7.4Hz, 1H), 1.87 (s, 3H), 1.82 (d, J=1.9Hz, 3H), 1.71 (dt, J=12.7, 10.0Hz, 1H), 1.57 (dd, J=6.9,1.5Hz, 3H).

MS: (M+H) += 295, (M+Na) + = 317, (M-H)-=293, (M+CF3COO-)-=407.

Example 64 (#)- (2R, 3S, 5R. 1'R. 2'R)-2- (1-Acetamido-2-hvdroxv-2-heptafluoropropvl ethvl-3- (cis-propen-1-vl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI242.1 64A (i)-(2R. 3S. 5R. 1'R. 2'R)-1-t-Butoxvcarbonyl-2-(1-acetamido-2-hydroxy-2- heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-ButylEster.

()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl 2-(1-acetamido-1-formyl) methyl-3 (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (41 mg, 0.10 mmol) and heptafluoropropyl iodide (0.144 mL, 1.0 mmol, 10 equivalents) in THF (2 mL) were reacted with 1 M phenylmagnesium bromide (0.90 mL, 0.90 mmol, 9 equivalents) at-78 C for 5 minutes. The reaction mixture was allowed to warm to room temperature over 1 h. The reaction was quenched with saturated aqueous ammonium chloride (10 mL) and water (10 mL) followed by extraction using ethyl acetate (3 X 25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.STDC0396 The residue was purified by column chromatography on silica gel using 1/2: ethyl acetate/hexane to provide the title compound ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl 2- (1-acetamido-2-hydroxy- 2-heptafluoropropyl) ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 12.6 mg, 22%).

()- (2R, 3S, 5R, 1'R, 2'R) MS: (M+H) +=581, (M+Na) +=603, (2M+Na) +=1183, (M-H)-=579. EMI243.1 STDC0763 64B ()- (2R. 3S. 5R. 1'R. 2'R)-2- (1-Acetamido-2-hvdroxv-2- heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcidTrifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-heptafluoropropyl) ethyl-3-(cis-propen-1-yl)-pyrrolidine-5carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl 2- (1-acetamido-2-hydroxy) butyl-3- (c/s-propen-1-yl)-pyrroiidine-5-carboxylicacid t- butyl ester (yield: 0.003 g, 100%).STDC0548 1H NMR (DMSO-d6) d 7.84 (d, J=9.3 Hz, 1H), 5.45 (m, 1H), 5.26 (m, 1H), 4.71 (t, J=9.7 Hz, 1H), 4.63 (d, J=22.0 Hz, 1H), 4.51 (m, 1H), 3.59 (t, J=9.3 Hz, 1H), 3.19 (quint., 8.3Hz, 1H), 2.43 (dt, J=12.7,7.3Hz, 1H), 1.76 (s, 3H), 1.74 (m, 1H), 1.53 (dd, J=6.8,1.4Hz, 3H).

MS: (M+H) + = 425, (M+Na) + = 447, (M-H)-= 423, (2M-1)-= 847.

Example 65 ()- (2R, 3S, 5R, 1'R. 2'S)-2-(1-Acetamido-2 4-dihydroxv) butyl-3-(cis-propen-1 pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI244.1 65A(i)-(2R, 3S, 5R, 1'R, 2'S)-1-t-Butoxvcarbonvl-2-(1-acetamido-2, 4- dihvdroxv) butvl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'R, 2'S)-1-t-Butoxycarbonyl-2- (1-acetamido-2-hydroxy-3- ethoxycarbonyl) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (35 mg, 0.07 mmol) was reacted with lithium borohydride (8 mg, 0.35 mmol) inTHF (5 mL) at 25 C and reacted for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL) and water (2 mL) followed by extraction using dichloromethane (2 X 10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.STDC0354 The residue was purified by column chromatography on silica gel using 5% methanol in dichloromethane to provide the title compound ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxywarbonyl 2-(1- t-acetamido-2,4-dihydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid butyl ester (yield: 14 mg, 44%).

()- (2R, 3S, 5R, 1'R, 2'S) =MS: (M+H)+=457, (M-H)-=455 EMI245.1 65B (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2,4-hydroxy)butyl-3-(cis-propen- 1-yl)pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2,4-dihydroxy) butyl 3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid tbutyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido2-hydroxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.

1H NMR (DMSO-d6) # 7. 93 (d, J=9. OHz, 1H), 5.56 (m, 1H), 5.31 (m, 1H), 4.43 (m, 1H), 4.14 (m, 1H), 3.69 (m, 1H), 3.63 (m, 1H), 3.23 (m, 2H), 3.07 (m, 1H), 2.43 (m, 1H), 2.06 (s, 3H), 1.83 (m, 2H), 1.79 (m, 1H), 1.62 (dd, J=6.71,1.22Hz, 3H) MS: (M+H) +=301, (M-H)-=299.

Example 66 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2,4-dihydroxy)butyl-3-(cis-propen-1-yl)- pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI246.1 66A (2R. 3S. 5R. 1'R. 2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2, 4t-ButylEster.dihydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboyxlicAcid The title compound was prepared according to the method described inExample 65A substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-ethoxycarbonyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl 2-(1-acetamido-2-hydroxy-3-ethoxycarbonyl)STDC0104 ethyl-3-(cis-propen-1-yl)-pyrrolidine- 5-carboxylic acid t-butyl ester. (yield: 11 mg, 70%).

1H NMR (CDC13) 8 5.58 (m, 1H), 5.38 (m, 1H), 4.16 (m, 1H), 4.05 (m, 1H), 3.97 (m, 1 H), 3.78 (m, 2H), 3.20 (m, 1 H), 2.66 (m, 1 H) 2.54 (m, 1 H), 2.04 (s, 3H), 1.80 (m, 1H), 1.55 (m, 2H), 1.47 (s, 9H), 1.44 (s, 9H) MS:STDC0816 (M+H) +=457, (M-H)-=455 EMI247.1 66B (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2,4-dihydroxy)butyl-3-(cis-propen- 1-yl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1acetamido-2,4-dihydroxy) butyl 3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid tbutyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t butoxycarbonyl-2- (1-acetamido- 2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 8 mg, 96%).

'H NMR (DMSO-d6) # 7.91 (d, J=9.1Hz, 1H), 5.50 (m, 1H), 5.25 (m, 1H), 4.43 (m, 1 H), 4.30 (m, 1 H), 4.22 (m, 1 H), 3.94 (m, 1 H), 3.86 (m, 1 H), 3.62 (m, 1H), 3.18 (m, 1H), 2.43 (m, 1H), 1.85 (s, 3H), 1.75 (m, 1H), 1.65 (m, 2H), 1.58 (dd, J=6.70,1.81 Hz, 3H).

MS: (M+H) +=301, (M-H)-=299.

Example 67 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-(phenylacetylen-1-yl))ethyl-3- (cis-propen-1-ipvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI248.1 67A (#)-(2R,3S,5R,1'R, 2'R) and (i)-(2R. 3S. 5R. 1'R. 2'S)-1-t-Butoxvcarbonyl-2- (1-acetamido-2-hydroxy-2-(phenylacetylen-2-yl))ethyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxvlic Acid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41 B, substituting lithium phenylacetylide for ethyl magnesium bromide to provide ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido-2-hydroxy- 2- (phenylacetylen-1-yl)) ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic(phenylacetylen-1-yl)) ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid tbutyl ester (yield: 0.0010 g, 4%) and ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl- 2- (1-acetamido-2-hydroxy-2- (phenylacetylen-1-yl)) ethyl-3- (cis-propen-1-yl)pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0050 g, 21%).

()- (2R, 3S, 5R, 1'R, 2'S) MS: (M+H) +=513, (M+Na) +=535, (2M+Na) +=1047, (M-H)-=511.

()- (2R, 3S, 5R, 1'R, 2'R) MS: (M+H) +=513, (M+Na) +=535, (2M+Na) +=1047, (M-H)-=511. EMI249.1 STDC074167B (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-(phenylacetylen-1- yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound is prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2- (phenylacetylen-1-yl)) ethyl-3- (cis-propen-1-yl)-pyrrolidine- 5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-tbutoxycarbonyl-2-(1-acetamido-2-hydroxy)-butyl-3-(cis-propen-1-yl)-pyrrolidine-5carboxylic acid t-butyl ester.

Example 68 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-2-(phenylacetylen-1-yl))ethyl- 3- (cis-propen-1-vl)-yrrolidine-5-carboxrlic Acid Trifluoroacetic Acid SaltEMI249.2 68A (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-2-(phenylacetylen-1- vl)) ethyl-3- (cis-propen-1-yl-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t butoxycarbonyl-2- (1- acetamido-2-hydroxy-2- (phenylacetylen-1-yl)) ethyl-3- (cis-propen-1-yl)-pyrrolidine- 5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)STDC0174-1-t butoxycarbonyl-2- (1-acetamido-2-hyd roxy) butyl-3- (cis-propen-1-yl)-pyrrolid ine-5- carboxylic acid t-butyl ester (yield: 0.0034 g, 100%).

1H NMR (DMSO-d6) 5 9.2 (bs, 1H), 8.04 (d, J=9.2 Hz, 1 H), 7.45-7.35 (m, 5H), 5.50 (m, 1 H), 5.29 (m, 1 H), 4.64 (d, J=4.9,1 H), 4.5-4.4 (m, 2H), 3.81 (m, 1H), 3.22 (quint., J=8.5Hz, 1H), 2.45 (dt, J=12.8,7.3Hz, 1H), 1.89 (s, 3H), 1.74 (dt, J=12.7, 10.0Hz, 1H), 1.58 (dd, J=7.3,1.8Hz, 3H).

MS: (M+H) + = 357, (M+Na) + = 379, (M-H)-= 355.

Example 69 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1- TrifluoroaceticAcidSaltyl)-pyrrolidine-5-carboxylicAcidEMI250.1 69A (#)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-oxo-3- ethvl) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 42A, substituting ()- (2R, 3S, 5R, 1'R, 2', R)-1-t-butoxycarbonyl-2-(1 acetamido-2-hydroxy-3-ethyl) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (2R, 3S, 5R, 1'R, 2'R)-l-t-butoxycarbonyl-2- (l- acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 8 mg, 81%).

MS: (M+H) +=481, (M-H)-=479 EMI251.1 69B (i)-(2R, 3S. 5R, 1'R, 2'S)-1-t-Butoxvcarbonvl-2-(1-Acetamido-2-hydroxv-3- t-ButylEster.ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid The title compound was prepared according to the method described inExample 42B, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2-(1-acetamido2-oxo-3-ethyl) pentyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl 2-(1-acetamido-2-oxo)butyl-3-(cispropen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 5 mg, 63%).

MS: (M+H) +=483, (M-H)-=481EMI251.2 69C (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis- propen-1-yl)-pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-ethyl) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4 mg, 95%).

'H NMR (DMSO-d6) b 7.67 (d, J=8.9Hz, 1H), 5.48 (m, 1H), 5.23 (m, 1H), 4.42 (m, 1H), 4.21 (m, 1H), 3.58 (m, 2H), 3.22 (m, 1H), 2.43 (m, 1H), 1.82 (s, 3H), 1.74 (m, 1H), 1.58 (dd, J=6.71,1.23 Hz, 3H), 1.52 (m, 1H), 1.38 (m, 1H), 1.29 (m, 2Hz), 1.13 (m, 1H), 0.80 (m, 6H) MS:STDC0457 (M+H) +=327, (M-H)-=325 Example 70 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1- vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI252.1 70A (#)-(2R,3S,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-3- ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 41 B, substituting 3-pentyl magnesium bromide in place of ethyl magnesium bromide (yield: 13mg, 45%).

MS: (M+H) +=483, (M-H)-=481 EMI253.1 70B (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis- TrifluoroaceticAcidSaltpropen-1-yl)-pyrrolidine-5-carboxylicAcid The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (#)-(2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1t-butylacetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ester (yield: 3 mg, 96%).

'H NMR (DMSO-d6) # 7.85 (d, J=9.2 Hz, 1H), 5.47 (m, 1H), 5.30 (m, 1H), 4.28 (m, 1H), 4.19 (m, 1H), 3.67 (m, 1H), 3.58 (m, 1H), 3.17 (m, 1H), 2.43 (m, 1H), 1.81 (s, 3H), 1.63 (m, 1H), 1.58 (dd, J=6.71,1.82 Hz, 3H), 1.40 (m, 2H), 1.28 (m, 1H), 1.10 (m, 1H), 1.05 (m, 1H), 0.83 (m, 6H) MS:STDC0522 (M+H) +=327, (M-H)-=325 Example 71 ()- (2R. 3S, 5R. 1'R. 2'R)-2- (1-Acetamido-2-hydroxy-2-phenvl ethvl-3- (cis-propen-1- vD-pyrrolidine-S-carboxylic Acid Trifluoroacetic Acid SaltEMI254.1 71A(#)-(2R,3S,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-2- phenyl) et (cispropen-1-vl)-pvrrolidine-5-carboxvlic(cispropen-1-vl)-pvrrolidine-5-carboxvlic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 41 B, substituting phenyl magnesium bromide in place of ethyl magnesium bromide (yield: 36 mg, 60%).

MS: (M+H)+= 489, (M+Na) += 511, (M-H)-= 487. EMI254.2 STDC0741 71 B - (2R, 3S, 5R. 1'R. 2'R)-2- (1-Acetamido-2-hydroxy-2-phenvl) ethvl-3- (cis- propen-1-vl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrroiidine-5-carboxylic acid t-butyl ester (yield: 5.5 mg, 100%).

1H NMR (DMSO-d6) d 7.79 (d, J= 9.2Hz, 1H), 7.36 (m, 2H), 7.31 (m, 2H), 7.22 (m, 1 H), 5.49 (m, 1 H), 5.22 (m, 1 H), 4.94 (d, J= 3.0Hz, 1 H), 4.52 (m, 1 H), 4.35 (m, 1 H), 3.62 (t, J= 8.5Hz, 1 H), 3.22 (m, 1 H), 2.46 (m, 1 H), 1.77 (m, 1 H), 1.65 (s, 3H), 1.57 (dd, J= 6.7,0.8Hz, 3H).

MS: (M+H) += 333, (M+Na) + = 355, (M-H)-= 331.

Example 72 ()- (2R. 3S, 5R, 1'R. 2'S)-2- ! 1-Acetamido-2-hvdroxy-2-phenyl) ethyl-3- (cis-propen-1- yrlLpvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI255.1 72A ()- (2R, 3S. 5R. 1'R)-1-t-Butoxvcarbonyl-2 (1-Acetamido-2-oxo-2- phenvl) ethyl-3- (cis-propen-1-vl)-pvrrolidine-5-carboxyiic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 42A, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (2R, 3S, 5R, 1'R, 2'R)-1-t butoxycarbonyl 2- (1- t-butylacetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ester (yield: 24 mg, 84%).

MS: (M+H) += 487, (M+Na) += 509, (M-H)-= 485. EMI256.1 STDC021072B (#)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-2- phenvrL) ethyl-3- (cis-propen-1-vl)-pyrrolidine-5-carboxylic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 42B, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2- (1-acetamido2-oxo-2-phenyl) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl 2-(1-acetamido-2-oxo)butyl-3-(cispropen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 7.9 mg, 52%).

MS: (M+H) += 489, (M+Na) += 520, (M-H)-= 487.EMI256.2 STDC079772C (?)-(2R. 3S. 5R. 1'R. 2'S)-2-(1-Acetamido-2-hvdroxv-2-nhenvl) ethvl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-phenyl) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- t-butylacetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ester (yield: 7.5 mg, 100%).

'H NMR (DMSO-d6) d 7.83 (d, J= 9.2Hz, 1H), 7.36 (m, 2H), 7.32 (m, 2H), 7.25 (m, 1 H), 5.47 (m, 1 H), 5.33 (m, 1 H), 4.54 (d, J= 9.8Hz, 1 H), 4.36 (m, 1 H), 4.23 (m, 1 H), 3.78 (m 1 H), 3.20 (m, 1 H), 2.43 (m, 1 H), 1.63 (m, 1 H), 1.56 (dd, J= 6.7,1.2Hz, 3H), 1.53 (s, 3H).

MS: (M+H) += 333, (M+Na) += 355, (M-H)-= 331.

Example 73 ()- (2R. 3S. 5R. 1'R. 2'R)-2- (1-Acetamido-2-hydroxy-2- (thiophen-2-yl)) ethyl-3- (cis- propen-1-vl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI257.1 73A (i)-(2R. 3S. 5R. 1'R, 2'R)-1-t-Butoxvcarbonyl-2-(1-acetamido-2-hydroxy-2- (thiophen-2-yl)) ethyl-3-!-pvrrolidine-5-carboxviic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl 2- (1-acetamido-2-formyl) ethyl-3(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (40 mg, 0.098 mmol) inTHF (2 mL) was added dropwise to a solution of 2-thienyllithium (1 M in THF, 0.505 mmol, 5 equivalents) in THF (1 mL) at 25 C and reacted for 20 minutes.

The reaction was quenched with saturated aqueous ammonium chloride (2 mL) and water (5 mL) followed by extraction using dichloromethane (2 X 10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/1: ethyl acetate/hexane to provide the title compound (yield: 9.5 mg, 20%).

MS: (M+H) += 495, (M+Na) += 517, (M-H)-= 493. EMI258.1 STDC076773B (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-2-(thiophen-2-yl))ethyl- 3- !-pvrrolidine-5-carboxviic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy-2-(thiophen-2-yl)) ethyl-3-(cis-propen-1-yl)-pyrrolid ine-5- carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl 2- (1-acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t- butyl ester (yield: 4.3 mg, 100%).

'H NMR (DMSO-d6) 8 7.86 (d, J= 9.8Hz, 1H), 7.63 (dd, J= 5.4,1.0 Hz, 1H), 7.07 (m, 1 H), 6.98 (m, 1 H), 5.58 (m, 1 H), 5.43 (m, 1 H), 4.55 (m, 1 H), 4.39 (m, 1H), 3.72 (m, 1H), 3.11 (m, 2H), 2.43 (m, 1H), 2.04 (s, 3H), 1.80 (m, 1H), 1.57 (m, 3H).

MS: (M+H) += 339, (M+Na) + = 361, (M-H)-= 337.

Example 74 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl- 3- (cis-propen-1-vl)-pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI259.1 74A (t)- (2R. 3S, 5R, 1'R, 2'S and ()- (2R. 3S. 5R. 1'R. 2'R)-1-t-Butoxvcarbonyl-2- (1-Acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic Acid t-Butyl Ester.

1.6 M n-Butyllithium (0.125 mL, 0.20 mmol, 4 equivalents) was added to a solution of 2,4-dimethylthiazole (28.3 mg, 0. 25 mmol, 5 equivalents) in 1 mL ofTHF at-78 C and reacted for 30 minutes. ( ()- (2R, 3S, 5R, 1'R)-1-t- butoxycarbonyl 2-(1-acetamido-2-formyl) ethyl-3-(cis-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester (20.5 mg, 0.050 mmol) in THF (1 mL) was added dropwise to the above solution and reacted for 30 minutes at-78 C and then for 30 minutes at room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) and water (5 mL) followed by extraction using dichloromethane (3 X 25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.STDC0641 The residue was purified by column chromatography on silica gel using 1/2: ethyl acetate/hexane to provide ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3- (4-methylthiazol-2-yl)) propyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid tbutyl ester (yield: 3.3 mg, 13%) and ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl- 2- (1-acetamido-2-hyd roxy-3- (4-methylthiazol-2-yl)) propyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylic acid t-butyl ester (yield: 7.5 mg, 29%).

(2R, 3S, 5R, 1'R, 2'S) MS: (M+H) +=524, (M+Na) +=546, (2M+Na) +=1069, (MH)-=522.

(2R, 3S, 5R, 1'R, 2'R) MS: (M+H) +=524, (M+Na) +=546, (2M+Na) +=1069, (MH)-=522.EMI260.1 STDC080474B (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-(4-methylthiazol-2- vl)) propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic AcidSalt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3- (4-methylthiazol-2-yl)) propyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t butoxycarbonyl-2- (1-acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester (yield: 0.0030 g, 100%).

1 H NMR (DMSO-d6) 8 9. 0 (bs, 1 H), 8.10 (d, J=8.3Hz, 1 H), 7.11 (d, J=1.0 Hz, 1H), 5.48 (m, 1H), 5.30 (m, 1H), 4.30 (m, 1H), 4.10 (m, 1H), 3.88 (dt,J=9.4,2.6Hz, 1H), 3.78 (m, 1H), 3.25-3.15 (m, 2H), 2.93 (dd, J=15.1,8.3Hz, 1H), 2.41 (dt, J=12.3,7.3Hz, 1H), 2.33 (d, J=1.0Hz, 3H), 1.86 (s, 3H), 1.66 (dt, J=12.7, 10.3Hz, 1H), 1.61 (dd, J=6.8,1.5Hz, 3H).

MS: (M+H) + = 368, (M+Na) + = 390, (M-H)-= 366.

Example 75 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl- 3- (cis-propen-1-yl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI261.1 The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-f-butoxycarbonyl-2- (1acetamido-2-hydroxy-3- (4-methylthiazol-2-yl)) propyl-3- (cis-propen-1-yl)pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t butoxycarbonyl-2- (1-acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester (yield: 0.0030 g, 100%).

'H NMR (DMSO-d6) d9.0 (bs, 1H), 7.77 (d, J=9.3Hz, 1H), 7.11 (s, 1H), 5.47 (m, 1H), 5.25 (m, 1H), 4.45 (m, 1H), 4.20 (m, 2H), 3.58 (t, J=9.1Hz, 1H), 3.19 (m, 1H), 2.96 (m, 2H), 2.41 (m, 1H), 2.33 (d, J=1.0Hz, 3H), 1.85 (s, 3H), 1.73 (dt, J=12.7,10.3Hz, 1H), 1.54 (dd, J=6.9,1.5Hz, 3H).

MS: (M+H)+= 368, (M+Na) + = 390, (M-H)-= 366, (M+CF3COOH)-=480, (2M-H)-=733.

Example 76 ()- (2R, 3S. 5R, 1'R, 2'RS)-2- (1-Acetamido-2-hvdroxy-3- (thiazolin-2-vl)) propvl-3- cis-propen-1-yl)-pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI262.1 76A ()- (2R, 3S, 5R, 1'R, 2'RS)-1-t-Butoxywarbonyl-2-(1-Acetamido-2- hydroxy-3- (thiazolin-2-yl)) propyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester ()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl 2- (1-acetamido-2-formyl) ethyl-3 (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (20.5 mg, 0.05 mmol) in THF (1 mL) was added dropwise to a solution of the (thiazolin-2-yl) methyl lithium (0.20 mmol, 4 equivalents,STDC0609 prepared from 0.025 g of 2-methylthiazoline and 0.125 mL of 1.6 M n-BuLi at-78 C) in THF (2 mL) at-78 C and reacted for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and water (5 mL) followed by extraction using dichloromethane (3X 20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/1: ethyl acetate/hexane to provide the title compound as a mixture of isomers (yield: 10 mg, 40%).STDC0063 MS: (M+H) += 512, (M+Na) +=534, (M-H)-=510. EMI263.1 STDC077476B (#)-(2R,3S,5R,1'R,2'RS)-2-(1-Acetamido-2-hydroxy-3-(thiazlin-2- yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic AcidSalt The title compounds were prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'RS)-1-t-butoxycarbonyl-2- (1acetamido-2-hydroxy-3- (thiazolin-2-yl)) propyl-3- (cis-propen-1-yl)-pyrrolidine-5- carboxylic acid ()- (2R. 3S. 5R. 1'R. 2'S)-2-(1-Acetamido-2-hvdroxv-3.3-difluoro-3-vinvl)proDvl-3- (cis-propen-1-vl)-pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI264.1 77A ()- (2R. 3S.STDC0833 5R, 1'R, 2'S)-1-t-Butoxycarbonvl-2- (1-acetamido-2-hydrox-3, 3difluoro-3-vinvl) propyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxvlic Acid t-Butvl Ester ()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl 2-(1-acetamido-2-formyl) ethyl-3(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (41 mg, 0.10 mmol) and 1,1-difluoroallyl iodide (94 mg, 0.60 mmol, 6 equivalents) in THF (2 mL) was reacted with zinc dust (33 mg, 0.50 mmol, 5 equivalents) at 0 C for 5 minutes and then at room temperature for 4 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and water (15 mL) and extracted with 3 X 25 mL dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.STDC0149 The residue was purified by column chromatography on silica gel using 1/3: ethyl acetate/hexane to provide the title compound (yield: 35 mg, 71%).

MS: (M+H)+=489, (M+Na) +=511, (2M+Na) +=999, (M-H)-=487. EMI265.1 STDC079977B ()- (2R, 3S, 5R, 1'R. 2'S)-2- (1-Acetamido-2-hvdroxv-3,3-difluoro-3- vinyl) prop. yl-3- (cis-propen-1-vl)-pyrrolidine-5-carboxvlic Acid Trifluoroacetic AcidSalt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1 acetamido-2-hydroxy-3,3-difluoro-3-vinyl) propyl-3- (cis-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbobyl 2- (1-acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t- butyl ester (yield: 0.0026 g, 96%).

1H NMR (DMSO-d6) d7.68 (d, J=7.8Hz, 1H), 5.97 (m, 1H), 5.55-5.45 (m, 2H), 5.43 (m, 1H), 5.23 (m, 1H), 4.45 (m, 2H), 4.10 (m, 1H), 3.16 (quint. J=9. 1Hz, 1H), 2.41 (dt, J=12.8,7.3Hz, 1H), 1.72 (s, 3H), 1.70 (dt, J=12.8,10.3Hz, 1H), 1.61 (dd, J=6.7,1.2Hz, 3H).

MS: (M+H)+=333, (M+Na)+=355, (M-H)-= 331, (2M-H)-=663.

Example 78 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3- (cis-propen-1-vl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI266.1 78A(i)-(2R. 3S, 5R. 1'R)-1-t-Butoxycarbonvl-2-(1-Acetamido-2-oxo-3.STDC0862 3-difluoro- t-ButylEster.3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid The title compound was prepared according to the method described inExample 42A, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1acetamido-2-hydroxy-3,3-difluoro-3-vinyl) propyl-3- (cis-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester in place of (2R, 3S, 5R, 1'R, 2'R)-2- (1-acetamido-2hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester to provide ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2- (1-acetamido-2-oxo-3, 3-difluoro- 3,3-difluoro-3-vinyl) propyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0050g, 44%).

MS: (M+H) +=487, (M+Na) +=509, (M-2F) +=448, (M-H)-=485. EMI267.1 STDC022278B (#)-(2R,3S,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-)1-Acetamido-2-hydroxy-3,3- difluoro-3-vinvl) propvl-3- (cis-propen-1-vl)-pvrrolidine-5-carboxvlic Acid t-ButylEster.

The title compound is prepared according to the method described inExample 42B, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2- (1-acetamido 2-oxo-3-difluoro-3-vinyl) propyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t- butyl ester in place of (2R, 3S, 5R, 1'R)-2- (1-acetamido-2-oxo) butyl-3- (cis-propen- 1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.EMI267.2 STDC073878C ()- (2R. 3S, 5R. 1'R. 2'R)-2- (1-Acetamido-2-hvdroxv-3.3-difluoro-3- vinvl) propvl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxic Acid Trifluoroacetic Acid The title compound is prepared according to the method described in Example 41C, substituting (t)- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2- (1acetamido-2-hydroxy-3,3-difluoro-3-vinyl) propyl-3- (cis-propen-1-yl)-pyrrolidine-5carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl 2-(1-acetamido-2-hydroxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t- butyl ester.

Example 79 ()- (2R, 3S. 5R, 1'R. 2'R)-2- (1-Acetamido-2-hydroxy-2- (cis-buten-2-vl)) v(cis- propen-1-yl)-pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI268.1 79A(#)-(2R,3S,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-2 (cis-buten-2-vl)) ethyl-3- (cis-propen-1-vl)-pyrrolidine-5-carboxvlic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl 2-(1-acetamido-2-formyl) ethyl-3 (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (30 mg, 0.073 mmol) in THF (5 mL) was reacted with cis-2-buten-2-yl lithium (0.75 mL (0.5M), 0.37 mmol) at 25 C for 45 min. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and water (5mL) followed by extraction using dichloromethane (2 X 10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/1: ethyl acetate/hexane to provide the title compound (yield: 20 mg, 59%).

H NMR (CDC13) 8 6.19 (d, J=8.9 Hz, 1H), 5.61 (m, 1H), 5.35 (m, 1H), 5.27 (m, 1 H), 4.48 (m, 1 H), 4.18 (m, 1 H), 4.77 (m, 2H), 3.10 (m, 1 H), 2.72 (m, 1 H), 1.99 (s, 3H), 1.82 (m, 1H), 1.73 (m, 3H), 1.55 (m, 6H), 1.47 (s, 9H), 1.44 (s, 9H) MS:STDC0737 (M+H) += 467, (M-H)-= 465 EMI269.1 79B(#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-2-(cis-buten-2-yl))ethyl- 3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy-2- (cis-buten-2-yl)) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonylt-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid butyl ester (yield: 4 mg, 96%).

1H NMR (DMSO-d6) 8 8.09 (d, J=9.0 Hz, 1H), 5.50 (m, 1H), 5.32 (m, 1H), 5.16 (m, 1H), 4.50 (m, 1H), 4.38 (m, 1H), 4.19 (m, 1H), 3.43 (m, 1H), 3.20 (m, 1H), 2.43 (m, 1H), 1.88 (s, 3H), 1.74 (m, 1H), 1.70 (s, 3H), 1.62 (m, 3H), 1.58 (m, 3H) MS:STDC0560 (M+H) +=311, (M-H)-=309 Example 80 ()- 2R, 3S, 5R. 1'R, 2'R, 3'R) and ()- (2R, 3S. 5R. 1'R. 2'R. 3'S)-2- (1-Acetamido-2hvdroxv-3-methvl)pentyl-3- (cis-propen-1-vl)vrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI270.1 and(#)-(2R,3S,5R,1'R,2'R,3'S)-1-t-80A(#)-(2R,3S,5R,1'R,2'R,3'R)Butoxvcarbonvl-2- 1-acetamido-2-hydroxv-3-methvl) pentvl-3- (cis-propen-1-yl)- pvrrolidine-5-carboxylic Acid -Butvl Ester.

()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl 2-(1-acetamido-1-formyl) methyl-3(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (60 mg, 0.15 mmol) inTHF (1 mL) was added dropwise to a solution of 2-butylmagnesium bromide (3M in ether) (0.45 mL, 0.85 mmol) at room temperature and reacted for 40 minutes.

The reaction was quenched with saturated NH4C1 (1 mL) followed by extraction using dichloromethane (3 x 1 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/4: ethyl acetate/hexane to provide the title compounds ()- (2R, 3S, 5R, 1'R, 2'R, 3'S)-1-t-butoxycarbonyl 2- (1-acetamido-2- hydroxy-3-methyl) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester Rf= 0.65 (1: 1 ethyl acetate: hexanes) (yield:STDC0291 19 mg, 27%) and ()- (2R, 3S, 5R, 1'R, 2'R, 3'R)-1-t-bytoxycarbonyl 2-(1-acetamido-2-hydroxy-3methyl) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester Rf= 0. 5) (1: 1 ethyl acetate: hexanes) (yield: 19 mg, 27%).

Rf= 0. 65 1H NMR (CDCl3) # 5.98 (d, J=8.8Hz, 1 H), 5.62 (t, J=10.5Hz, 1H), 5.35 (m, 1H), 4.66 (d, J=4.4Hz, 1H), 4.16 (d, J=9.5Hz, 1H), 3.78 (m, 3H), 3.12 (m, 2H), 2.73 (m, 1H), 2.0 (s, 3H), 1.81 (d, J=13.2Hz, 1H), 1.54 (br s, 3H), 1.47 (s, 9H), 1.44 (s, 9H), 1.25 (m, 1 H), 0.81 (m, 6H) MS: (M-H)-= 467; (M+H) + = 469.

Rf= 0. 5 1H NMR (CDCl3) # 6.00 (d, J=10.2Hz, 1H), 5.61 (brt, 1H), 5.36 (m, 1H), 4.58 (d, J=4.7Hz, 1H), 4.14 (d, J=8.8Hz, 1H), 3.82 (m, 3H), 3.13 (m, 2H), 2.73 (m, 1 H), 1.99 (s, 3H), 1.80 (d, J=13.9Hz, 1 H), 1.54 (br s, 3H), 1.46 (s, 9H), 1.44 (s, 9H), 1.43 (m, 1 H), 0.97 (d, J=6.8Hz, 3H), 0.81 (t, J=7.2Hz, 3H) MS: (M-H)-= 467; (M+H) + = 469.EMI271.1 STDC066480B (#)-(2R,3S,5R,1'R,.2'R,3'S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3- (cis-propen-1-yl)eyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ()- (2R, 3S, 5R, 1'R, 2'R, 3'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy3-methyl) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (2.5 mg, 0.005 mmol) was reacted with trifluoroacetic acid (0.8 mL) in dichloromethane (0.2 mL) at room temperature for 6 hrs. The reaction was concentrated in vacuo overnight and triturated with acetonitrile (2 x 1 mL) to provide the title compound (yield: 2.0 mg, 100%).

1 H NMR (DMSO-d6) 8 7.68 (d, J=8.8Hz, 1 H), 5.45 (m, 1 H), 5.23 (t,J=7.3Hz, 1H), 4.24 (brt, 1H), 4.18 (m, 1H), 3.52 (t, J=7.3Hz, 1H), 3.45 (m, 1H), 3.16 (m, 1H), 2.38 (m, 1H), 1.83 (s, 3H), 1.68 (m, 1H), 4.8Hz, 3H), 1.37 (m, 2H), 0.99 (m, 1 H), 0.89 (d, J=6.8Hz, 3H), 0.79 (t, J=7.4Hz, 3H) MS: (M-H)-= 311; (M+H) + = 313, (M+Na) + = 335.

Example 81 (#)-(2R,3S,5R,1'R,2'R,3'R)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI272.1 The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'R, 3'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hyd roxy-3-methyl) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (Rf= 0.5,1: 1, ethyl acetate: hexanes) in place of (#)- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)bytyl-3-(cispropen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 1.6 mg, 76%).

1H NMR (DMS0-d6) # 7.55 (d, J=9.3Hz, 1H), 5.45 (m, 1H), 5.23 (m, 1H), 4.31 (brt, 1H), 4.20 (t, J=8.3Hz, 1H), 3.51 (t, J=9.3Hz, 1H), 3.43 (d, J=7.4Hz, 1H), 3.17 (m, 1H), 2.40 (m, 1H), 1.80 (s, 3H), 1.70 (m, 1H), 1.55 (dd, J=1.4, 5.4Hz, 3H), 1.36 (m, 2H), 1.14 (m, 1H), 0.84 (t, J=7.3Hz, 3H), 0.73 (d, J=6.9Hz, 3H) MS: (M-H)-= 311; (M+H)+= 313, (M+Na) + = 335.

Example 82 ()- (2R, 3S, 5R. 1'R. 2'S,3'S)-2- (1-Acetamido-2-hvdroxy-3-methyl) pentvl-3- (cis- propen-1-vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.EMI273.1 STDC020382A (#)-(2R,3S,5R,1'R,3RS)-1-t-Butoxycarbonyl-2-(1-acetamido-2-oxo-3- methvl) pentv (cis-propen-1-vl)-pvrrolidine-5-carboxylic Acid t Butyl Ester.

The title compound was prepared according to the method described inExample 42A, substituting ()- (2R, 3S, 5R, 1'R, 2'R, 3'RS)1-t-butoxycarbonyl-2-(1 acetamido-2-hydroxy-3-methyl) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'R) 1-t-bytoxycarbonyl-2-(1t-butylacetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid (yield: 12 mg, 63%).EMI273.2 STDC028382B ()- (2R, 3S. 5R. 1'R, 2'S, 3'S) and f)-f2R. 3S. 5R. 1'R. 2'S. 3'R)-14- Butoxycarbonvl-2- (1-acetamido-2-hvd roxy-3-methyl) pentyl-3- (cis-propen-1-yl)pyrrolidine-5-carboxylic Acid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 42B, substituting ()- (2R, 3S, 5R, 1'R, 3'RS)-1-t-butoxycarbonyl-2-(1acetamido-2-oco-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid f-butyl ester (Rf= 0.5 and 0.65,1: 1, ethyl acetate: hexanes) in place of (2R, 3S, 5R, 1'R)-2- (1-acetamido-2-oxo) butyl-3- (cis-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester to give ()- (2R, 3S, 5R, 1'R, 2'S, 3'S)-1-t butoxycarbonyl-2- (1-acetamido-2-hydroxy-3-methyl) pentyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylic acid t-butyl ester (Rf= 0.15,1: 1, ethyl acetate: hexanes) (yield:STDC0337 6.0 mg, 50%) and ()- (2R, 3S, 5R, 1'R, 2'S, 3'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hyd roxy-3-methyl) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (Rf= 0.10,1: 1, ethyl acetate: hexanes) (yield: 2.5 mg, 63%).EMI274.1 STDC078682C (#)-(2R,3S,5R,1'R,2'R,2'S,3'S)-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3- (cis-propen-1-vl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S, 3'S)-1-t-butoxycarbonyl-1-(1acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (Rf= 0.15,1: 1, ethyl acetate: hexanes) in place of ()- (2R, 3S, 5R, 1'Rj,2'S(-1-t-butoxyacrbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cispropen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 6.0 mg, 100%).

1H NMR (DMSO-d6) # 7.78 (d, J=9.2Hz, 1H), 5.42 (m, 1H), 5.29 (t, J=10.3Hz, 1H), 4.08 (m, 1H), 3.96 (brt, 1H), 3.51 (m, 2H), 3.08 (m, 1H), 2.33 (m, 1H), 1.78 (s, 3H), 1.56 (d, J=6.3Hz, 3H), 1.52 (m, 1H), 1.40 (m, 1H), 1.29 (m, 1H), 1.21 (m, 1 H), 0.84 (t, J=7.3Hz, 3H), 0.73 (d, J=6.9Hz, 3H) MS: (M-H)-= 311; (M+H) + = 313, (M+Na) + = 335.

Example 83 ()- (2R, 3S, 5R, 1'R, 2'S, 3'R)-21-Acetamido-2-hvdroxv-3-methvl)pentvl-3- (cis- propen-1-vl)-pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI275.1 The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S, 3'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-utyl ester (Rf= 0.10,1: 1 ethyl acetate: hexanes) in place of (#) (2R, 3S, 5R, 1'R,2'S)-1-t-bytoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cispropen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 2.5 mg, 100%).

1H NMR (DMSO-d6) 8 7.85 (d, J=8.7Hz, 1H), 5.45 (m, 1H), 5.29 (t,J=9.3Hz, 1H), 4.20 (m, 2H), 3.63 (t, J=8.3Hz, 1H), 3.42 (br d, 1H), 3.14 (m, 1H), 2.41 (m, 1H), 1.79 (s, 3H), 1.62 (m, 1H), 1.58 (d, J=5.4Hz, 3H), 1.43 (m, 2H), 1.0 (m, 1H), 0.88 (d, J=6.8Hz, 3H), 0.80 (t, J=7.3Hz, 3H) MS: (M-H)-=311 ; (M+H) + = 313, (M+Na)+ = 335.

Example 84 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)- pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI276.1 84A-(2R. 3S. 5R. 1'R, 2'S)-1-t-Butoxycarbonvl-2-(1-acetamido-2- methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Ester ()- (2R, 3S, 5R, 1'R, 2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2- hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (22 mg, 0.05 mmole) was reacted with methyl iodide (0.016 mL, 0.25 mmole), potassium hydroxide (14 mg, 0.25 mmole) and 18-crown-6 (0.7 mg, 0.0025 mmole) in N, N-dimethylformamide (2 mL) at room temperature for 23 hours.

Water (5 mL) was then added to the reaction mixture, followed by extraction with ether (2 x 10 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 66% ethyl acetate/hexanes to provide the title compound, as a colorless oil (yield: 5.2 mg, 23%).

MS: (M+H) += 455, (M-H)-= 453. EMI277.1 STDC068584B (#)-(2R,3S,5R,1'R,2'S)-1-(1-Acetamido-2-methoxy)bytyl-3-(cis-propen-1- vl)-pvrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-methoxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t- butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4.7 mg, 98%).

'H NMR (DMSO-d6) 5 7.96 (d, J= 9.2Hz, 1H), 5.50 (m, 1H), 5.24 (m, 1H), 4.25 (m, 2H), 3.70 (m, 1H), 3.23 (s, 3H), 3.19 (m, 2H), 2.40 (m, 2H), 1.86 (s, 3H), 1.68 (m, 2H), 1.62 (dd, J= 7.0,1.8Hz, 3H), 1.39 (m, 1H), 0.77 (t, J= 7.3Hz, 3H).

MS: (M+H) += 299, (M+Na) += 321, (M-H)-= 297 Example 85 ()- 5R. 1'R, 2'R)-2-(1-Acetamido-2-methoxv) butvl-3-(cis-nroPen-1-vl ! pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI278.1 85A(i)-(2R, 3S. 5R, 1'R, 2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2- methox butyl-3- (cis-propen-1-vl)-pvrrolidine-5-carboxylic Acid t-Butvl Ester ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-Butoxycarbonyl-2- (1-acetamido-2hydroxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (17 mg, 0.04 mmole) was reacted with methyl iodide (28 mg, 0.19 mmole), potassium hydroxide (8 mg, 0.19 mmole) and 18-crown-6 (0. 002 mmole) in N, Ndimethylformamide (1.5 mL) at room temperature for 6 hours.STDC0102 Water (5 mL) was then added to the reaction mixture, followed by extraction with ether (2 x 10 mL).

The organic layer was washed with water, and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound, (yield: 5 mg, 29%).

MS: (M+H) +=455, (M-H)-=453 EMI279.1 85B (#)-(2R,3Sj,5Rj,1'R,2'R)-2-(1-Acetamido-2-methoxy)bytyl-3-(cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- t-acetamido-2-methoxy)bytyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrroEidine-5-carboxylic(cis-propen-1-yl)-pyrroEidine-5-carboxylic acid t-butyl ester (yield: 4 mg, 95%).

1H NMR (DMSO-d6) d 8.00 (d, J=9.8HZ, 1H), 5.57 (m, 1H), 5.35 (m, 1H), 4.42 (m, 1H), 4.28 (m, 1H), 3.95 (m, 1H), 3.54 (m, 1H), 3.28 (s, 3H), 2.80 (m, 1H), 2.30 (m, 1H), 1.92 (s, 3H), 1.65 (m, 1H), 1.60 (m, 3H), 1.43 (m, 2H), 0.82 (t,J=7.31HZ, 3H).

MS: (M+H) +=299, (M-H)-=297 Example 86 (#)-(2R,3S,5Rj,1'Rj,2'S)-2-(1-Acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen- 1-vl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI280.1 86A )-2R. 3S. 5R, 1'R, 2'S)-1-t-Butoxvcarbonyl-2- (1-acetamido-2-methoxy-3- methvl) butvl-3- (cis-propen-1-vl)-yrrolidine-5-carboxylic Acid t-Butvl Ester The title compound is prepared according to the method described inExample 84A, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-)1 acetamido-2-hydroxy-3-methyl) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)STDC0161-1-t-butoxycarbonyl-2- (1acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.EMI280.2 STDC0689 86B(#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-3-methyl)bytyl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound is prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-methoxy-3-methyl) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1 acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.

Example 87 (f22R. 3S. 5R. 1'R, 2'R)-2- ( 1-Acetamido-2-methoxy-3-methyl) butvl-3- (cis-propen- 1-yl)-pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI281.1 86A (#)-(2R,3S,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-3- math butyl-3- (cis-propen-1-vl)-pvrrolidine-5-carboxvlic Acid t-Butyl Ester The title compound was prepared according to the method described inExample 84A, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy-3-methyl) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1acetamido-2-hydroxy)STDC0095 butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 6.8 mg, 33%).

MS: (M+H) += 469, (M+Na) += 491, (M-H)-= 467. EMI282.1 STDC0713 87B(#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-methoxy-3-methyl)bytyl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-methoxy-3-methyl)bytyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. ester (yield: 6.6 mg, 100%).

1H NMR (DMSO-d6) 8 7.65 (d, J= 9.2Hz, 1H), 5.43 (m, 1H), 5.23 (m, 1H), 4.42 (m, 1H), 4.37 (m, 1H), 3.56 (m, 1H), 3.46 (s, 3H), 3.17 (m, 2H), 2.44 (m, 1H), 1.80 s, 3H), 1.78 (m, 1H), 1.70 (m, 1H), 1.57 (dd, J= 6.7,1.2Hz, 3H), 0.94 (d, J= 6.7Hz, 3H), 0.82 (d, J= 6.7Hz, 3H).

MS: (M+H) += 313, (M+Na) + = 335, (M-H)-= 311.

Example 88 ()- (2R. 3S, 5R. 1'R. 2'S)-2- (1-Acetamido-2-methoxv) pentvl-3- (c/s-propen-1-vl)- TrifluoroaceticAcidSaltpyrrolidine-5-carboxylicAcidEMI283.1 88A (#)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2- methoxv) pentI-3- (cis-propen-1-yi)-pvrrolidine-5-carboxvlic Acid t-Butyl Ester The title compound was prepared according to the method described inExample 84A, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxyiic acid t- butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido2-hydroxy) butyl-3- (cis-propen-1-yl)STDC0069-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 11.9 mg, 36%).

MS: (M+H) += 469, (M+Na) += 491, (M-H)-= 467.EMI283.2 88B(#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)bytyl-3-(cis-propen-1- yl)-pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample <RTI ID=2 2-hydroxy)bytyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.

(yield: 11.5 mg, 100%).

1H NMR (DMSO-d6) # 7.95 (d, J=9.8Hz, 1H), 5. 49 (m, 1H), 5.23 (m, 1H), 4.25 (m, 2H), 3.68 (m, 1H), 3.24 (s, 3H), 3.22 (m, 1H), 3.18 (m, 1H), 2.40 (m, 1H), 1.85 (s, 3H), 1.66 (m, 1H), 1.62 (m, 3H), 1.58 (m, 1H), 1.38 (m, 1H), 1.27 (m, 2H), 0.86 (t, J= 7.3Hz, 3H).

MS: (M+H) += 313, (M+Na) +=335, (M-H)-= 311.

Example 89 #)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)- nvrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI284.1 89A (#)-(2R,3S,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2- methopentyl-3- (cis-propen-1-vl)-pvrrolidine-5-carboxvlic Acid t-Butyl Ester The title compound was prepared according to the method described inExample 84A, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) pentyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t- butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido- 2-hydroxy) butyl-3- (cis-propen-1-yl)STDC0068-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4.3 mg, 21%).

MS: (M+H) += 469, (M+Na) += 491, (M-H)-= 467. EMI285.1 STDC068989B (#)-(2R,3S,5R,1'Rj,2'R)-2-(1-Acetamido-2-methoxy)pentyl-3-)cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- t-acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido2-hydroxy) butyl-3- (cis-propen-1-yi)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4.8 mg, 100%).

1H NMR (DMSO-d6) 6 7.70 (d, J= 9.8Hz, 1H), 5.45 (m, 1H), 5.24 (m, 1H), 4.40 (m, 1 H), 4.25 (m, 1H), 3.57 (t, J= 8.5Hz, 1H), 3.40 (m, 1H), 3.35 (s, 3H), 3.17 (m, 1H), 2.42 (m, 1H), 1.82 (s, 3H), 1.69 (m, 1H), 1.56 (dd, J= 7.1,1.2Hz, 3H), 1.24 (m, 4H), 0.88 (t, J= 7. OHz, 3H).

MS: (M+H)+= 313, (M+Na) += 335, (M-H)-= 311 Example 90 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1- vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI286.1 90A ()- (2R.STDC0710 3S, 5R, 1'R, 2'S)-1-t-Butoxvcarbonyl-2-1-acetamido-2-methoxv-2- allyl) ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Este The title compound was prepared according to the method described inExample 84A, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-allyl) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 8 mg, 31%).

MS: (M+H) +=467, (M-H)-=465 90B(#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis- ropen-1-vl)-pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-methoxy-2-allyl) ethyl-3- (cis-propen-1-yl)-pyrrolid ine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t butoxycarbonyl-2- (1- acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. ester (yield: 6 mg, 96%).

'H NMR (DMSO-d6) 6 8.02 (d, J=8.6HZ, 1H), 5.75 (m, 1H), 5.51 (m, 1H), 5.24 (m, 1 H), 5.05 (m, 2H), 4.27 (m, 1 H), 4.22 (m, 1 H), 3.74 (m, 2H), 3.26 (s, 3H), 3.18 (m, 1H), 2.47 (m, 1H), 2.39 (m, 1H), 2.17 (m, 1H), 1.87 (s, 3H), 1.67 (m, 1H), 1.63 (dd, J=6.71,1.23 HZ, 3H).

MS: (M+H) +=311, (M-H)-=309 Example 91 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamideo-2-methoxy-2-allyl)ethyl-3-(cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI287.1 91A ()- (2R, 3S. 5R, 1'R. 2'R)-1-t-Butoxvcarbonvl1-acetamido-2-methoxv-2- t-ButylEsterallyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid The title compound was prepared according to the method described inExample 84A, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t butoxycarbonyl-2- (1- acetamido-2-hydroxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1 acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)STDC0077-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4.0 mg, 16%).

MS: (M+H) +=467, (M-H)-=465 EMI288.1 91B(#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis- proprn-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting (#)-(2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-methoxy-2-allyl) ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1t-butylacetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylicacid ester (yield: 3 mg, 96%).

1H NMR (DMSO-d6) 8 7.75 (d, J=9.2 HZ, 1H), 5.75 (m, 1H), 5.47 (m, 1H), 5.24 (m, 1 H), 5.06 (m, 2H), 4.42 (m, 1H), 4.25 (m, 1H), 3.58 (m, 1H), 3.50 (m, 1H), 3.37 (s, 3H), 3.17 (m, 1H), 2.42 (m, 1H), 2.36 (m, 1H), 1.83 (s, 3H), 1.71 (m, 1H), 1.55 (dd, J=6.73,1.83 HZ, 3H) MS: (M+H) +=311, (M-H)-=309 Example 92 ()- (2R, 3S. 5R, 1'R. 2'S)-2- (1-Acetamido-2-hydroxv-4-vinvl) butyl-3- (cis-propen-1- yl !-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.EMI289.1 STDC026792A (#)-(2R$,3S,5R,1'R, 2'S) and ()- (2R, 3S, 5R, 1'R, 2'R)-l-t-Butoxvcarbonyl-2 (1-acetamido-2-hvdroxy-4-vinyi butvl-3- (cis-propen-1-yl)-pvrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41 B, substituting 1-buten-4-yl magnesium bromide for ethyl magnesium bromide to provide ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido-2hydroxy-4-vinyl) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0030 g, 6%) and ()- (2R, 3S, 5R, 1'R, 2'R)-1-t butoxycarbonyl-2- (1- acetamido-2-hydroxy-4-vinyl) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0145 g, 28%).

()- (2R, 3S, 5R, 1'R, 2'S) MS: (M+H) +=467, (M+Na) +=489, (2M+Na) +=955, (M-H)-=465.

()- (2R, 3S, 5R, 1'R, 2'R)-MS: (M+H) +=467, (M+Na) +=489, (2M+Na) +=955, (M-H)-=465. EMI290.1 STDC0671 92B(#)-2R,3S,5R,1'R,2'S(-2-(1-Acetamido-2-hydroxy-4-vinyl)bytyl-3-(cis- propen-1-vl)-pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting (#)-(2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamdio-2-hydroxy-4-vinyl)bytyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (#)-(2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1t-butylacetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ester (yield: 0.0027 g, 100%).

1H NMR (DMSO-d6) # 8.93 (bs, 1H), 7.90 (d, J=9.2 Hz, 1H), 5.80 (m, 1H), 5.48 (m, 1H), 5.28 (m, 1H), 5.00 (dd, J=17.1,1.8Hz, 1H), 4.94 (dd, J=10.4,1.8Hz, 1H), 4.29 (bt, J=8.3Hz, 1H), 4.03 (m, 1H), 3.71 (m, 1H), 3.49 (m, 1H), 3.15 (quint., J=8.5Hz, 1H), 2.41 (dt, J=12.8,7.3Hz, 1H), 2.16 (M, 1H), 2.05 (m, 1H), 1.83 (s, 3H), 1.79-1.75 (m, 1H), 1.64 (m, 1H), 1.58 (dd,STDC0034 J=6.7,1.8Hz, 3H), 1.34 (m, 2H).

MS: (M+H) + = 311, (M+Na) + = 333, (M-H)- = 309, (M+CF3COO-)-=423 Example 93 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-4-vinyl)bytyl-3-(cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.EMI291.1 STDC078993A (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis- propen-1-vl)-pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy4-vinyl) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0027 g, 100%).

1H NMR 9DMSO-d6 # 7.;68 (d, J=9.6 Hz, 1H),. 5. 81 (m, 1H), 5.48 (m, 1H), 5.25 (m, 1H), 5.01 (dd, J=17.1,1.8Hz, 1H), 4.95 (dd, J=10.3,1.7Hz, 1H), 4.43 (t,J=8.5Hz, 1H), 4.10 (m, 1H), 3.74 (m, 1H), 3.56 (t, J=8.9Hz, 1H), 3.16 (quint., J=8.9Hz, 1H), 2.42 (dt, J=12.8,7.3Hz, 1H), 2.11 (M, 1H), 2.07 (m, 1H), 1.83 (s, 3H), 1.72 (dt, J=12.8,9.8Hz, 1H), 1.55 (dd, J=6.7,1.8Hz, 3H), 1.5-1.35 (m, 2H).

MS: (M+H) + = 311, (M+Na)+ = 333, (M-H)- = 309, (M+CF3COO-)-=423, (2M-H)-=619.

Example 94 (#)-(2R,3S,5R,1'R,2'S,3'S)-2-(1-Acetamido-2-methoxy-3-methyl)pentyl-3-(cis- propen-1-vl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI292.1 94A(s)-(2R. 3S. 5R. 1'R. 2'S. 3'S)-1-t-Butoxvcarbonyl-2-(1-acetamido-2-methoxv 3-methy pentyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound is prepared according to the method described inExample 84A, substituting ()- (2R, 3S, 5R, 1'R, 2'S, 3'S)-1-f-butoxycarbonyl-2- (1- acetamido-2-hydroxy-3-methyl) pentyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1acetamido-2-hydroxy)STDC0116 butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.EMI292.2 STDC075294B (#)-(2R,3S,5R,1'R,2'S,3'S)-2-(1-Acetamido-2-methoxy-3-methyl)pentyl-3- (cis-propen-1-vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound is prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S, 3'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-methoxy-3-methyl) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1 t-butylacetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ester.

Example 95 ()- (2R, 3S. 5R. 1'RS)-2- (1-Acetamido-2-oxo-2-heptafluoropropyl) ethyl-3- (cis- propen-1-vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI293.1 95A (#)-(2R,3S,5R,1'RS)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-oxo-3- heptafluoropropvl) eth (cis-propen-1-yl)-pvrrolidine-5-carboxvlic Acid t-Butyi Ester.

The title compound was prepared according to the method described inExample 42A, substituting ()- (2R, 3S, 5R, 1'R, 2'RS)-1-t-butoxycarbonyl-2- (1acetamido-2-hydroxy-3-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5carboxylic acid t-butyl ester for ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- t-butylacetamido-2-hydroxy)butyl-3-(cis-propen-1yl)-pyrrolidine-5-carboxylicacid ester (yield: 6.8 mg, 88%).

MS: (M+H) +=579, (M-H)-=577. EMI294.1 STDC080495B (#)-(2R,3S,5R,1'RS)-2-(1-Acetamido-2-oxo-2-heptafluoropropyl)ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'RS)-1-t-butoxycarbonyl-2- (1- acetamido-2-oxo-3-heptafluoropropyl) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl- 2- (1-acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t- butyl ester (yield: 0.0037 g, 100%).

MS: (M+H) +=423, (M-H)-=421.

Example 96 (#)-(2R,3S,5R,1'RS)-2-(1-Acetamido-2-oxo-2-heptafluoropropyl)ethyl-3-(cis- propen-1-vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI295.1 96A -) (2R, 3S. 5R. 1'RS)-1-t-Butoxvcarbonyl-2- (1-Acetamido-2-oxo-3- heptafrluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-ButylEster.

The title compound was prepared according to the method described inExample 42A, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-heptafluoropropyl) ethyl-3-(cis-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester for ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 6.8 mg, 88%).

MS: (M-H)-=577.EMI295.2 STDC078896B ()- (2R, 3S, 5R. 1'RS)-2- 1-Acetamido-2-oxo-2-heptafluoropropvl) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy-3-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl- 2- (1-acetamido-2-hyd roxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t- butyl ester (yield: 0.0037 g, 100%).

MS: (M+H) +=423, (M-H)-=421.

Example 97 ()-(2R. 3S, 5R, 1'R)-2-1-Acetamido-2-oxo) pentyl-3- (cis-propen-1-yl)-pyrrolidine- 5-carboxylic Acid Trifluoroacetic Acid Salt.EMI296.1 STDC071097A (#)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-oxo)prntyl-3-(cis- t-ButylEster.propen-1-yl)-pyrrolidine-5-carboxylicAcid The title compound was prepared according to the method described inExample 42A, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2- (1- acetamido-2-hdroxy) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2- hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 14 mg, 58%).

MS: (M+H) + = 453, (M+Na) + = 475; (M-H)-= 451. EMI297.1 STDC019097B ()- (2R, 3S, 5R. 1'R)-2- (1-Acetamido-2-oxo) pentyl-3- (cis-propen-1-vl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R)-1-t butoxycarbonyl-2- (1- acetamido-2-oxo) pentyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 1.4 mg, 28%).

'H NMR (DMSO-d6) 8.31 (d, J=8.3Hz, 1H), 5.40 (m, 1H), 5.19 (brt, 1H), 4.26 (t, J=6.8Hz, 1 H), 3.63 (t, J=8.3Hz, 1 H), 3.35 (m, 1 H), 2.97 (m, 1 H), 2.45 (m, 1 H), 2.34 (dt, J=3.4,7.4Hz, 1 H), 2.20 (m, 1 H), 1.84 (s, 3H), 1.58 (dd,J=2,4.3Hz, 3H), 1.43 (m, 3H), 0.82 (t, J=7.3Hz, 3H) MS: (M-H)-= 295; (M+H) + = 297, (M+Na) + = 319.

Example 98 ()- (2R. 3S. 5R, 1'R)-2- (1-Acetamido-2-oxo) butyl-3- (cis-propen-1-pvrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt.EMI298.1 STDC0542 The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2-(1t-butylacetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ester prepared in Example 42A in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t- butoxycarbonyl-2- (1-acetamido-2-hyd roxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester (yield: 5.0 mg, 100%).

1H NMR (DMSO-d6) 6 8.52 (d, J= 8.6Hz, 1H), 5.47 (m, 1H), 5.15 (m, 1H), 4.54 (m, 1H), 4.39 (dd, J= 11.0,6.7Hz, 1 H), 3.84 (t, J= 9.2Hz, 1H), 3.17 (m, 1H), 2.50 (m, 1 H), 2.38 (m, 1 H), 2.33 (m, 1 H), 1.83 (s, 3H), 1.63 (m, 1 H), 1.58 (dd, J= 6.7,1.8Hz, 3H), 0.94 (t, J= 7.5Hz, 3H).

MS: (M+H) += 283, (M+Na) + = 305, (M-H)-= 281.

Examples 99-115 The title compounds were prepared according to the methods described inExamples 20 and 40-42 by substituting the respective reactants.

Example 99EMI299.1 (#)-(2Rj,3S,5R,1'R)-2-(1-Acetamido-2-oxo-2-allyl)ethyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 1H NMR (DMSO-d6) # 8.38 (d, J= 8.5Hz, 1H), 5.73 (m, 1H), 5.37 (m, 1H), 5.05 (m, 3H), 4.32 (t, J= 7.9Hz, 1H), 3.90 (m, 1H), 3.49 (m, 1H), 3.13 (m, 2H), 2.98 (m, 1H), 3.18 (m, 1H), 1.78 (s, 3H), 1.51 (dd, J= 5.5,1.2Hz, 3H), 1.44 (m, 1H).

MS: =293.(M-H- Example 100EMI299.2 (#)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-oxo-3-methyl)butyl-3-vinyl-pyrrolidine-5- carboxvlic Acid Trifluoroacetic Acid Salt 1H NMR (DMSO-d6) # 8.64 (d, J= 8.5Hz, 1H), 5.59 (m, 1H), 5.08 (d, J= 17. 1Hz, 1H(, 5.02 (d, J= 9.8Hz, 1H), 4.65 (t, J= 8.6Hz, 1H), 4.32 (m, 1H), 3.82 (t,J= 9.2Hz, 1 H), 2.82 (m 2H), 2.36 (m, 1 H), 1.83 (s, 3H), 1.80 (m, 1 H), 1.03 (d, J= 6.7Hz, 3H), 0.97 (d, J= 6.7Hz, 3H).

MS: (M+H)+= 283, (M+Na) + = 305, (M-H)-= 281.

Example 101EMI300.1 (#)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-oxo)propyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 1H NMR (DMSO-d6) # 8.96 (d, J= 7.9Hz, 1H), 5.71 (m, 1H), 5.27 (d, J=17.7Hz, 1H), 5.17 (d, J=11.0HzJ, 1H), 4.38 (m, 1H), 4.29 (m, 1H), 3.81 (m, 1H), 2.61 (m, 1H), 2.22 (m, 1H), 2.13 (s, 3H), 2.01 (s, 3H), 1.24 (m, 1H).

MS: (M+H)+= 255, (M+Na) + = 277, (M-H)-= 253.

Example 102EMI300.2 (#)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-oxo)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 1H NMR (DMSO-d6) # 8.61 (d, J= 8.5Hz, 1H), 5.60 (m, 1H), 5.10 (d, J= 17.7Hz, 1H), 5.03 (dd, J= 10.4,1.2Hz, 1H), 4.54 (t, J= 8.5Hz, 1H), 4.38 (dd, J= 11.0,6.7Hz, 1 H), 3.86 (m, 1 H), 2.84 (m, 1 H), 2.52 (m, 1 H), 2.37 (m, 2H), 1.85 (s, 3H), 1.82 (m, 1 H), 0.94 (t, J= 7. OHz, 3H).

MS: (M+H) += 269, (M+Na) + = 291, (M-H)-= 267.

Example 103EMI301.1 (#)-(2R,3S,5R,1'R)-2-(1-Acetamido020oxo)pentyl030vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-d6) 8 8.60 (d, J= 9.7Hz, 1H), 5.60 (m, 1H), 5.07 (m, 2H), 4.65 (m, 1H), 4.54 (m, 1H), 4.38 (m, 1H), 3.86 (m, 1H), 2.84 (m, 1H), 2.45 (m, 1 H), 2.36 (m, 1 H), 1.86 (s, 3H), 1.82 (m, 1 H), 1.47 (m, 2H), 0.87 (t, J= 5.8Hz, 3H).

MS: (M+H)+= 283, (M+Na) += 305, (M-H)-= 281.

Example 104EMI301.2 (#)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-hydroxy)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-d6) 5 8.00 (d, J= 9.9Hz, 1H), 5.63 (m, 1H), 5.08 (m, 1H), 4.98 (m, 1 H), 4.35 (m, 1 H), 4.25 (m, 1 H), 4.08 (m, 1 H), 3.55 (m, 1 H), 3.45 (m, 1 H), 3.38 (m, 1 H), 2.83 (m, 1 H), 2.33 (m, 1 H), 1.78 (s, 3H).

MS: (M+H) += 243, (M+Na) += 265, (M-H)-= 241.

Example 105EMI302.1 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)propyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt 1H NMR (DMSO-d6) 8 7.96 (d, J= 9.7Hz, 1H), 5.74 (m, 1H), 5.12 (m, 1H), 5.03 (m, 1H), 4.27 (m, 1H), 3.96 (m, 1 H), 3.77 (m 1 H), 3.65 (m, 1 H), 2.87 (m, 1H), 2.38 (m, 1H), 1.82 (s, 3H), 1.80 (m, 1H), 1.08 (d, J= 6. OHz, 3H).

MS: (M+H)+= 257, (M+Na) += 279, (M-h)- = 255.

Example 106EMI302.2 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt 1H NMR (DMSO-d6) #7. 99 (d, J= 9. OHz, 1H), 5.75 (m, 1H), 5.13 (d, J= 17.1Hz, 1H), 5.04 (d, J= 10.5Hz, 1H), 4.27 (t, J= 8.4Hz, 1H), 4.04 (m, 1H), 3.78 (m, 1H), 3.48 (m, 1H), 2.89 (m, 1H), 2.40 (m, 1H), 1.88 (m, 1H), 1.85 (s, 3H), 1.54 (m, 1H), 1.28 (m, 1H), 0.86 (t, J= 7.2Hz, 3H).

MS: (M+H) += 271, (M+Na) + = 293, (M-H)-= 269.

Example 107EMI303.1 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5- carboxvlic Acid Trifluoroacetic Acid Salt 1H NMR (DMSO-d6) # 7.99 (d, J= 9.9Hz, 1H), 5.75 (m, 1H), 5.08 (m, 2H), 4.28 (m, 1 H), 4.03 (m, 1 H), 3.77 (m, 1 H), 3.52 (m, 1 H), 2.88 (m, 1 H), 2.40 (m, 1 H), 1.86 (s, 3H), 1.75 (m, 1 H), 1.45 (m, 2H), 1.25 (m, 2H), 0.87 (t, J= 5.9Hz, 3H).

MS: (M+Na)+=307,(M-h)-=283.285, Example 108EMI303.2 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-methyl)butyl-3-vinyl- pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-d6) 5 7.97 (d, J= 9.3Hz, 1H), 5.75 (m, 1H), 5.12 (d, J= 17.1 Hz, 1 H), 5.04 (d, J= 11.2Hz, 1H), 4.24 (m, 1H), 4.13 (m, 1H), 3.74 (dd, J= 9.8,6.1Hz, 1H), 3.44 (dd, J= 10.3,2. OHz, 1H), 2.87 (m, 1H), 2.40 (m, 1H), 1.84 (m, 1 H), 1.83 (s, 3H), 1.75 (m, 1 H), 0.89 (d, J= 6.8,3H), 0.75 (d, J= 6.8Hz, 3H).

MS: (M+H) += 285, (M+Na) + = 307, (M-H)-= 283.

Example 109EMI304.1 ()- (2R. 3S, 5R. 1'R, 2'S)-2- (1-Acetamido-2-hvdroxy-2-cvclopropvl) ethvl-3-vinyl- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-d6) # 7.81 (d, J= 10.0Hz, 1H), 5.73 (m, 1H), 5.05 (m, 2H), 4.39 (m, 1H), 4.20 (m 1 H), 3.90 (m, 1 H), 3.61 (m, 1 H), 3.08 (m, 1 H), 2.86 (m, 1 H), 2.42 (m, 1H), 1.85 (s, 3H), 0.88 (m, 1H), 0.45 (m, 1H), 0.35 (m, 2H), 0.11 (m, 1H).STDC0075 MS: (M+H) += 283, (M+Na) += 305, (M-H)-= 281.

Example 110EMI304.2 ()- (2R, 3S. 5R. 1'R. 2'R)-2- (1-Acetamido-2-hvdroxy) propvl-3-vinvl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt !H NMR (DMSO-d6) # 7.77 (d, J= 9.7Hz, 1H), 5.72 (m, 1H), 5.07 (m, 2H), 4.40 (m, 1 H), 4.03 (m, 1 H), 3.95 (m 1 H), 3.57 (m,

Example 111EMI305.1 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-htydroxy)butyl-3-vinyl-pyrrolidine-5- carboxvlic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-d6) 87.72 (d, J= 9.8Hz, 1H), 5.73 (m, 1H), 5.08 (d, J= 17.1Hz, 1H), 5.03 (d, J= 10.4Hz, 1H), 4.41 (m, 1H), 4.13 (m, 1H), 3.68 (m, 1H), 3.63 (m, 1 H), 2.88 (m, 1 H), 2.44 (m, 1 H), 1.90 (m, 1 H), 1.83 (s, 3H), 1.38 (m, 2H), 0.84 (t, J= 7.3Hz, 3H).

MS: (M+H) += 271, (M+Na) + = 293, (M-H)-= 269.

Example 112EMI305.2 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-d6) 8 7.72 (d, J= 9.9Hz, 1H), 5.72 (m, 1H), 5.06 (m, 2H), 4.42 (m, 1 H), 4.09 (m, 1 H), 3.77 (m, 1 H), 3.61 (m, 1 H), 2.87 (m, 1 H), 2.43 (m, 1H), 1.90 (m, 1 H), 1.83 (s, 3H), 1.37 (m, 2H), 1.27 (m, 2H), 0.87 (t, J= 5.9Hz, 3H).

MS: (M+H) += 285, (M+Na) += 307, (M-H)-= 283.

Example 113EMI306.1 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-3-methyl)butyl-3-vinyl- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-d6) #7. 71 (d, J= 9.3Hz, 1 H), 5.70 (m, 1 H), 5.08 (d, J= 17.1Hz, 1H), 5.03 (d, J= 10.3Hz, 1H), 4.42 (m, 1H), 4.25 (m, 1H), 3.61 (m, 1H), 3.35 (dd, J= 8.3,2.5Hz, 1 H), 2.90 (m, 1 H), 2.44 (m, 1 H), 1.92 (m, 1 H), 1.82 (s, 3H), 1.58 (m, 1 H), 0.95 (d, J= 6.8Hz, 3H), 0.79 (d, J= 6.4Hz, 3H).

MS: (M+H) += 285, (M+Na) + = 307, (M-H)-= 283.

Example 114EMI306.2 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydrôxy-2-cyclopropyl)ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 1H NMR (DMSO-d6) # 7.94 (d, J= 9.6Hz, 1H), 5.76 (m, 1H), 5.12 (m, 2H), 4.40 (m, 1H), 4.21 (m, 1H), 3.90 (m, 1H), 3.53 (m, 1H), 3.13 (m, 1H), 2.81 (m, 1H), 2.25 (m, 1H), 1.87 (s, 3H), 0.90 (m, 1H), 0.47 (m, 1H), 0.37 (m, 2H), 0.15 (m, 1H).STDCDBPG0075* MS: (M+H) += 283, (M+Na)+= 305, (M-H)-= 281.

Example 115EMI307.1 ()- (2R, 3S. 5R. 1'R. 2'R)-2- (1-Acetamido-2-hvdroxv-4-methvl) pentvl-3-vinvi- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-d6) 8 7.71 (d, J= 9.7Hz, 1H), 5.83 (m, 1H), 5.06 (d, J= 17.1 Hz, 1 H), 5.02 (d, J= 10.3Hz, 1 H), 4.41 (m, 1 H), 4.06 (m, 1 H), 3.83 (m, 1 H), 3.59 (t, J= 8.8Hz, 1 H), 2.84 (m, 1 H), 2.42 (m, 1 H), 1.90 (m, 1 H), 1.82 (s, 3H), 1.71 (m, 1 H), 1.34 (m, 1 H), 1.07 (m, 1 H), 0.89 (d, J= 6.8Hz, 3H), 0.86 (d, J= 6.3Hz, 3H).

MS: (M+H) += 299, (M+Na) + = 321, (M-H)-= 297.

Example 116 ()- (2R, 3S. 5R. 1'R)-2- (1-Acetamido-2-hydroxy-2-methyl)propyl-3-vinyl-pyrrolidine5-carboxylic Acid Trifluoroacetic Acid SaltEMI308.1 116A ()- (2R, 3S, 5R. 1'R)-t-Butoxvcarbony1-Acetamido-2-hvdroxy-2- methyl) propvl-3-vinvl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'R)-t-Butoxycarbonyl 2-(1-acetamido-2-oxo) propyl-3-vinylpyrrolidine-5-carboxylic acid t-butyl ester (11 mg, 0.027 mmol) was reacted with methyl magnesium bromide (3 M) (0. 05mL, 0. 134 mmol) in THF (2 mL) at 25 C for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL) and water (2 mL) followed by extraction using dichloromethane (2X 5 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2/1: ethyl acetate/hexane to provide the title compound (yield: 1.9 mg, 17%).

MS: (M+H) +=427, (M-H)-=425 EMI309.1 116B (#)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-hydroxy-2-methyl)propyl-3-vinyl- pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2-(1t-butylacetamido-2-hydroxy-2-methyl)propyl-3-vinyl-pyrrolidine-5-carboxylicacid ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 1.6 mg, 99%).

1H NMR (DMSO-d6) 6 7.70 (d, J=9.9Hz, 1H), 5.75 (m, 1H), 5.02 (m, 2H), 4.37 (m, 1H), 4.15 (m, 1H), 3.61 (m, 1H), 2.78 (m, 1H), 2.41 (m, 1H), 1.81 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H) MS:STDC0881 (M+H) + =271, (M+23) + =293, (M-H)-=269 Example 117 (#)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-hydroxy-2-ethyl)butyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid SaltEMI310.1 117A ()- (2R. 3S. 5R. 1'RW-Butoxvcarbonvl-2- (1-Acetamido-2-rivdroxv-2- t-ButylEster.ethyl)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid ()- (2R, 3S, 5R, 1'R)-t-Butoxycarbonyl-2-(1-acetamido-2-oxo) butyl-3-vinylpyrrolidine-5-carboxylic acid t-butyl ester (37mg, 0.087 mmol) was reacted with ethyl magnesium bromide (3 M) (0. 15mL, 0. 44mmol) in THF (5 mL) at 25 C for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride 5 mL) and water (5 mL) followed by extraction using dichloromethane (2 X 10 mL).STDC0237 The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2/1: ethyl acetate/hexane to provide the title compound (yield: 14 mg, 35%).

MS: (M+H) += 455, (M-H)-=453 EMI311.1 116B(?)-(2R. 3S. 5R. 1'R)-2-(1-Acetamido-2-hydroxv-2-ethyl) butyl-3-vinyl- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R)-1-t butoxycarbonyl-2- (1- acetamido-2-hydroxy-2-ethyl) butyl-3vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t butoxycarbonyl-2- (1-acetamido-2- hydroxy)butyl-3-(cis-propen-1-yl)-pyrrlidine-5-carboxylic acid t-butyl ester (yield: 5.8 mg, 98%).

1 H NMR (DMSO-d6) # 7.62 (d, J=9.6HZ, 1 H), 5.75 (m, 1H), 5.03 (m, 2H), 4.39 (m, 1H), 4.31 (m, 2H), 3.87 (m, 1H), 3.38 (m, 1H), 2.88 (m, 1H), 2.40 (m, 1H), 1.83 (s, 3H), 1.55-1.30 (m, 4H), 0.86 (m, 6H) MS:STDC0822 (M+H) + =299, (M-H)-=297 Example 118 ()- 3S. 5R. 1'S)-2- (1-Acetamido) allvl-3- (cis-propen-1-yl)-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid SaltEMI312.1 118A(#)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamdio)allyl-3-(cis-propen- 1-vl)-pvrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described inExample 20K, substituting ()- (2R, 3S, 5R, 1'S)-2-t-butoxycarbonyl-2-(1-acetamido2-formyl) methyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido-3-methyl)STDC0123 butyl-3- formyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 15.3 mg, 61.4%).

MS: (M+H) += 409.EMI312.2 STDC0640 118B(#)-(2R,3S,5R,1'S)-2-(1-Acetamdio)allyl-3-(cis-propen-1-yl)-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'S)-1-t butoxycarbonyl-2- (1- acetamido) allyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S(-1-t-butoxycarbonyl-2-(1-acetamido-2 hydroxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 13.1 mg, 100%).

1H NMR (DMSO-d6): #1. 58 (dd, 3H), 1.74 (dt, 1H), 1.88 (s, 3H), 2.41 (dt, 1H), 3.17 (m, 1H), 3.56 (dd, 1H), 4.35 (dd, 1H), 4.70 (dd, 1H), 5.22-5.30 (m, 3H), 5.51 (m, 1H), 5.82 (m, 1H), 8.15 (d, 1H), 9.18 (brs, 2H).

MS: (M+H) += 253.

Example 119 trans)buten-1-yl)-3-(cis-propen-1-(#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(cisand yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI313.1 and119A(#)-(2R,3S,5R,1'S)-2-t-Butoxycarbonyl-2-)1-Acetamido-2-(cis t-ButylEstertrans)buen-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid The title compound was prepared according to the method described inExample 20K, substituting ()- (2R, 3S, 5R, 1'S)-1-t butoxycarbonyl-2- (1-acetamido- 2-formyl) methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido-3-methyl)STDC0162 butyl-3formyl-pyrrolidine-5-carboxylic acid f-butyl ester and ethyltriphenylphosphonium bromide for methyltriphenylphosphonium bromide (yield: 12.4 mg, 48.2%).

MS: (M+H) += 423 EMI314.1 119Btrans)buten-1-yl)-3-(cisand propen-1-vl)-pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41 C, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido- trans)buten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacidt-2-(cisand butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 11.8 mg, 100%).

'H NMR (DMSO-d6): #1. 63 (dd, 3H), 1.66 (dd, 3H), 1.74 (m, 1H), 1.88 (s, 3H), 2.41 (dt, 1H), 3.17 (m, 1H), 3.50 (dd, 1H), 4.34 (dd, 1H), 4.95 (m, 1H), 5.23 (m, 1H), 5.39 (m, 1H), 5.53 (m, 1H), 5.68 (m, 1H), 8.21 (d, 1H), 9.18 (br s, 2H).

MS: (M+N)+= 267 Example 120 (t)- (2R. 3S, 5R, 1'S)-1-Acetamido-3, 3-dimethyl) allyl-3- (cis-propen-1-y pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI315.1 120A(#)-(2R,3S,5R,1'S)-1-t-Butxycarbonyl-2-(1-acetamido-3,3-dimethyl)allyl-3- (cis-propen-1-vl)-pyrrolidine-5-carboxvlic Acid t-Buyl Ester The title compound was prepared according to the method described inExample 20K, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxydcarbonyl-2-(1-acetamido2-formyl) methyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido-3-methyl)STDC0165 butyl-3formyl-pyrrolidine-5-carboxylic acid t-butyl ester and isopropyltriphenylphosphonium bromide for methyltriphenylphosphonium bromide (yield: 8.2 mg, 25.9%).

MS: (M+H) += 437EMI315.2 120B ()- (2R. 3S. 5R. 1'S)-2- (1-Acetamido-3.3-dimethvl) allvl-3-(cis-Pronen-1-vl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido- 3, 3-dimethyl)allyl-3-(cis-propen-1-yl)-=pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. ester (yield: 7.5 mg, 100%).

'H NMR (DMSO-d6): 61.53 (dd, 3H), 1.57 (s, 3H), 1.61 (s, 3H), 1.66 (m, 1 H), 1.77 (s, 3H), 2.32 (dt, 1 H), 3.07 (m, 1H), 3.39 (dd, 1H), 4.26 (m, 1 H), 4.75 (m, 1H), 5.07 (d, 1H), 5.15 (m, 1H), 5.44 (m, 1H), 8.06 (d, 1H).

MS: (M+H) += 281.

Example 121 tir 1'S)-2- (1-Acetamido-2-(cis and trans) penten-1-yl)-3- (cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI316.1 -2-(cisand121A(#)-(2R,3S,5R,1;A)-1-t-Butoxycarbonyl-2-(1-Acetamido t-ButylEstertrans)penten-1-yl)3-3(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid The title compound was prepared according to the method described inExample substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido-2formyl) methyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido-3-methyl)STDC0192 butyl-3formyl-pyrrolidine-5-carboxylic acid t-butyl ester and n-butyltriphenylphosphonium bromide for methyltriphenylphosphonium bromide (yield: 21.0 mg, 66.2%).

MS: (M+H) += 437. EMI317.1 andtrans)penten-1-yl)-3-(cis-121B(#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(cis propen-1-yl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido2- (cis and trans) penten-1-yl)-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid tbutyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t butoxycarbonyl-2- (1-acetamido- 2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. ester (yield: 16.0 mg, 98.1%).

1H NMR (DMSO-d6): 8 0.93 (t, 3H), 1.62 (dd, 3H), 1.75 (m, 1H), 1.87 (s, 3H), 2.07 (m, 2H). 2.40 (m, 1H), 3.17 (m, 1H), 3.50 (m, 1H), 4.34 (m, 1H), 4.94 (m, 1 H), 5.23 (m, 1 H), 5.34 (m, 1 H), 5.53 (m, 1 H), 5.58 (m, 1 H), 8.24 (d, 1 H), s,2H).9.25(br MS: (M+H) += 281.

Example 122 ()- (2R. 3S. 5R. 1'S)-2- (l-Acetamido-4-hydroxy-2- (cis and trans) buten-1-yl)-3- (cis- propen-1-vl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI318.1 122A(#)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-Acetamido-4-(t- trans)buten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-butyldimethylsilyloxy)-2-(cisand 5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described inExample substituting ()- (2R, 3S, 5R, 1'S)-1-t butoxycarbonyl-2- (1-acetamido-2- formyl) methyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R,STDC0240 1'S)-1-t-butoxycarbonyl-2- (1-acetamido-3-methyl) butyl-3formyl-pyrrolidine-5-carboxylic acid t-butyl ester and 4- (t-butyldimethylsilyloxy)butyltriphenylphosphonium bromide for methyltriphenylphosphonium bromide (yield: 23.1 mg, 66.9%).

MS: (M+H) += 567.EMI318.2 STDC0771 122B (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-4-hydroxy-2-(cis and trans) buten-1-vl)- 3- (cis-propen-1-vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido- 2-(cis and trans)-4-hydroxy-butenyl-2-yl)-3-(cis-propen-1-yl)-pyrrolid ine-5- carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl 2- (1-acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t- butyl ester (yield: 16.9 mg, > 100%).

'H NMR (DMSO-d6): 51.67 (dd, 3H), 1.78 (dt, 1H), 1.91 (s, 3H), 2.44 (m, 1 H), 2.50 (m, 1 H), 2.56 (m, 1H), 2.65 (m, 1H), 3.23 (m, 1H), 3.54 (m, 1 H), 4.40 (m, 1 H), 4.47 (m, 2H), 5.01 (m, 1H), 5.26 (m, 1 H), 5.54 (m, 2H), 5.63 (m, 1H), 8.32 (d, 1H), 9.27 (br s, 2H).

MS: (M+H) += 297.

Example 123 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid HydrochlorideEMI319.1 <RTI ID=319.12>123A ()- (2R. 3R,5R)-1-Benzyl-2-vinyl-3-t-butyldiphenylsilyloxvmethvlpyrrolidine-5-carboxylic Acid t-Butvl Ester.

()- (2R, 3R, 5R)-1-Benzyl-2-vinyl-3-hydroxymethyl-pyrrolidine-5-carboxylic</RTI> acid t-butyl ester (30.8 g, 97.1 mmol) was reacted with t-butyldiphenylsilyl chloride (49.5 mL, 190.4 mmol) and imidazole in dichloromethane (650 mL) at 0 C for 1 hour. The reaction was quenched methanol followed by extraction with dichloromethane (600 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2/1: chloroform/hexane to provide the title compound (yield: 52.9 g, 98%).

'H NMR (CDC13) 7.62-7.67 (m, 4H), 7.32-7.44 (m, 6H), 7.25-7.30 (m, 5H), 5.58-5.72 (m, 1H), 5.06-5.14 (m, 2H), 3.90 (d, 1H), 3.72-3.78 (m, 1H), 3.58-3.68 (m, 2H), 3.44-3.52 (m, 2H), 2.26-2.40 (m, 1H), 2.10-2.23 (m, 1H), 1.68-1.78 (m, 1H), 1.38 (s, 9H), 1.03 (s, 9H).

MS: (M+H) +=556 EMI320.1 123B (t)- (2R. 3R. 5R. 1'RS)-1-Benzyl-2- (1, 2-dihydroxv) ethyl-3-t- butyldiphenvlsilvloxymethyl-pvrrolidine-5-carboxvlic Acid t-Butvl Ester.

()- (2R, 3R, 5R)-1-Benzyl-2-vinyl-3-t-butyldiphenylsilyloxymethyl- pyrrolidine-5-carboxylic acid t-butyl ester (22.7 g, 41 mmol) was reacted with Os04 (4%) (2.5 mL, 0.7 mol. %) and N-methyl morpholine N-oxide (18.5 g, 2.77 eq.) in acetone (500 mL) and water (60 mL) for 48h at room temperature. The reaction was quenched with 10% aqueous Na2S203 (200 mL). The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate/water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 35% ethyl acetate/hexane to provide the title compound (yield: 11 g, 55%).

'H NMR (DMSO-d6) 8 7.58-7.63 (m, 5H), 7.40-7.48 (m, 7H), 7.20-7.35 (m, 3H), 4.41-4.45 (m, 2H), 3.98 (d, 1 H), 3.75-3.84 (m, 2H), 3.50-3.68 (m, 2H), 3.43.46 (m, 1H), 3.16-3.25 (m, 1H), 2.97-3.0 (m, 1H), 2.09-2.28 (m, 1H), 1.62-1.89 (m, 1H), 1.34-1.39 (m, 1H), 1.30 (s, 9H),. 98,. 96 (2s, 9H).

MS: (M+H)+=590EMI321.1 123C(2R, 3R, 5R, 1'RS)-2-(1, 2-dihvdroxy) ethvl-3-t- butyldiphenvlsilvloximethyl-pvrrolidine-5-carboxvlic Acid t-Butvl Ester.

()- (2R, 3R, 5R, 1'RS)-1-Benzyl-2-(1, 2-dihydroxy) ethyl-3-t- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (11 g, 18.7 mmol) was reacted under 1 atmosphere of hydrogen with 20% Pd (OH) 2/C (5 g) and in ethanol (40 mL) vigorously stirred for 2.5 days at room temperature. The reaction was filtered, and the catalyst was washed with methanol (3x30 mL). The filtrate was evaporated in vacuo to give the title compound as an oil (yield: 8 g, 94%)EMI321.2 123D(#)-(2R,3R,5R,1'R)-1-t-Butoxycarbonyl-2-(1,2-dihydroxy)ethyl-3-t- butyldiphenvlsilvloxymethvl-pyrrolidine-5-carboxvlic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 40D, substituting (t)- (2R, 3R, 5R, 1'RS)-2- (1, 2-dihydroxy) ethyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (2R, 3R, 5R, 1'RS)-2- (1, 2-dihydroxy) ethyl-3-acetoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester. The residue was purified by column chromatography on silica gel using 35% ethyl acetate/hexane to provide the title compound (yield: 20.5 g, 60%).

'H NMR (DMSO-d6) 7.57-7.60 (m, 4H), 7.38-7.48 (m, 6H), 4.85,4.77 (2d, 1H), (m, 1H), (m, 1H), 3.80-3.95 (m, 1H), 3.73,3.68 (2s, 1H), 3.45-3.67 (m, 2H), 3.18-3.28 (m, 2H), 2.36-2.46 (m, 2H), 1 ; 86,1.70 (2d, 1H), 1.40,1.35 (2s, 9H), 1.32,1.26 (2s, 9H), 1.0,0.98 (2s, 9H).

MS: (M+H) += 600EMI322.1 123E (s)-(2 R. 3 R. 5R. 1'R)-1-t-Butoxvcarbonvl-2-(1-methanesulfonyioxv-2- t-Butylacetoxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcidEster.

()- (2R, 3R, 5R, 1'R)-1-t-Butoxycarbonyl-2- (1, 2-dihydroxy) ethyl-3-tbutyidiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (20.5 g, 34.2 mmole) was reacted with acetic anhydride (16.1 mL, 171 mmole) and triethylamine (47.7 mL, 342 mmole) in dichloromethane (360 mL) at 0 C for 16h.

The reaction was treated with methanol (35 mL) for 10 minutes and diluted with dichloromethane (1300 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was reacted with methanesulfonyl chloride (4.0 mL, 51.3 mmole) and triethylamine (14.3 mL, 103 mmole) in dichloromethane (350 mL) at 0 C for 1.5 hours. The reaction was quenched with water (300 mL) and diluted with dichloromethane (1200 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 30% ethyl acetate/hexanes to provide the title compound (yield: 23.8 g, 97%).

'H NMR (DMSO-d6) 67.58-7.62 (m, 4H), 7.38-7.50 (m, 6H), 5.12-5.26 (2m, 1H), (m, 3H), 4.00 (d, 1H), 3.46-3.68 (m, 2H), 3.20,3.18 (2s, 3H), 2.402.48 (m, 1H), 2.02,1.99, (2s, 3H), 1.68-1.88 (m, 1H), 1.42,1.36 (2s, 9H), 1.31,1.25 (2s, 9H), 1.00,0.98 (2s, 9H).

MS: (M+H) += 720, (M+NH4) +=737EMI323.1 123F (#)-(2R,3R,5R,1'S)-1-t-Butoxycarbonyl-2-oxiranyl-3-t- butyldiphenylsilyloxymethyl-pvrrolidine-5-carboxilic Acid t-Butyl Ester.

()- (2R, 3R, 5R, 1'S)-1-t-Butoxycarbonyl-2- (1-methanesulfonyloxy-2acetoxy) ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (23.8 g, 33.1 mmole) was reacted with potassium carbonate (10.1 g, 66.2 mmole) in methanol (160 mL) and THF (160 mL) at 25 C for 18 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 25% ethyl acetate/hexanes to provide the title compound, as an oil (yield: 16.7 g, 87%).

'H NMR (CDC13) 6 7.60-7.68 (m, 4H), 7.32-7.45 (m, 6H), (m, 2H), 3.67-3.78 (m, 1H), 3.52-3.62 (m, 1H), 3.0-3.08 (m, 1H), 2.68-2.75 (m, 1H), 2.47-2.52 (m, 3H), 1.80-1.90 (m, 1H), 1.48,1.42 (2s, 9H), 1.37,1.35 (2s, 9H), 1.07,1.03 (2s, 9H).

MS: (M+H) += 582 EMI324.1 123G ()- (2R, 3R, 5R, 1'S)-1-t-Butoxycarbonyl-2-oxiranyl-3-hvdroxymethvl- pyrrolidine-5-carboxylic Acid t-Butyl Ester.

()- (2R, 3R, 5R, 1'S)-1-t-Butoxycarbonyl-2-oxiranyl-3-t- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (4.17 g, 7.2 mmole) was reacted with tetrabutylammonium fluoride (1 M) (14 mL, 14.0 mmole) in THF (7 mL) for 20 minutes at 0 C then for 1.5 hours at 25 C. The reaction was concentrated in vacuo the residue was dissolved in ethyl acetate and washed with pH 7.0 buffer and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound, as an oil (yield: 2.4 g, 97%).

1H NMR (DMSO-d6) # 4.72-4.78 (m, 1 H), 3.94-4.05 (m, 2H), 3.35-3.47 (m, 1H), 3.18-3.28 (m, 1H), 3.03-3.08 (m, 1H), 2.63-2.73 (m, 1H), 2.37-2.44 (m, 1H), 2.30-2.36 (m, 1H), 2.08-2.20 (m, 1H), 1.58-1.75 (m, 1H), 1.40 (s, 9H), 1.37,1.34 (2s, 9H).STDC0245 MS: (M+H) += 344, (M+Na) += 366 EMI325.1 123H ()- (2R. 3R, 5R. 1'S)-1-t-Butoxycarbonvl-2-oxiranvl-3-formyl-pyrrolidine-5- carboxvlic Acid t-Butyl Ester.

()- (2R, 3R, 5R, 1'S)-1-t-Butoxycarbonyl-2-oxiranyl-3-hydroxymethyl- pyrrolidine-5-carboxylic acid t-butyl ester (2.4 g, 7.0 mmole) and triethylamine (3.9 mL 28.0 mmole) in dichloromethane (70 mL) at 0 C was reacted with sulfur trioxide pyridine complex (3.35 g, 21.0 mmole) in dimethylsulfoxide (21 mL) by dropwise addition followed by reaction for an additional 3 hours. The reaction was quenched with water (50 mL) and diluted with et 25 C. ()- (2R, 3R, 5R, 1'S)-1-t-Butoxycarbonyl-2-oxiranyl-3-formyl-pyrrolidine-5- carboxylic acid t-butyl ester (2.2 g, 6.5 mmole) in THF (10 mL) was added to the above solution at 0 C and stirred for 0.5 hours.STDC0110 The reaction was quenched with saturated ammonium chloride (50 mL) and diluted with ethyl acetate (200 mL).

The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound (yield: 2 g, 84%).

'H NMR (DMSO-d6) 5.80-5.95 (m, 1H), 5.08 (d, 1H), 4.94-5.04 (1H), (m, 1H), 3.59,3.90 (2t, 1H), 3.07-3.16 (m, 1H), 2.73-2.81 (m, 1H), 2.652.72 (m, 1H), 2.35-2.48 (m, 1H), 1.59-1.76 (m, 1H), 1.42 (s, 9H), 1.38,1.35 (2s, 9H).

MS: (M+H) + = 340EMI326.1 123J(#)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-methanesulfonyloxy-3azido) ethvl-3-vinvl-pvrrolidine-5-carboxylic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'S)-1-t-Butoxycarbonyl-2-oxiranyl-3-vinyl-pyrrolidine-5carboxylic acid t-butyl ester (1.72 g, 5.1 mmole) and ammonium chloride (1.36 g, 25.4 mmole) in ethanol (45 mL) and water (5 mL) was reacted with lithium azide (1.2 g, 24.5 mmole) for 7 hours at 50 C. The reaction was concentrated in vacuo and diluted with ethyl acetate (200 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue (2.15 g) was dissolved in dichloromethane (50 mL) and reacted with methanesulfonyl chloride (0.8 mL, 10.2 mmole) and triethylamine (2.8 mL, 20.4 mmole) for 0.5 hours at 0 C. The reaction was quenched with aqueous sodium bicarbonate (50 mL) and diluted with ethyl acetate (200 mL).STDC0276 The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound (yield: 1.87 g, 80%).

'H NMR (DMSO-d6) 5 5.77-5.98 (m, 1H), 4.94-5.11 (m, 3H), 4.12-4.19 (m, 1H), 3.99-4.06 (m, 1H), 3.66,3.71 (2d, 1H), 3.25,3.22 (2s, 3H), 2.92-3.02 (m, 1H), 2.55-2.63 (m, 1H), 1.68-1.82 (m. 1H), 1.45,1.42 (2s, 9H), 1.38,1.36 (2s, 9H).

MS: (M+H) += 461EMI327.1 123K (t)- (2R, 3S. 5R, 1'S)-1-t-Butoxvcarbonyl-2-aziridinyl-3-vinyl-pvrrolidine-5carboxylic Acid t-Butvl Ester.

()- (2R, 3S, 5R, 1'S)-1-t-Butoxycarbonyl-2- (1-methanesulfonyloxy-3azido) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (2.12 g, 4.6 mmole) was reacted with triphenylphosphine (1.81 g, 6.9 mmole) in THF (30 mL) and water (7.5 mL) at 65 C for 1 hour. The reaction was concentrated in vacuo and redissolved in ethyl acetate (200 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 4% methanol in dichloromethane to provide 2 g of the crude title compound containing approximately 60% product and 40% Ph3PO which was used directly for acylation.

'H NMR (DMSO-d6) a 5.78-5.5.98 (m, 1H), 4.12 (d, 1H), 3.42,3.19 (2d, 1 H), 2.53-2.73 (m, 2H), 2.00-2.15 (m, 1 H), 1.68-1.76 (m, 1 H), 1.62-1.68 (m, 1 H), 1.41 (s, 9H), 1.37,1.36 (2s, 9H).

MS: (M+H) + = 339, (M+Na) + = 361EMI328.1 123L ()- (2R, 3S, 5R. 1'S)-1-t-Butoxycarbonvl-2- (N-acetvlaziridiny)-3-vinylpvrrolidine-5-carboxvlic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'S)-1-t-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5- carboxylic acid t-butyl ester (1.03 g, 3.1 mmole) was reacted with acetic anhydride (. 42 mL, 4.7 mmole) and triethylamine (1.3 mL, 9.3 mmole) in dichloromethane (30 mL) at 25 C for 1 hours. The reaction was quenched with water (50 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with water, and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 20% ethyl acetate/hexanes to provide the title compound (yield:. 75 g, 64%).

1H NMR (DMSO-d6) # 5.78-5.98 (m, 1 H), 5.05 (d, 1 H), 4.98,4.94 (2d, 1 H), (m, 1H), 3.54,3.42 (2dd, 1H), 2.54-2.98 (m, 3H), 2.40,2.49 (2d, 1H), 2.15,2.19 (2d, 1H), 2.02,2.04 (2s, 3H), 1.68-1.82 (m, 1H), 1.42 (s, 9H), 1.48.1.45 (2s, 9H).

MS: (2M+Na) += 783 EMI329.1 123M (+)-(2R, 3S. 5R. 1'S)-1-t-Butoxvcarbonvl-2-(1-acetamido) butvl-3-vinylpyrrolidine-5-carboxylic Acid t-Butvl Ester.

To a suspension of copper (l) bromide-dimethyl sulfide complex (0.051g, 0.248 mmol) in THF (1.0 ml) at 0 C was added ethylmagnesium bromide (1 M) (1.0 ml, 1.0 mmol) in THF. After stirring for 10 minutes at 0 C, a portion of this solution (0.60 ml) was added dropwise to a solution of ()- (2R, 3S, 5R, 1'S)-1-f- Butoxycarbonyl-2- (N-acetylaziridinyl)-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (0.020 g, 0.053 mmole) in THF (0.40 ml) at-78 C. After stirring for 20 minutes at-78 C, the reaction was warmed to 0 C and stirred for 30 minutes.

The reaction was quenched with saturated ammonium chloride (1.0 mL) and diluted with ethyl acetate (10 mL). The organic layer was washed with water and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using a gradient of 0-75% ethyl acetate/hexanes to provide the title compound (yield: 0.004 g, 19%).

'H NMR (DMSO-d6) (rotamers) 5 7.48 (d, J=9.5Hz, 1H), 5.98-5.80 (m, 1H), 5.00-4.90 (m, 2H), 4.45-4.25 (m, 1 H), 3.96-3.91 (m, 1 H), 3.60-3.57 and 3.53-3.50 (2m, 1H), 2.91-2.76 (m, 1H), 2.59-2.42 (m, 1H), 1.80 (s, 3H), 1.73-1.59 (m, 1H), 1.42 and 1.41 (2s, 9H), 1.40-1.15 (m, 4H), 1.37 and 1.34 (2s, 9H), 0.89-0.82 (m, 3H) MS:STDC0647 (M-H)-= 409, (M+H) + = 411 EMI330.1 123N ()- (2R, 3S, 5R, 1'S)-2- (l-Acetamido) butyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloric Acid Salt The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3S, 5R, 1'$)-1-t-butoxycarbonyl-2-(1acetamido) butyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethyl-pyrrolidine-5- carboxylic acid t-butyl ester (yield: 3.1 mg, 99%).

'H NMR (DMSO-d6) 8 8.11 (d, J=7.3Hz, 1H), 5.76-5.69 (m, 1H), 5.16 (d,J-17.1Hz, 1H), 5.07 (dd, J=1.5,10.3Hz, 1H), 4.30 (dd, J=7.3,9.8Hz, 1H), 4.13 (m, 1 H), 3.50 (dd, J=5.9,9.8Hz, 1 H), 2.90 (m, 1 H), 2.39 (m, 1 H), 1.92-1.85 (m, 1H), 1.87 (s, 3H), 1.52-1.18 (m, 4H), 0.85 (t, J=7.3,3H) MS:STDC0573 (M-H)-= 253, (M+H) + = 255Examples 124-130EMI330.2 <SEP> <tb> <SEP> 1. <SEP> Organocuprate<tb> <SEP> OtBu <SEP> AcHN? <SEP> ., <SEP> OH<tb> ,-e <SEP> 2. <SEP> 6N <SEP> HCI <SEP> N"d<tb> <SEP> H <SEP> Boc <SEP> R <SEP> H <SEP> 0<tb> <SEP> HCI<tb> The following title compounds were prepared in two steps according to the methods described in Examples 123M and 123N, the denoted reagents and their respective methods of preparation are substituted in place of diethylcuprate and its preparation in Example 123M for step 1.

Example 124EMI331.1 ()) (2R 3S, 5R, 1'S)-2- (1-Acetamido) hexyl-3-vinvl-pvrrolidine-5-carboxylic Acid Hydrochloric Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper (l) bromide-dimethyl sulfide complex according to the methods described in Example 123M, substituting 2M butylmagnesium chloride for 1 M ethylmagnesium bromide.

'H NMR (MeOD-d3) 5 5.82-5.70 (m, 1H), 5.29 (d, J=17. 0Hz, 1H), 5.17 (dd,J=1.3,10.2Hz, 1H), 4.35 (dd, J=7.5,10.2Hz, 1H), 4.19 (m, 1H), 3.65 (dd, J=3.4, 9.8Hz, 1 H), 3.01 (m, 1 H), 2.55 (m, 1 H), 2.08-1.97 (m, 1 H), 2.04 (s, 3H), 1.62-1.31 (m, 8H), 0.91 (t, J=6.4Hz, 3H) MS:STDC0513 (M-H)-= 281, (M+H) + = 283 Example 125EMI332.1 ()- (2R. 3S. 5R. 1'S)-2- (1-Acetamido-4-methvhpentvl-3-vinvl-pyrrolidine-5- carboxylic Acid Hydrochloric Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper (l) bromide-dimethyl sulfide complex according to the methods described in Example 123M, substituting iso-butylmagnesium chloride for ethylmagnesium bromide..

'H NMR (MeOD-d3) 8 5.83-5.71 (m, 1H), 5.29 (dd, J=0.7,17.0Hz, 1H), 5.17 (dd, J=0.7,10.2Hz, 1H), 4.34 (dd, J=7.5,10.2Hz, 1H), 4.15 (m, 1H), 3.66 (dd,J=3.4,9.8Hz, 1 H), 3.01 (m, 1 H), 2.55 (m, 1 H), 2.08-1.97 (m, 1 H), 2.04 (s, 3H), 1.65-1.10 (m, 5H), 0.91 (d, J=6.4Hz, 3H), 0.91 (d, J=6.5Hz, 3H) (M+H) + = 283 Example 126EMI333.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-3,3dimethyl)butyl-3-vinyl-pyrrolidine-5- carboxylic Acid Hydrochloric Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper (l) bromide-dimethyl sulfide complex according to the methods described in Example 123M,STDC0106 substituting 1M tert-butylmagnesium chloride for 1 M ethylmagnesium bromide.

'H NMR (MeOD-d3) 8 5.84-5.71 (m, 1H), 5.31 (d, J=17.0Hz, 1H), 5.19 (d, J=10.2Hz, 1H), 4.39-4.33 (m, 2H), 3.66 (dd, J=3.4,9.8Hz, 1H), 3.02 (m, 1H), 2.57 (m, 1H), 2.08-1.97 (m, 1H), 2.02 (s, 3H), 1.55 (dd, 6Hz, 1H), 1.42 (dd,J=1.4,14.6Hz, 1H), 0.95 (s, 9H) (M+H) + = 283 Example 127EMI334.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-phenyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloric Acid Salt Lithium diphenylcurpate was prepared according to the method described by Lipshutz, B.STDC0339 H. in Organometallics in Svnthesis; Schlosser, M., Ed.; Wiley andSons: New York, 1994; p. 292. This cuprate was used according to the methods described in Example 123M, substituting lithium diphenylcuprate for the Grignard derived diethylcuprate complex.

1H NMR (MeOD-d3) # 7.35-7.21 (m, 5H), 5.87-5.75 (m, 1H), 5.37 (d, J=16.6Hz, 1H), 5.26 (dd, J=1.0, 10.2Hz, 1H), 4.53 (m, 1H), 4.37 (dd, J=7.5, 9.8Hz, 1H), 3.70 (dd, J=3.7,9.8Hz, 1H), 3.11 (m, 1H), 2.97 (dd, J=6.1,14.2Hz, 1H), 2.84 (dd, J=9.5,14.2Hz, 1H), 2.59 (m, 1H), 2.08-1.99 (m, 1H), 1.93 (s, 3H) (M-H)-=(M-H)-=301, (M+H)+ 303 Example 128EMI335.1 ()- (2R, 3S, 5R, 1'S)-2-(1-Acetamido-4-phenyl)STDC0368butyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloric Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper (l) bromide-dimethyl sulfide complex according to the methods described in Example 123M, substituting 1M phenethylmagnesium chloride for 1 M ethylmagnesium bromide.

1H NMR (MeOD-d3) 6 7.29-7.13 (m, 5H), 5.77-5.65 (m, 1 H), 5.24 (d, J=16.6Hz, 1H), 5.13 (dd, J=1.0,9.8Hz, 1H), 4.33 (dd, J=7.5,10.2Hz, 1H), 4.22 (m, 1 H), 3.62 (dd, J=3.4,9.8Hz, 1H), 2.98 (m, 1H), 2.63 (m, 2H), 2.54 (m, 1 H), 2.06-1.95 (m, 1H), 2.03 (s, 3H), 1.79-1.STDC0571 55 (m, 4H) (M+H)+=331(M-H)-=329, Example 129EMI336.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-3-phenyl)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloric Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper (l) bromide-dimethyl sulfide complex according to the methods described in Example 123M, substituting 2M benzylmagnesium chloride for 1M ethylmagnesium bromide.

1H NMR (MeOD-d3) 8 7.30-7.17 (m, 5H), 5.82-5.70 (m, 1H), 5.28 (d, J=17. 0Hz, 1H), 5.17 (d, J=11.2Hz, 1H), 4.33 (dd, J=7.5,10.2Hz, 1H), 4.18 (m, 1H), 3.64 (dd, 8Hz, 1H), 3.01 (m, 1H), 2.78 (m, 1H), 2.66-2.50 (m, 2H), 2.07 (s, 3H), 2.07-1.85 (m, 3H) (M+H)+=317(M-H)-=315, Example 130 (t)--(2R. 3S. 5R, 1'S)-2- (1-Acetamido-2-propen-2-yl) ethyl-3-vinvl-pvrrolidine-5- carboxylic Acid Trifluoroacetic Acid SaltEMI337.1 130A (t)- (2R. 3S, 5R.STDC0150 1'S)-1-t-Butoxycarbonyl-2- (N-t-Butoxycarbonvlaziridinyl)-3- vinyl-pyrrolidine-5-carboxviic Acid t-Butyl Ester.

(#)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5- carboxylic acid t-butyl ester (0.058 g, 0.17 mmole) was reacted with di-tbutyldicarbonate (95 mg, 0.44 mmole) and triethylamine (0.12 mL, 0.86 mmole) in dichloromethane (2.0 mL) at room temperature for 1 hour. The reaction was quenched with saturated sodium bicarbonate (1.0 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using a gradient of 0-15% ethyl acetate/dichloromethane to provide the title compound (yield: 0.060 g, 80%).

'H NMR (DMSO-d6) (rotamers) 8 5.97-5.78 (m, 1H), 5.06-4.93 (m, 2H), 4.15 (dd, J=2.0,9.8Hz, 1H), 3.40-3.28 (m, 1H), 2.94-2.49 (m, 3H), 2.39 and 2.33 (2d, J=6.1,6.4Hz, 1H), 2.17 and 2.11 (2d, J=3.7,3.4,1H), 1.81-1.69 (m, 1H), 1.42-1.36 (m, 27H) MS: (M+Na) += 461 (weak) EMI338.1 130B ()- (2R,3S. 5R. 1'S)-1-t-Butoxvcarbonyl-2- (1-N-t-butoxvcarbonylamino-2- propen-2-yl) ethyl-3-vinvl-pyrrolidine-5-carboxvlic Acid t-Butvl Ester.

To a suspension of copper (l) bromide-dimethyl sulfide complex (0.026g, 0.127 mmol) in THF (1.0 ml) at 0 C was added isopropenylmagnesium bromide (0.5M) (1.0 ml, 0.50 mmol) in THF. After stirring for 10 minutes at 0 C, the mixture was cooled to-78 C and a solution of ()- (2R, 3S, 5R, 1'S)-1-t- butoxycarbonyl-2- (N-t-butoxycarbonylaziridinyl)-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (0.030 g, 0.068 mmole) in THF (1.0 ml) was added dropwise.

After stirring for 10 minutes at-78 C, the reaction was warmed to 0 C and stirred for 2 hours. The reaction was quenched with saturated ammonium chloride (1.0 mL) and diluted with ethyl acetate (10 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using a gradient of 0-10% ethyl acetate/dichloromethane to provide the title compound (yield: 0.026 g, 79%).

1H NMR (DMSO-d6) (rotamers) 6 6.64 (m, 1H), 5.96-5.76 (m, 1H), 4.98- 4.89 (m, 2H), (m, 2H), (m, 1 H), 3.94 (m, 1 H), 3.60-3.53 (m, 1H), 3.02-2.86 (m, 1H), 2.62-2.42 (m, 1H), 2.10-1.99 (m, 2H), 1.72 and 1.70 (2s, 3H), 1.72-1.55 (m, 1 H), 1.44-1.34 (m, 27H) MS:(M+H)+=481479, EMI339.1 130C (ffi)-(2R. 3S. 5R, 1'S)-1-t-Butoxvcarbonvl-2-(1-N-t-butoxvcarbonviacetamido- 2-propen-2-vl) yl-3-vinvl-pvrrolidine-5-carboxylic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'S)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2- propen-2-yl) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (0.024 g, 0.050 mmole) was reacted with lithium hexamethyidisilazide (1 M) (0.60 mL, 0.60 mmole) in THF (2.0 mL) at-25 C for 1 hour. To the above reaction was then added acetyl chloride (0.085 mL, 1.20 mmole) at-25 C and the mixture was stirred for 30 minutes. The reaction was quenched with saturated sodium bicarbonate (2.0 mL) and stirred for 30 minutes at room temperature. The reaction was diluted with ethyl acetate (20 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo.STDC0199 The residue was purified by chromatography on silica gel using a gradient of 0-15% ethyl acetate/hexanes to provide the title compound (yield: 0.015 g, 58%) along with unreacted starting material.

'H NMR (DMSO-d6) (rotamers) 8 6.01-5.84 (m, 1H), 4.99-4.89 (m, 2H), (m, 3H), 4.33 and 4.23 (2d, J=7.8,8.1Hz, 1H), (m, 1H), 2.69 (m, 1H), 2.62-2.42 (m, 1H), 2.29 (br s, 3H), 2.35-2.14 (m, 2H), 1.76-1.55 (m, 1H), 1.60 (s, 3H), 1.50-1.35 (m, 27H) MS:STDC0631 (M+H) += 523 EMI340.1 130D -3-vinyl-pyrrolidine5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-N-tbutoxycarbonylacetamido-2-propen-2-yl) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (#)-(2R, 3S, 5R, 1'R, 2'S)-1-t butoxycarbonyl-2- (1- acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. (yield: 12 mg, 99%).

1H NMR (MeOD-d3) # 5.83-5.70 (m, 1H), 5.30 (dd, J=0.7,17.0Hz, 1H), 5.19 (d, J=10.2Hz, 1H), 4.79 (s, 1H), 4.71 (s, 1H), 4.46 (m, 1H), 4.30 (dd, J=7.8, 9.8Hz, 1H), 3.66 (dd, J=3.7,9.8Hz, 1H), 3.03 (m, 1H), 2.56 (m, 1H), 2.40-2.19 (m, 2H), 2.08-1.96 (m, 1H), 2.01 (s, 3H), 1.76 (s, 3H) (M-H)-= 265, (M+H) + = 267 Examples 131-135 EMI340.2 <tb> <SEP> <tb> <SEP> 1. <SEP> Organocuprate<tb> <SEP> . <SEP> OtBu <SEP> AcHN?,.,OH<tb> <SEP> 2.STDC0824 <SEP> LiHMDS'N<tb> BocHNs <SEP> H <SEP> goc <SEP> <tb> <SEP> 4. <SEP> TFA/CH2CI2<tb> <SEP> TFA<tb> The following title compounds were prepared in 4 steps according to the methods described in Example 130 the denoted reagents for step 1 and their respective methods of preparation are substituted in place of isopropenyl cuprate and its preparation in 130B Example 131EMI341.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-1-(cis and trans)-propen-1-vl) ethyl-3-vinvl- pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper (l) bromide-dimethyl sulfide complex according to the methods described in Example 130B,STDC0122 substituting 0.5M 1-propenylmagnesium bromide (mixture of cis and trans isomers) for 0.5M isopropenylmagnesium bromide.

'H NMR (MeOD-d3) (2: 1 trans: cis ratio) 6 5.81-5.54 (m, 2H), 5.43-5.30 (m, 1H), 5.33-5.27 (m, 0.33H, cis isomer), 5.31-5. 25 (m, 0.66H, trans isomer), 5.205.15 (m, 1H), (m, 2H), 3.65 (dd, J=3.4,9.8Hz, 1H), 2.98 (m, 1H), 2.582.48 (m, 1H), 2.45-2.19 (m, 2H), 2.08-1.94 (m, 1H), 2.02 (s, 3H), 1.68 (m, 2H, trans isomer), 1.63 (m, 1 H, cis isomer) (M-H)-= 265, (M+H) + = 267 Example 132EMI342.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-allyl)methyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper (l)STDC0174 bromide-dimethyl sulfide complex according to the methods described in Example 130B, substituting 1M vinylmagnesium bromide for 0.5M isopropenylmagnesium bromide.

'H NMR (MeOD-ds) 8 5.83-5.70 (m, 2H), 5.28 (d, J=17.0Hz, 1H), 5.19-5.13 (m, 3H), 4.28 (m, 1H), 4.19 (dd, J=8.5,9.1Hz, 1H), 3.66 (dd, J=3.4,9.5Hz, 1H), 2.99 (m, 1H), 2.57-2.48 (m, 1H), 2.44-2.26 (m, 2H), 2.05-1.93 (m, 1H), 2.01 (s, 3H) (M+H) + = 253 Example 133EMI343.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido)-2-(1-buten-2-yl)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper (1) bromide-dimethyl sulfide complex according to the methods described in Example 130B,STDC0116 substituting 0.5M 1-buten-2-ylmagnesium bromide for 0.5M isopropenylmagnesium bromide.

1H NMR (MeOD-d3) 5 5.81-5.73 (m, 1H), 5.30 (d, J=17.1Hz, 1H), 5.19 (d, J=10. 0Hz, 1H), 4.93 (s, 1H), 4.83 (s, 1H), 4.45 (m, 1H), 4.31 (dd, J=7.6,9.8Hz, 1H), 3.69 (dd, J=3.2,9.8Hz, 1H), 3.03 (m, 1H), 2.59-2.53 (m, 1H), 2.38 (dd,J=5.9,14.9Hz, 1H), 2.30 (dd, J=9.5,14.9Hz, 1H), 2.07 (q, J=7.6Hz, 2H), 2.051.99 (m, 1 H), 2.01 (s, 3H), 1.05 (t, J=7.6Hz, 3H) (M+H) + = 281 Example 134EMI344.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(trans-2-buten-2-yl)STDC0445ethyl-3-vinyl-pyrrolidine- 5-carboxylic Acid Trifluoroacetic Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper (l) bromide-dimethyl sulfide complex according to the methods described in Example 130B, substituting 0.5M 1-methyl-1- propenylmagnesium bromide for 0.5M isopropenylmagnesium bromide.

1H NMR (MeOD-d3) # 5.83-5.71 (m, 1H), 5.41 (q, J=6.8Hz, 1H), 5.31 (d, J=17.3Hz, 1H), 5.19 (d, J=10.2Hz, 1H), 4.42 (m, 1H), 4.31 (dd, J=7.5,9.8Hz, 1H), 3.61 (dd, J=4.0,9.8Hz, 1 H), 3.01 (m, 1 H), 2.62-2.52 (m, 1 H), 2.46 (dd, J=9.5, 13.9Hz, 1H), 2.26 (dd, J=5.8,13.9Hz, 1H), 2.09-1.99 (m, 1H), 2.00 (s, 3H), 1.72 (s, 3H), 1.59 (d, J=6.8Hz, 3H) (M+H) + = 281 Example 135EMI345.1 ()- (2R. 3S. 5R. 1'S.STDC0412 3'RS)-2- (1-Acetamido-3-methvl) pentvl-3-vinvl-pvrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper (l) bromide-dimethyl sulfide complex according to the methods described in Example 130B, substituting 2M sec-butylmagnesium bromide for 0.5M isopropenylmagnesium bromide.

'H NMR (MeOD-d3) (1: 1 mixture of methyl isomers) 8 5.82-5.69 (m, 1H), 5.27 (d, J=17.0Hz, 0.5H), 5.25 (d, J=17.0Hz, 0.5H), 5.15 (d, J=10.2Hz, 1H), 4.33 (m, 1H), 4.18 (dd, J=2.7,7.5Hz, 0.5H), 4.15 (dd, J=3.0,7.8Hz, 0.5H), 3.62 (dd,J=3.1,9.8Hz, 0.5H), 3.57 (dd, 8Hz, 0.5H), 2.97 (m, 1H), 2.57-2.47 (m, 1H), 2.03-1.92 (m, 1H), 2.03 (s, 1.5H), 2.02 (s, 1.5H), 1.72-1.06 (m, 5H), 0.950.86 (m, 6H) (M+H) + = 283 Example 136 ()- (2R, 3S, 5R. 1'RS)-2- (1-Acetamido-1- (N-methyl-N-benzyicarbamovl) methyl-3- vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI346.1 1 36A (i)-(2R. 3S. 5R.STDC0547 1'R)-1-t-Butoxycarbonvl-2-(1-acetamido-1-carboxvl) methyl- 3-vinvl-pvrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method of Example 2B substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2-(1-acetamido-1- formyl) methyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester for () (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3-ethyl) pentyl-3-formyl-pyrrolidine-5carboxylic acid t-butyl ester.EMI346.2 STDC0574 136B(#)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N- benzvlcarbamoyl) methvl-3-vinyl-pvrrolidine-5-carboxvlic Acid t-Butyl Ester ()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl-2-(1-acetamido-1-carboxyl) met acetate (20mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound.

MS: (M+H) +=516, (M-H)-=514EMI347.1 136C (i)-(2R. 3S. 5R. 1'RS)-2-(1-Acetamido-1-(N-methvl-N- benzvlcarbamovl) methyl-3-vinvl-pvrrolidine-5-carboxylic Acid Trifluoroacetic AcidSalt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'RS)-1-t-butoxycarbonyl-2- (1acetamido-2- (N-methyl-N-benzylcarbamoyl) methyl-3-vinyl-pyrrolidine-5- carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl- 2- (1-acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid tbutyl ester (yield: 7 mg, 95%).

'H NMR (DMSO-d6) 8 8.52 ( d, J=9.7HZ, 1H), 7.30 (m, 5H), 5.65 (m, 1H), 5.12 (m, 4H), 4.62 (m, 1H), 4.40 (m, 2H), 3.70 (m, 1H), 2.90 (s, 3H), 2.20 (m, 2H), 1.96 (s, 3H), MS: (M+H) +=360, (M+23) + =382 Example 138 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(N-phenyl-carbonyloxy)ethyl-3-vinyl- nvrrotidine-5-carboxviic Acid Trifluoroacetic Acid SaltEMI348.1 138A (t)- (2R, 3S.STDC0861 5R, 1'R)-1-t-Butoxvcarbonvl-2- (1-acetamido-2-N-phenvl- carbonyloxy) ethvl-3-vinyi-pyrrolidine-5-carboxylic Acid t-Butvl Ester ()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-ydroxy) ethyl-3vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (18 mg, 0.045 mmole) was reacted with phenylisocyanate (16 mg, 0.14 mmole) and pyridine (0.1 ml) in THF (3 mL) at 25 C for 16 hours. The reaction was quenched with water (2 mL) and diluted with ethyl acetate (10 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound (yield: 7.5 mg, 33%).

MS: (M+H) +=518, (M-H)-=516 EMI349.1 138B(#)-(2R,3S,5R,1'S)-2-(1-Acetamido-1-(N-phenylcarbonyloxy)ethyl-3-vinyl- pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-N-phenyl-carbonyloxy) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t- butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4 mg, 95%).

1H NMR (DMSO-d6) d 8.36 ( d, J=9.7HZ, 1H), 7.30 (m, 5H), 5.78 (m, 1H), 5.22 (m, 1H), 5.10 (m, 1H), 4.58 (m, 1H), 4.45 (m, 1H), 4.14 (, 2H), 3.58 (m, 1H), 2.88 (m, 1H), 2.27 (m, 1H), 2.12 (m, 1H), 1.88 (s, 3H) MS:STDC0816 (M+H) +=362, (M+23) + =384, (M-H)-=360, (M+35)-=396 Example 139 ()- (2R, 3S. 5R, 1'R)-2--Acetamido-1-isobutyryloxy) ethvl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid SaltEMI350.1 139A ()- (2R. 3S. 5R. 1'R)-1-t-Butoxvcarbonvl-2- (1-acetamido-2isobutvrvloxy) ethvl-3-vinpyrrolidine-5-carboxylic Acid t-Butvl Ester ()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl-2- (1-acetamido-2-hydroxy) ethyl-3vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (15 mg, 0.04 mmole) was reacted with isobutyryl chloride (8 mg, 0.08 mmole) and triethylamine (8 mg, 0.08 mmole) in dichloromethane (4 mL) at 0 C for 2 hours. The reaction was quenched with water (3 mL) and diluted with ethyl acetate (20 mL).STDC0275 The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 30% ethyl acetate/hexanes to provide the title compound (yield: 11 mg, 63%).

MS: (M+H) +=469, (M-H)-=467 EMI351.1 139B (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-1-isobutyryloxy)ethyl-3-vinyl- pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2-(1acetamido-2-isobutyryloxy) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 6.0 mg, 96%).

'H NMR (DMSO-d6) 6 8.00 ( d, J=9.9HZ, 1H), 5.63 (m, 1H), 5.08 (m, 1H), 4.98 (m, 1 H), 4.35 (m, 1 H), 4.25 (m, 1 H), 4.08 (m, 1 H), 3.55 (m, 1 H), 3.45 (m, 1 H), 3.38 (m, 1H), 2.83 (m, 1H), 2.33 (m, 1H), 1.78 (s, 3H) MS:STDC0811 (M+H) + =243, (M+23) + =265, (M-H)-=241 Example 140 ()- (2R, 3S. 5R. 1'R)-2- (1-Acetamido-2-N-ethyl-thiocarbonvloxy) ethvl-3-vinvl- Qyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI352.1 140A ()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonvl-2- (1-Acetamido-2-N-ethyl- thiocarbonvloxv) ethvl-3yl-pyrrolidine-5-carboxvlic Acid t-Butvl Ester ()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl-2- (1-acetamido-2-hydroxy) ethyl-3vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (17 mg, 0.04 mmole) was reacted with ethylisothiocyanate (19 mg, 0.21 mmole) in pyridine (2 mL) at 70 C for 17 hours.STDC0359 The reaction was quenched with water (3 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 70% ethyl acetate/hexanes to provide the title compound (yield: 10 mg, 48%).

MS: (M+H) +=486, (M+23) + =508, (M-H)-= 485 EMI353.1 140B (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-N-ethyl-thiocarbonyloxy)ethyl-3- vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting (#)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1- t-acetamido-2-N-ethyl-thiocarbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 7 mg, 94%).

1H NMR (DMSO-d6) #8. 30 (d, J=9.7HZ, 1H), 5.78 (m, 1H), 5. 25 (m, 1H), 5.12 (m, 1H), 4.50 (m, 1H), 4.33 (m, 1H), 4.18 (m, 2H), 3.72 (m, 1H), 3.55 (m, 2H), 2.30 (m, 1H), 2.10 (m, 1H), 1.82 (s, 3H), 1.17 (m, 3H) MS:STDC0441 (M+H) + =330, (M-H)-=328 Example 141 ()- (2R, 3S, 5R, 1'S)-2- (1-Acetamido-2-amino) ethyl-3-vinyl-pvrrolidine-5-carboxvlic Acid HydrochlorideSaltEMI354.1 141A(#)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-tbutoxycarbonylamino) ethyl-3-vinvi-pvrrolidine-5-carboxvlic Acid t-Butvl Ester.

()- (2R, 3S, 5R, 1'S)-1-t-Butoxycarbonyl-2- (1-acetamido-2-azido) ethyl-3-vinylpyrrolidine-5-carboxylic acid t-butyl ester (9.5 mg, 0.022 mmole) was reacted with triphenylphosphine (23.5 mg, 0.090 mmole) in ethanol (180 FL) and water (45 pL) at 70 C for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (220 pL) and to it was added di-tert- butyl dicarbonate (7.3 mg, 0.034 mmol) and N, N-diisopropylethylamine (11.7 mL, 0.067 mmol) at 25 C. After 1 hour the reaction mixture was diluted with water and extracted with ethyl acetate.STDC0301 The organic layers were combined, washed with brine, dried over MgS04, and concentrated in vacuo. The residue was purified by chromatography on silica gel using 100% dichloromethane to 50% dichloromethane/ethyl acetate to provide the title compound (yield: 7.5 mg, 67%).

'H NMR (DMSO-d6) (rotamers) 6 7.51 (d, J=10.5Hz, 1 H), 6.80-6.66 (m, 1 H), 5.90-5.76 (m, 1H), (m, 2H), (m, 1H), 3.98-3.94 (m, 1H), 3.683.62 (m, 1H), 3.09-2.73 (m, 2H), 2.60-2.42 (m, 1H), 1.80 (s, 3H), 1.72-1.62 (m, 1H), 1.42-1.34 (m, 27H).

MS: (M+H) +=498, (M+Na) +=520, (M-H)-=496, (M+CI)--532 EMI355.1 141 B (+)-(2R. 3S, 5R, 1'S)-2-(1-Acetamido-2-amino) ethvl-3-vinvl-nvrrolidine-5- carboxylic Acid DiHvdrochloride The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido2-t-butoxycarbonylamino) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of () (2R, 3R, 5R, 1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethylpyrrolidine-5-carboxylic acid t-butyl ester (yield: 3.65 mg, 99%).

'H NMR (DMSO-d6) 6 8. 24 (d, J=7.9Hz, 1H), 5.75-5.68 (m, 1H), 5.16 (d,J=17.1Hz, 1H), 5.06 (d, J=10.4Hz, 1H), 4.37-4.27 (m, 2H), 3.60-3.16 (m, 2H), 3.002.88 (m, 2H), 2.46-2.36 (m, 1H), 1.91-1.81 (m, 1H), 1.86 (s, 3H).

MS: (M+H) +=242, (M+Na) +=264, (M-H)-=240, (2M-H)-=481 Example 142 ()- 3S, 5R, 1'S)-2- (1-Acetamido-2-acetamido) ethvl-3-vinvl-pvrrolidine-5- carboxvlic Acid HvdrochlorideEMI356.1 142A (#)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-acetamido)ethyl- 3-vinyi-pyrrolidine-5-carboxvlic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'S)-1-t-Butoxycarbonyl-2- (1-acetamido-2-amino) ethyl-3vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (9.4 mg, 0.024 mmole) was reacted with acetic anhydride (11.2 p. L) and triethylamine (33.1 L) in dichloromethane (0.23 mL) at 0 C for 1 hour. The reaction was diluted with water (3 mL), extracted with ethyl acetate (12 mL), washed with brine, dried overMgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel using 100% ethyl acetate to 90% ethyl acetate/methanol to provide the title compound (yield: 6.8mg, 66%).

'H NMR (DMSO-d6) (rotamers) # 7.79-7.74 (m, 1H), 7.54 (d, J=9.8Hz, 1H), 5.97-5.81 (m, 1H), (m, 2H), (m, 1H), 3.97-3.90 (m, 1H), 3.683.63 (m, 1H), 3.21-3.15 (m, 1H), 3.10-2.76 (m, 1 H), 2.88-2.78 (m, 1H), 2.58-2.45 (m, 1H), 1.81 (s, 3H), 1.78 (s, 3H), 1.76-1.64 (m, 1H), 1.42-1.36 (m, 18H).

MS: (M+H) +=439, (M+Na) +=462, (M-H)-=438, (M+35)-=474 EMI357.1 142B ()- (2R. 3S, 5R. 1'S)-2- (1-Acetamido-2-acetamido) ethyl-3-vinvl-pyrrolidine-5- carboxylic Acid Hvdrochloride The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3S, 5R, 1'S)-2- (1,2-di-acetamido) butyl-3-vinylpyrrolidine-5-carboxylic acid Hydrochloridesalt in place of () (2R, 3R, 5R, 1'S)-2- (1- acetamido-3-ethyl) pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 3.30 mg, 80%).

MS: (M+Cl)-=318(M-H)-=282, Example 143 (i)-(2R, 3S, 5R, 1'S)-2-(1-Acetamido-2-azido) ethvl-3-vinvl-nvrrolid ine-5-carboxylic Acid HydrochlorideEMI357.2 143A(3)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-N-acetamido-2-azido)ethyl-3t-ButylEster.vinyl-pyrrolidine-5-carboxylicAcid ()- (2R, 3S, 5R, 1'S)-1-t-Butoxycarbonyl-2-(N-acetylaziridinyl)-3-vinyl-pyrrolidine-5carboxylic acid t-butyl ester (21.6 mg, 0.064 mmole) was reacted with sodium azide (41.6 mg, 0.64 mmole) and ammoniun chloride (34.2 mg, 0.64 mmol) in ethanol (270 pL) and water (30 L) at 75 C for 1 hour. The ethanol was then removed in vacuo and the remaining aqueous was extracted with ethyl acetate.

The combined organics were washed with brine, dried over MgSO4, and concentrated in vacuo (crude yield: 20mg, 82%). To the crude mixture was added acetic anhydride (31 L, 0.33 mmol) and triethylamine (92 pL, 0.66 mmol) in dichloromethane (330 pL) at 0 C for 30 minutes. The reaction mixture was then concentrated in vacuo. The residue was purified by chromatography on silica gel using 100% dichloromethane to 50% dichloromethane/ethyl acetate to provide the title compound (yield: 10 mg, 60%).

'H NMR (DMSO-d6) (rotamers) 6 7.85 and 7.81 (d, J=9.5Hz and 9.8Hz, 1H), 5.94-5.80 (m, 1H), (m, 2H), (m, 1H), 4.04-3.96 (m, 1H), 3.72-3.66 (m, 1H), 3.41-3.21 (m, 2H), 3.09-2.79 (m, 1H), 2.59-2.46 (m, 1H), 1.841.82 (m, 3H), 1.79-1.53 (m, 1H), 1.43-1.35 (m, 18H).

MS: (M+H) +=424, (M+Na) +=446, (2M+Na) +=869, (M-H)-=422, (M+CI)-=458 EMI358.1 1 43B (+)-(2R, 3S, 5R. 1'S)-2-(1-Acetamido-2-azido) ethvl-3-vinvl-pvrrolidine-5- carboxylic Acid Hydrochloric Salt.

The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3S, 5R, 1'S)-1-t butoxycarbonyl-2- (1-acetamido- 2-azido) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of () (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethyl-pyrrolidine-5carboxylic acid t-butyl ester (yield: 2.94 mg, 93%).

'H NMR (DMSO-d6) # 8.24 (d, J=8.55Hz, 1H), 5.74-5.67 (m, 1H), 5.14 (d,J=17. 1Hz, 1H), 5.06 (d, J=10.4Hz, 1H), 4.41-4.35 (m, 2H), 3.57-3.36 (m, 3H), 2.932.90 (m, 1H), 2.44-2.38 (m, 1H), 1.96-1.84 (m, 1H), 1.84 (s, 3H).

MS: (M+H) +=268, (M-H)-=266, (M+CI)-=302 Example 144 ()- (2R. 3S. 5R. 1'S)-2-(1-Acetamido-2-N-methylamino)ethyl-3-vinyl-pyrrolidine-5carboxylic Acid DihvdrochlorideEMI359.1 144A (t)- (2R. 3S. 5R, 1'S)-1-t-Butoxvcarbony1-N-acetamido-2-N- methylamino) ethyl-3-vinvl-pyrrolidine-5-carboxylic Acid t-butyl Ester.

Methylamine (. 016 g,. 53 mmole) was reacted with N, O-bis- trimethylsilylacetamide (. 079 g,. 39 mmole) in DMSO (0.8 mL) at 0 C for 1 hour.

()- (2R, 3S, 5R, 1'S)-1-t-Butoxycarbonyl-2- (N-acetylaziridinyl)-3-vinyl-pyrrolidine-5- carboxylic acid t-butyl ester (. 040 g,. 11 mmole) was then reacted with the above reagent N-trimethylsilylmethylamine at 75 C for 18 hours. The reaction was diluted with ethyl acetate (7 mL) washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using chloroform-methanol-ammonia to provide the title compound (yield:. 011 g, 25%).

'H NMR (CDC13) 8 5.78-5.98 (m, 1H), 5.90-5.04 (2m, 2H), 4.40-4.55 (brm, 1H), 3.90-4.02 (m, 1 H), 3.64-3.75 (2m, 1 H), 2.25-2.40 (brm 3H), 2.83,2.85 (2d, 3H), 1.42,1.44 (2s, 9H), 1.34,1.37 (2s, 9H).

MS : (M+H) += 412 EMI360.1 144B ()- (2R. 3S. 5R, 1'S)-2- (1-Acetamido-2-N-methvlamino) ethvl-3-vinyl- Pvrrolidine-5-carboxylic Acid Dihvdrochloride Salt The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido- 2-N-methylamino) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of () (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethyl-pyrrolidine5-carboxylic acid t-butyl ester (yield: 7.2 mg, 99%).

1H NMR (DMSO-d6) 5 8.25 (d, 1H), 5.70 (m, 1H), 5.10 (m, 2H), 4.50 (m, 1H), 4.40 (m, 1H), 2.55 (s, 3H), 1.85 (s, 3H).

MS: (M+H) += 256 Examples 145-164EMI361.1 The following title compounds were prepared according to the methods described in Examples 141-144 where R'is equal to hydrogen. Where R or R' are not equal to hydrogen the corresponding amine is used directly without the intermediacy of trimethylsilylation.

Example 145EMI361.2 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-N-isopropylamino)ethyl-3-vinyl-pyrrolidine- 5-carboxylic Acid Dihvdrochloride Salt 'H NMR (DMSO-d6) 8.30 (d, 1H), 5.70 (m, 1H), 5.10 (m, 2H), 4.40 (br, 2H), 3.52-3.68 (br, 1H), 3.10-3.20 (br, 1H), 2.82-2.97 (br, 1H), 2.37-2.47 (br, 1H), 1.88 (s, 3H), 1.25 (d, 6H).

MS: (M+H) += 284 Example 146EMI362.1 ()- (2R, 3S, 5R, 1'S)-2-(1-Acetamido-2-N-butylamino)ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Dihydrochloride Salt 1 NMR (DMSO-d6) 8.25 (d, 1H), 5.70 (m, 1H), 5.10 (m, 2H), 4.50 (m, 1 H), 4.38 (m, 1 H), 3.60 (m, 1 H), 2.90 (m, 3H), 2.40 (m, 2H), 1.87 (s, 3H), 1.62 (m, 2H), 1.33 (m, 2H), 0.90 (t, 3H).

MS: (M+H) += 298 Example 147EMI362.2 ()- (2R, 3S, 5R. 1'S)-2- (1-Acetamido-2-N-benzvlamino) ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid HvdrochlorideSalt 1H NMR (DMSO-d6) # 7.56-7.43 (m, 5H), 5.74-5.67 (m, 1H), (m, 2H), 4.56 (m, 1H), 4.27-3.93 (m, 3H), 3.66-3.15 (m, 3H), 2.91-2.88 (m, 1H), 2.642.34 (m, 2H), 1.86 (s, 3H).

MS: (M+H) +=332, (M+Na) +=354, (M-H)-=330, (2M-H)-=661 Example 148EMI363.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-N-phenethylamino)ethyl-3-vinyl-pyrrolidine- 5-carboxylic Acid Salf 1H NMR (DMSO-d6) # 8.25 (d, 1H), 7.30 (m, 5H), 5.70 (m, 1H), 5.10 (m, 2H), 4.50 (br, 1H), 4.35 (br, 1H), 3.61 (m, 1H), 3.17 (m, 3H), 2.98 (m, 3H), 2.42 (m, 1H), 1.88 (s, 3H).

MS: (M+H)+= 346 Example 149EMI363.2 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-N,N-dimethylamino)ethyl-3-vinyl-pyrrolidine- 5-carboxylic Acid Salt 1H NMR (DMSO-d6) 8 8.34 (d, J=9.2Hz, 1H), 5.74-5.67 (m, 1H), 5.12 (d,J=17.1Hz, 1H), 5.04 (d, J=10.4Hz, 1H), 4.67-4.62 (m, 1H), 4.40 (dd, J=7.3,10.4Hz, 1H), 3.60-3.11 (m, 3H), 2.96-2.83 (m, 1H), 2.50 (s, 6H), 2.44-2.38 (m, 1H), 1.921.84 (m, 1H), 1.84 (s, 3H). MS: (M+H) +=270, (M+Na) +=292, (M-H)-=268.

Example 150EMI364.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-N,N-diethylamino)ethyl-3-vinyl-pyrrolidine- 5-carboxylic Acid Dihvdrochloride Salt 1H NMR (DMSO-d6) 5 8.23 (d, 1H), 5.70 (m, 1H), 5.10 (m, 2H), 4.60 (br, 1H), 4.40 (br, 1H), 3.12 (m, 4H), 2.88 (m, 1H), 2.42 (m, 1H), 1.85 (s, 3H), 1.22 (t, 3H).

MS: (M+H) += 298 Example 151EMI365.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-N,N-dibutylamino)ethyl-3-vinyl-pyrrolidine- 5-carboxylic Acid Dihydrochloride Salt 1H NMR (DMSO-d6) # 8.24 (d, 1H), 5.70 (m, 1H), 5.08 (m, 2H), 4.48-4.62 (br, 1 H), 4.28-4.43 (1 H), 3.05 (m, 4H), 2.77-2.92 (br, 1 H), 2.34-2.46 (br, 2H), 1.84 (s, 3H), 1.64 (m, 4H), 1.30 (m, 4H), 0.93 (t, 6H).

MS: (M+H) += 354 Example 152EMI365.2 ()- (2R, 3S. 5R. 1'S)-2- (1-Acetamido-2- (N-2-hvdroxyethylamino)) ethyl-3-vinvl- pvrrolidine-5-carboxvlic Acid Dihvdrochloride Salt NMR (DMSO-de) 8.20 (d, 1H), 5.70 (m, 1H), 5.15 (d, 1H), 5.08 (d, 1H), 4.50 (brm, 1H), 4.38 (brm, 1 H), 3.68 (M, 1 H), 3.0 (brm, 2H), 2.90 (m, 1H), 2.41 (m, 1H), 1.85 (s, 3H).

MS: (M+H)+= 286 Example 153EMI366.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(N-2-hydorxyethyl-N-ethylamino))ethyl-3vinvl-pyrrolidine-5-carboxylic Acid Dihvdrochloride Salt 'H NMR (DMSO-d6) 8 5.81-5.74 (m, 1H), 5.38 (d, J=17. 1Hz, 1H), 5.22 (d, J=10. 0Hz, 1H), 4.92-4.88 (m, 1H), 4.48 (dd, J=7.6,9.8Hz, 1H), 3.91 (t, J=4.9Hz, 2H), 3.85 (dd, J=5.6, 10.0Hz, 1H), 3.63-3.53 (m, 2H), 3.46-3.39 (m, 4H), 3.163.13 (m, 1H), 2.66-2.61 (m, 1H), 2.08 (s, 3H), 2.06-2.01 (m, 1H), 1.38 (t, J=7.33, 3H).

MS: (M+H) +=314, (M+Na) +=336, (M-H)-=312, (M+CI)-=348, (2M-H)-=625 Example 154EMI367.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(N-2-hydroxyethyl-N-propylamino))ethyl-3- DihydrochlorideSaltvinyl-pyrrolidine-5-carboxylicAcid 1H NMR (DMSO-d6) # 8.36 (d, J=8.5Hz, 1H), 5.75-5.68 (m, 1H), 5.13 (d,J=17.1Hz, 1H), 5.04 (d, J=10.4Hz, 1H), 4.62 (m, 1H), 4.36 (m, 1H), 3.77 (t, J=4.9Hz, 2H), 3.63-3.59 (m, 1H), 3.50-3.23 (m, 3H), 3.22-3.19 (m, 2H), 3.08 (t, J=7.3Hz, 2H), 2.91-2.87 (m, 1H), 2.44-2.39 (m, 1H), 1.99-1.88 (m,STDC0091 1H), 1.84 (s, 3H), 1.75-1.70 (m, 2H), 0.90 (t, J=6.7Hz, 3H).

MS: (M+H) +=328, (M+Na) +=350, (M-H)-=326, (M+CI)-=362, (2M-H)-=653 Example 155EMI367.2 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(imidazol-1-yl))ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Dihydrochloride aH NMR (MeOD-d3) #. 9.06 (s, 1H), 7.72 (s, 1H), 7.58 (s, 1H), 5.84-5.76 (m, 1H), 5.39 (d, J=17.1Hz, 1H), 5.23 (d, J=10.25Hz, 1H), (m, 1H), 4.52 4.43 (m, 2H), 3.92-3.89 (m, 1H), 3.20-3.17 (m, 1H), 2.67-2. 62 (m, 1H), 2.11-2.04 (m, 1H), 1.95-1.89 (m, 1H), 1.91 (s, 3H).

MS: (M+H) +=293, (M-H)-=291, (M+35) +=327.

Example 156EMI368.1 ()- (2R. 3S, 5R. 1'S)-2- (1-Acetamido-2- (N, N-di- (2-hydroxvethylamino)) ethvl-3-vinyl- pyrrolidine-5-carboxvlic Acid Dihvdrochloride Salt MS:(M-H)-=328,(M+Cl)-=364(M+Na)+=352, Example 157EMI368.2 (W2R. 3S. 5R. 1'S)-2- (1-Acetamido-2- (N-acetvl-N-methvlamino) ethvl-3-vinvl- pvrrolidine-5-carboxylic Acid Hydrochloride Salt 1H NMR (DMSO-d6) # 8.01,7.95 (2d, 1H), 5.68-5.80 (m, 1H), 5.02-5.22 (m, 2H), (brm, 2H), 3.26,3.21 (2d, 1 H), 2.82-2.95 (brm, 1 H), 2.38-2.48 (m, 1 H), 1.98,2.02 (2s, 3H), 1.79,1.82 (2s, 3H).

MS: (M+H) += 298 Example 158EMI369.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(N-2-hydroxyethyl-N-methylamino))ethyl-3- vinyl-pyrrolidine-5-carboxylic Acid Dihvdrochloride Salt 'H NMR (DMSO-d6) 8 8.35 (d, J=9.15Hz, 1H), 5.74-5.67 (m, 1H), 5.12 (d,J=17.1Hz, 1H), 5.04 (d, J=10.4Hz, 1H), 4.70 (m, 1H), 4.39 (dd, J=7.3,10.4Hz, 1H), 3.80-3.75 (m, 3H), 3.61-3.43 (m, 3H), 3.23-3.16 (m, 2H), 2.91-2.82 (m, 1H), 2.82 (s, 3H), 2.44-2.39 (m, 1H), 1.92-1.84 (m, 1H), 1.84 (s, 3H).STDC0509 MS: (M+H) +=300, (M+Na) +=322, (2M+H-H20) +=581 Example 159EMI369.2 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(N-propyl-N-methylamino)ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Dihvdrochloride Salt 1H NMR (DMSO-d6) (broad) # 8.3 (1H), 5.7 (1H), 5.12-5.04 (2H), 4.6 (1H), 4.35 (1H), 2.61-2.35 (11H), 1.9 (3H), 1.78-1.63 (2H), 1.9 (3H).

MS: (M+H) +=298, (M+Na) +=320, (M-H)-=296, (M+CI)-332, (2M-H)-=593 Example 160EMI370.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(N-cyclohexyl-N-methylamino))ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Hydrochloride Salt 1H NMR (DMSO-d6) # 8.26 (m, 1H), 5.75-5.65 (m, 1H), 5.08 (d, J=17.1Hz, 1H), 5.02 (d, J=10.3Hz, 1H), 4.62 (m, 1H), 4.43-4.40 (m, 1H), 3.62-3.58 (m, 1H), 3.46-3.16 (m, 2H), 2.89-2.84 (m, 1H), 2.72 (s, 3H), 2.44-2.39 (m, 1H), 2.07-1.80 (m, 5H), 1.81 (s, 3H), 1.63 (m, 1H), 1.45-1.06 (m, 6H).

MS: (M+H) +=338, (M+Na) +=360, (M-H)-=336, (M+CI)-=372 Example 161EMI370.2 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(N-benzyl-N-methylamino))ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Dihvdrochloride Salt 'H NMR (DMSO-d6) # 8.36 (m, 1H), 7.61-7.46 (m, 5H), 5.69-5.64 (m, 1H), 5.07 (d, J=17.1Hz, 1H), 4.99 (d, J=10.1Hz, 1H), 4.77 (m, 1H), 4.44-4.39 (m, 2H), 4.25 (d, J=12.9,1H), 3.61 (m, 1H), 3.43 (m, 1H), 3.22 (m, 1H), 2.93-2.85 (m, 1H), 2.73 (s, 3H), 2.44-2.38 (m, 1H), 1.92-1.85 (m, 1H), 1.85 (s, 3H)STDC0003.

MS: (M+H) +=346 Example 162EMI371.1 ()- (2R. 3S. 5R. 1'S)-2- (1-Acetamido-2-(N-phenethyl-N-methylamino))ethyl-3-vinylpyrrolidine-5-carboxylic Acid Dihydrochloride Salt 1H NMR (DMSO-d6) 8 8.34 (d, J=8.55Hz, 1H), 7.37-7.26 (m, 5H), 5.765.69 (m, 1H), 5.14 (d, J=17.1Hz, 1H), 5.06 (d, J=10.4Hz, 1H), 4.72 (m, 1H), 4.464.42 (m, 1H), 3.83-3.20 (m, 6H), 3.13-2.99 (m, 2H), 2.86 (s, 3H), 2.95-2.83 (m, 1H), 2.46-2.40 (m, 1H), 1.95-1.81 (m, 1H), 1.86 (s, 3H).

MS: (M+H) +=360 Example 163EMI372.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(N-napythylmethyl-N-methylamino))ethyl-3- vinvl-pvrrolidine-5-carboxvlic Acid Dihydrochloride Salt 1H NMR (DMSO-d6) # 8.41 (d, J=7.3Hz, 1H), 8.32-7.59 (m, 7H), 5.60 (m, 1H), 5.04 (d, J=17.1Hz, 1H), 4.91 (d, J=9.8Hz, 1H), 4.97-4.73 (m, 3H), 4.39 (m, 1H), 3.70-3.13 (m, 3H), 2.90 (m, 1H), 2.72 (s, 3H), 2.43-2.41 (m, 1H), 2.01-1.74 (m, 1H), 1.87 (s, 3H).

MS: (M+H) +=395, (M+Na) +=418, (M-H)-=394, (M+Cl)-=430, (2M-H)-=789 Example 164EMI373.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(N-morpholinyl))ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Dihvdrochloride Salt 'H NMR (DMSO-d6) 8 8.28 (d, 1 H), 5.75-5.78 (m, 1 H), 5.15 (d, 1 H), 5.05 (d, 1 H), 4.65 (brm, 1 H), 4.42 (m, 1 H), 3.72-3.98 (brm, 3H), 3.62 (m, 1 H), 2.90 (m, 1H), 2.38-2.48 (m, 1H), 1.85 (s, 3H).

MS: (M+H) += 312 Example 165 (#)-(2R,3S,5R,1'S,3'R)-2-(1-Acetamido-2-(N-methyl-N-t-butylamino-N- oxide)) ethvl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride SaltEMI374.1 165A ()- (2R. 3S, 5R. 1'S. 3'R) and (i)-(2R, 3S, 5R, 1'S, 3'S)-1-t-Butoxvcarbonyl-2- (1-acetamido-2-(N-methyl-N-t-butylamino-N-oxide))ethyl-pyrrolidine-5-carboxylicAcid t-Butvl Ester.

()- (2R, 3S, 5R, 1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-tbutylamino)) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (37 mg,. 08 mmole) was reacted with the m-chloroperoxybenzoic acid (20 mg,. 08 mmole) inCH2CI2 (0. 9 mL) at 0 C for 1 hour. The reaction was chromatographed directly on silica gel eluting with a gradient of acetone to acetone/30% MeOH to provide the title compounds isomer ()- (2R, 3S, 5R, 1'S, 3'R) (yield:. 010 g, 27%) and isomer ()- (2R, 3S, 5R, 1'S, 3'S) (yield :.011 g, 29%).EMI374.2 STDC0697 165B(#)-(2R,3S,5R,1'S,3'R)-2-(1-Acetamido-2-(N-methyl-N-t-butylamino-N- oxide)) ethvl-3-vinvl-pvrrolidine-5-carboxylic Acid Hydrochloride Salt The title compound was prepared according to the method described inExample 15C substituting ()- (2R, 3S, 5R, 1'S, 3'R)-1-t butoxycarbonyl-2- (1- acetamido-2- (N-methyl-N-t-butylamino-N-oxide)) ethyl-pyrrolidine-5-carboxylic acid t-butyl ester for ()- (2R, 3S, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3(imidazol-2-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 6 mg, 80%).

'H NMR (CD30D) 5 5.72-5.87 (m, 1H), 5.40 (d, 1H), 5.20-5.28 (m, 2H), (dd, 1H), 3.73-3.95 (m, 3H), 3.57 (s, 3H), 3.08-3.19 (m, 1H), 2.59-2.72 (m, 1H), 2.05-2.15 (m, 1H), 2.04 (s, 3H), 1.54 (s, 9H).

MS: (M+H) += 328 Examples 166-178EMI375.1 <tb> <SEP> = <SEP> 1. <SEP> MCPBA <SEP> =<tb> <SEP> 2.chromatographic<tb> OH <SEP> separation <SEP> ? <SEP> ACH <SEP> N-It <SEP> OH<tb> <SEP> 3. <SEP> sNHC <SEP> O <SEP> H <SEP> H"<tb> R'RN <SEP> R'RN<tb> <SEP> HCI<tb> The following title compounds were prepared according to the method described in Example 165.

Example 166EMI376.1 (#)-(2R,3S,5R,1'S,3'R)-2-(1-Acetamido-2-(N-methyl-N-isopropylamino-N- oxide)) ethyl-3-vinvl-pvrrolidine-5-carboxylic Acid Hydrochloride Salt 1 H NMR (MeOD-d3) # 5.87-5.74 (m, 1 H), 5.46-5.40 (m, 1 H), 5.27-5.23 (m, 1H), 5.21-5.18 (m, 1H), 4.50 (dd, J=8.1,9.8Hz, 1H), 4.04-3.87 (m, 4H), 3.54 (s, 3H), 3.20-3.14 (m, 1H), 2.69-2.60 (m, 1H), 2.12-2.01 (m, 1H), 2.05 (s, 3H), 1.50 (d, J=6.4Hz, 3H), 1.48 (d, J=6.4Hz, 3H).

MS: (M+H)+=314, (M+Na) +=336, (2M+1) += 627, (2M+Na) +=649.

Example 167EMI376.2 (#)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-methyl-N-propylamino-N-oxideethyl- HydrochlorideSalt3-vinyl-pyrrolidine-5-carboxylicAcid 1 H NMR (MeOD-d3) 8 5.87-5.74 (m, 1 H), 5.46-5.40 (m, 1 H), 5.27-5.23 (m, 1H), 5.21-5.18 (m, 1H), 4.50 (dd, J=8.1,9.8Hz, 1H), 4.04-3.87 (m, 4H), 3.54 (s, 3H), 3.20-3.14 (m, 1H), 2.69-2.60 (m, 1H), 2.12-2.01 (m, 1H), 2.05 (s, 3H), 1.50 (d, J=6.4Hz, 3H), 1.48 (d, J=6.4Hz, 3H).

MS: (M+H) +=314, (M+H-H20)-=295 Example 168EMI377.1 (#)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-methyl-N-ethylamino-N-oxide))ethyl- HydrochlorideSalt3-vinyl-pyrrolidine-5-carboxylicAcid 1 H NMR (MeOD-d3) 6 5.82-5.75 (m, 1H), 5.44 (d, J=17.1Hz, 1H), 5.26 (d, J=10.4Hz, 1H), 5.14-5.11 (m, 1H), (m, 1H), 4.9 (d, J=4.9Hz, 2H), 3.87 (dd, J=4.9,10.4Hz, 1H), 3.76 (q, J=6.7Hz, 2H), 3.54 (s, 3H), 3.17-3.09 (m, 1H), 2.68-2.62 (m, 1 H), 2.06 (s, 3H), 2.09-2.03 (m, 1 H), 1.45 (t, J=7.3Hz, 3H).

MS: (M+H) +=300, (M+Na) +=322, (M+H-H20) +=282 Example 169EMI378.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(N,N-dimethylamino-N-oxide)ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Hydrochloride Salt 'H NMR (DMSO-d6) # 8.58 (d, 1H), 5.67-5.78 (m, 1H), 5.20 (d, 1H), 5.08 (d, 1 H), (brm, 1 H), 4.25-4.42 (brm, 1 H), 4.06 (d, 1 H), 3.85-3.95 (brm, 1H), 3.88-3.98 (brm, 1H), 3.35-3.50 (brs, 6H), 2.36-2.48 (m, 1H), 1.92 (m, 1H), 1.85 (s, 3H).

MS: (M+H) += 286 Example 170EMI378.2 (#)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-methyl-N-benzylamino-N- HydrochlorideSaltoxide))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid 1H NMR (MeOD-d3) 5 7.60-7.47 (m, 5H), 5.75-5.65 (m, 1H), 5.39 (d,J=6.35Hz, 1 H), 5.21 (d, J=8.8Hz, 1 H), 5.18-5.11 (m, 1 H), (m, 2H), 4.35 4.27 (m, 1H), 4.00-3.94 (m, 2H), 3.86-3.79 (m, 1H), 3.20 (s, 3H), 3.14-3.05 (m, 1H), 2.77-2.50 (m, 1H), 2.08 (s, 3H), 2.10-2.94 (m, 1H).

MS: (M+H) +=362, (M+Na) +=385, (M-H)-=360, (M+35)-=396 Example 171EMI379.1 (#)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-methyl-N-t-butylamino-N-oxide)ethyl3-vinvl-pyrrolidine-5-carboxylic Acid HvdrochlorideSalt 1H NMR (CD3OD) # 5.80 (m, 1H), 5.44 (d, 1H), 5.27 (d, 1H), 5.08 (m, 1H), (dd, 1H), 3.83-3.94 (m, 3H), 3.38 (s, 3H), 3.02-3.18 (m, 1H), 2.58-2.72 (m, 1H), 2.08 (s, 3H), 1.97-2.08 (m, 1H), 1.55 (s, 9H).

MS: (M+H) += 328 Example 172EMI380.1 ()- (2R. 3S. 5R. 1'S. 3'S)-2- (1-Acetamido-2- (N-methvl-N-isopropvlamino-Noxide))ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride Salt 1 H NMR (MeOD-d3) # 5.86-5.74 (m, 1H), 5.53-5.47 (m, 1H), 5.29-5.25 (m, 1H), 5.22-5.19 (m, 1H), 4.50 (dd, J=8.1,9.5Hz, 1H), 4.13-4.04 (m, 2H), 3.96 (dd,J=4.1,10.5Hz, 1H), 3.87-3.82 (m, 1H), 3.39 (s, 3H), 3.23-3.17 (m, 1H), 2.70-2.61 (m, 1H), 2.11 (s, 3H), 2.08-2.00 (m, 1H), 1.50 (d, J=6.4Hz, 3H), 1.49 (d, J=6.4Hz, 3H).

MS: (M+H)+=314, (M+Na) +=336, (2M+1) +=627, (2M+Na) +=649.

Example 173EMI380.2 (#)-(2R,3S,5R,1'S,3'R)-2-(1-Acetamido-2-(N-methyl-N-propylamino-N- HydrochlorideSaltoxide))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid 'H NMR (MeOD-d3) 8 5.82-5.75 (m, 1H), 5.45 (d, J=17.1Hz, 1H), 5.26 (d, J=10.4Hz, 1H), 5.07-5.13 (m, 1H), (m, 1H), 3.98 (d, J=5.5Hz, 2H), 3.86 (dd, J=4.3,9.8Hz, 1H), 3.67-3.64 (m, 2H), 3.46 (s, 3H), 3.16-3.01 (m, 1H), 2.68-2.62 (m, 1 H), 2.09-2.02 (m, 1 H), 2.06 (s, 3H), 1.92-1.86 (m, 2H), 1.04 (t,J=7.3Hz, 3H).

MS: (M+H-H2O)-=295 Example 174EMI381.1 (#)-(2R,3S,5R,1'S,3'R)-2-(1-Acetamido-2-(N-methyl-N-ethylamino-N-oxide))ethyl- 3-vinvl-pvrrolidine-5-carboxylic Acid Hydrochloride Salt 1 H NMR (MeOD-d3) 8 5.82-5.75 (m, 1H), 5.45 (d, J=17. 1Hz, 1H), 5.26 (d, J=10.4Hz, 1H), 5.13-5.10 (m, 1H), (m, 1H), 4.02-3.94 (m, 2H), 3.89 (dd,J=4.3,9.8Hz, 1H), 3.82 (q, J=7.3Hz, 2H), 3.46 (s, 3H), 3.18-3.10 (m, 1H), 2.68-2.62 (m, 1 H), 2.09 (s, 3H), 2.07-2.02 (m, 1 H), 1.46 (t, J=7.3Hz, 3H).

MS: (M+H) +=300, (M+Na) +=322, (M+H-H20) +=282 Example175EMI382.1 (#)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-methyl-N-benzylamino-N- HydrochlorideSaltoxide))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid 1H NMR (MeOD-d3) b 7.60-7.47 (m, 5H), 5.75-5.65 (m, 1H), 5.39 (d,J=6.35Hz, 1H), 5.21 (d, J=8.8Hz, 1H), 5.18-5.11 (m, 1H), (m, 2H), 4.354.27 (m, 1H), 4.00-3.94 (m, 2H), 3.86-3.79 (m, 1H), 3.40 (s, 3H), 3.14-3.05 (m, 1H), 2.77-2.50 (m, 1H), 2.08 (s, 3H), 2.10-2.94 (m, 1H).

MS: (M+H) +=362, (M+Na) +=385, (M-H)-=360, (M+35)-=396 Example 176EMI382.2 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(N,N-diethylamino-N-oxide))ethyl-3-vinyl- pvrrolidine-5-carboxvlic Acid Hydrochloride Salt 1H NMR (MeOD-d3) # 5.84-5.78 (m, 1H), 5.45 (d, J=16.85Hz, 1H), 5.26 (d, J=10. 0Hz, 1H), 5.09-5.05 (m, 1H), (m, 1H), 3.96-3.86 (m, 3H), 3.76 (q, J=6.6Hz, 2H), 3.70 (q, J=7.3Hz, 2H), 3.15-3.11 (m, 1H), 2.68-2.62 (m, 1H), 2.082.02 (m, 1H), 2.08 (s, 3H), 1.44-1.38 (m, 6H).

MS: (M+H)+=314, (M+Na) +=336, (M+2Na) +=358 Example 177EMI383.1 (#)-(2R,3S,5R,1'S,3'R)-2-(1-Acetamido-2-(N-pyrrolidinyl-N-oxide))ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Hydrochloride Salt 1H NMR (DMSO-d6) 8 8.74 (d, 1H), 5.65-5.80 (m, 1H), 5.28 (d, 1H), 5.10 (d, 1H), 4.82 (m, 1H), (dd, 1H), 4.30 (d, 1H), 3.60-4.12 (brm, 5H), 2.983.15 (m, 1H), 2.38-2.48 (m, 1H), 2.05-2.20 (brm, 5H), 1.88-1.98 (m, 1H), 1.87 (s, 3H).

MS: (M+H)+= 312 Example 178EMI384.1 ()- (2R, 3S. 5R, 1'S)-2- (1-Acetamido-2- (N-morpholinyl-N-oxide) ethvl-3-vinyl- pvrrolidine-5-carboxylic Acid Hydrochloride Salt 'H NMR (DMSO-d6) 8 8.65 (d, 1H), 5.66-5.80 (m, 1H), 5.22 (d, 1H), 5.09 (d, 1H), 4.78 (brs, 1H), (dd, 1H), (brm, 2H), (brm, 9H), 2.92-3.04 (brm, 1 H), 2.37-2.48 (m, 1 H), 1.88-1.96 (m, 1 H), 1.87 (s, 3H).

MS: (M+H) += 328 Example 179 (#)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl- HydrochlorideSalt3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcidEMI384.2 179A (#)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-oxiranyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1231, substituting ethyltriphenylphosphonium bromide in place of methyltriphenylphosphonium bromide (yield: 350 mg, 77%).

'H NMR (CDC13) (rotamers) 5.55-5.43 (m, 2H), (m, 2H), 3.143.11 (m, 2H), 2.76-2.50 (m, 3H), 1.75-1. 70 (m, 1H), 1.64 (d, 3H), 1.48-1.43 (m, 18H).

MS: (M+H) +=354, (M+Na) +=376, (2M+Na) +=729EMI385.1 179B (i)-(2R. 3S, 5R, 1'R)-1-t-Butoxycarbonvl-2-(1-methanesulfonvioxv-3- azido) ethyl-3- (cis-propen-1-vl)-pyrrolidine-5-carboxviic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 123J, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-oxiranyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (#)- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido) butyl-3-vinyl-pyrrolidine-5carboxylic acid t-butyl ester (yield: 1.08 g, 84%).

'H NMR (DMSO-d6) (rotamers) 8 5.53-5.33 (m, 2H), (m, 1H), 4.20-3.90 (m, 2H), 3.76-3.62 (m, 2H), 3.24 (s, 3H), 2.59-2.49 (m, 1H), 1.641.55 (m, 5H), 1.43-1.36 (m, 18H).

MS: (M+H) +=475, (M+Na) +=497, (2M+Na) +=971 EMI386.1 179C (3)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-aziridinyl-3-(cis-propen-1-yl)pvrrolidine-5-carboxvlic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 123K, substituting (2R, 3S, 5R, 1'S)-1-t butoxycarbonyl-2- (1- methanesulfonyloxy-3-azido) ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2- (1- methanesulfonyloxy-3-azido) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (crude yield: 564 mg, 71%).

'H NMR (DMSO-d6) (rotamers) 5 5.45-5.30 (m, 2H), 4.15-3.99 (m, 1H), 3.30-3.08 (m, 1 H), 3.07-2.84 (m, 1 H), 2.68-2.51 (m, 1 H), 2.13-1.85 (m, 1 H), 1.801.05 (m, 3H), 1.57 (d, J=5.4Hz, 3H), 1.41-1.35 (m, 18H).

MS: (M+H) +=352, (M+23) +=375, (2M+H) +=705, (2M+23) +=727EMI386.2 179D ()- (2R. 3S,5R, 1'S)-1-t-Butoxycarbonyl-2- (N-acetylaziridinvl)-3- (cis-proaen- 1-vl)-Dvrrolidine-5-carboxylic Acid t-Butvl Ester.

The title compound was prepared according to the method described inExample 123L, substituting (#)-(2R,3S,5R,1'S)-1-t-buutoxycarbonyl-2-aziridinyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 455 mg, 72%).

'H NMR (DMSO-d6) (rotamers) 8 5.74-5.34 (m, 2H), 4.17 (dd, J=2.4, 6.35Hz, 1H), 3.41 (dd, J=1.95,6.35Hz, 1H), 3.14-2.99 (m, 1H), 2.73-2.58 (m, 2H), 2.40 (d, J=6.35Hz, 1H), 2.17-2.12 (m, 1H), 2.05-2.00 (m, 3H), 1.66-1.55 (m, 1H), 1.56 (d, J=6.8Hz, 3H), 1.41-1.31 (m, 18H).

MS: (M+H) +=395, (M+Na) +=417, (M+H+Na) +=418,EMI387.1 179E(#)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-N-ethyl-Nmethylamino) eth (cis-propen-1-yl)-pyrrolidine-5-carboxvlic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 150, substituting N-ethyl-N-methyl-amine in place of diethylamine (yield: 30 mg, 87%).

MS: (M+H) +=454, (M+Na) +=476, (M-H)-=452, (M+35)-=488 EMI388.1 179E ()- (2R. 3S. 5R. 1'S. 3'R) and ()- (2R, 3S. 5R. 1'S. 3'S)-1-t-Butoxvcarbonyl-2 (1-acetamido-2- (N-ethyl-N-methvlamino-N-oxide)) ethyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described inExample 165A, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-(1- acetamido-2- (N-ethyl-N-methylamino)) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2 (1-acetamido-2-N-methyl-N-t-butylamino)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5carboxylic acid t-butyl ester (yield:STDC0032 15.2 mg, 51%).EMI388.2 STDC0694179F (#)-(2R,3S,5R,1'S,3'R)-2-(1-Acetamido-2-(N-ethyl-N-methylaminoi-N- HydrochlorideSaltoxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3S, 5R, 1'S, 3'R)-1-t-butoxycarbonyl-2- (1- acetamido-2- (N-methyl-N-ethyl-N-oxide)) ethyl-pyrrolidine-5-carboxylic acid t-butyl ester for ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3-methoxymethylpyrrolidine-5-carboxylic acid t-butyl ester (yield: 8.7 mg, 29%).

1H NMR (MeOD-d3) 5 5.75-5.69 (m, 1H), 5.37-5.30 (m, 1H), 5.07-5.04 (m, 1H), 4.49 (dd, J=7.8,10.2Hz, 1H), 4.05-3.74 (m, 4H), 3.61-3.32 (m, 1H), 3.55 (s, 3H), 2.69-2.60 (m, 1H), 2.04 (s, 3H), 1.95-1.84 (m, 1H), 1.75 (dd, J=2.0,7.1 Hz, 3H), 1.44 (t, J=7.1 Hz, 3H).

MS: (M+H) +=314, (M+35) +=348 Examples 179-184EMI389.1 <tb> <SEP> 1. <SEP> MCPBA/=<tb> <SEP> 2. <SEP> chromatographic<tb> <SEP> separation<tb> AcHN? <SEP> > .,,, <SEP> ZOU <SEP> AcHN?'., <SEP> OH<tb> <SEP> I <SEP> I <SEP> 3. <SEP> 6 <SEP> N <SEP> HCI <SEP> O <SEP> H <SEP> H"<tb> R'RN <SEP> R'RN<tb> <SEP> HCI<tb> The following title compounds were prepared according to the method described in Example 179.

Example 180EMI389.2 (#)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl- 3- (cis-propen-1-vll-pvrrolidine-5-carboxylic Acid Hvdrochloride Salt 'H NMR (MeOD-d3) 6 5.75-5.69 (m, 1H), 5.38-5.30 (m, 1H), (m, 1 H), 4.47 (dd, J=7.8,9.8Hz, 1 H), 4.02-3.77 (m, 4H), 3.56-3.39 (m, 1 H), 3.47 (s, 3H), 2.69-2.59 (m, 1H), 2.07 (s, 3H), 1.95-1.84 (m, 1H), 1.76 (dd, J=1.7,7.1 Hz, 3H), 1.46 (t, J=7. 1Hz, 3H).

MS: (M+H) +=314, (M+35) +=348 Example 181EMI390.1 (#)-(2R,3S,5R,1'S,3'R)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N- oxide)) ethyl-3-(cis-propen-1-yl)-p6rrolidine-5-carboxylic Acid Hydrochloride Salt 1H NMR (MeOD-d3) # 5.76-5.66 (m, 1H), 5.39-5.31 (m, 1H), 5.17-5.11 (m, 1H), 4.51 (dd, J=7.5,10.2Hz, 1H), 4.07-3.76 (m, 4H), 3.55 (S, 3H), 3.52-3.39 (m, 1H), 2.69-2.60 (m, 1H), 2.02 (S, 3H), 2.08-1.84 (m, 1H), 1.75 (dd, J=1.7,7.1 Hz, 3H), 1.50 (d, J=6. 1Hz, 3H), 1.48 (d, J=6.4Hz, 3H).

MS: (M+H) +=314, (M+35) +=348 Example 182EMI390.2 (#)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N- oxide)) ethvl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Hvdrochloride Salt 'H NMR (MeOD-d3) 5 5.76-5.68 (m, 1H), 5.39-5.31 (m, 1H), 5.10-5.05 (m, 1H), 4.49 (dd, 8Hz, 1H), 4.12-3.84 (m, 4H), 3.55-3.44 (m, 1H), 3.41 (S, 3H), 2.69-2.60 (m, 1H), 2.08 (S, 3H), 2.07-1.84 (m, 1H), 1.76 (dd, J=1.7,6.8Hz, 3H), 1.51 (d, J=2.4Hz, 3H), 1.49 (d, J=2.4Hz, 3H).

MS: (M+H) +=314, (M+35) +=348 Example 183EMI391.1 (i)-(2R, 3S, 5R, 1'S, 3'S)-2-(1-Acetamido-2-(N-isobutyl-N-methvlamino-N- oxide)) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxvlic Acid Hydrochloride Salt 'H NMR (MeOD-d3) 5 5.75-5.69 (m, 1H), 5.38-5.31 (m, 1H), 5.18-5.12 (m, 1 H), 4.53 (dd, J=7.5,9.8Hz, 1 H), 4.25-3.42 (m, 6H), 3.65 (s, 3H), 2.68-2.58 (m, 1H), 2.44-2.36 (m, 1H), 2.05 (s, 3H), 1.94-1.87 (m, 1H), 1.76 (d, J=2.7Hz, 3H), 1.14 (d, J=6.8Hz, 6H).

MS: (M+H) +=342, (M+Na) +=364, (M-H)-=340 Example 184EMI392.1 ()- (2R, 3S, 5R, 1'S. 3'R)-2- 1-Acetamido-2- (N-isobutyl-N-methylamino-N- oxide)) ethyl-3- (cis-propen-1-vl)-pvrrolidine-5-carboxvlic Acid Hydrochloride Salt 'H NMR (MeOD-d3) # 5.75-5.69 (m, 1H), 5.38-5.31 (m, 1H), 5.06-5.02 (m, 1 H), 4.48 (dd, J=7.5,9.8Hz, 1 H), 4.08-3.85 (m, 3H), 3.70-3.57 (m, 2H), 3.52 (s, 3H), 3.48-3.41 (m, 1H), 2.70-2.60 (m, 1H), 2.40-2.36 (M, 1H), 2.08 (s, 3H), 1.951.84 (m, 1H), 1.75 (dd, J=1.7,7. 1Hz, 3H), 1.14 (d, J=6.8Hz, 6H).

MS: (M+H) +=342, (M+Na) +=364, (M-H)-=340 Example 185 ()- (2R, 3S, 5R, 1'S)-2- (1-Acetamido-2- (N-isopropyl-N-hvdroxvamino)) ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid HydrochlorideSaltEMI393.1 165A (#)-(2R,3S,5R,1'S)-1-tButoxycarbonyl-2-(1-acetamido-2-(N-isopropyl-N- hydroxyamino)) ethyl-3-vinvl-pvrrolidine-5-carboxylic Acid t-Butvl Ester.

()- (2R, 3S, 5R, 1'S)-1-t-Butoxycarbonyl-2- (1-acetamido-2isopropylamino) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (21 mg, 0.048 mmole) was dissolved in 0.95 mL of acetone. It was then titrated with 0.14 mL of a solution of dimethyldioxirane (0.1 M) in acetone at-45 C for 0.5 hour.

The reaction was stopped by concentrating the mixture in vacuo. The residue was purified by chromatography on silica gel using 100% dichloromethane to 90% dichloromethane/methanol to provide the title compound (yield: 5.3 mg, 24%) and recovered starting material (yield 12 mg, 57%).

1 H NMR (MeOD-d3) 6 5.95-5.89 (m, 1 H), 5.08-4.94 (m, 2H), 4.75-4.68 (m, 1H), 4.13-3.83 (m, 2H), 2.85-2.47 (m, 4H), 1.96 (s, 3H), 1.82-1.76 (m, 1H), 1.521.44 (m, 18H), 1.45-1.29 (m, 1H), 1.07-1.04 (m, 6H).

MS: (M+H) +=456, (M+Na) +=478, (M-H)-=454, (M+35)-=490. EMI394.1 STDCDBPG0736*185B ( (2R. 3S. 5R, 1'S)-2- (1-Acetamido-2- (N-isopropvl-N-hydro amino)) ethvl- 3-vinyl-pyrrolidine-5-carboxvlic Acid Hydrochloride Salt The title compound was prepared according to the method described inExample 1 K, substituting ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido2- (N-isopropyl-N-hydroxyamino)) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid(N-isopropyl-N-hydroxyamino)) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of () (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3methoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 3.0 mg, 87%).STDC0392 1 H NMR (MeOD-d3) 8 5.83-5.71 (m, 1 H), 5.40 (d, J=17.3Hz, 1 H), 5.24 (d, J=10.2Hz, 1H), 4.48 (dd, J=7.8,10.2Hz, 1H), 3.88-3.59 (m, 4H), 3.17-3.10 (m, 1H), 2.67-2.58 (m, 1 H), 2.10-1.99 (m, 1 H), 2.09 (s, 3H), 1.33-1.17 (m, 1 H), 1.38 (d,J=6.4Hz, 6H).

MS: (M+H) +=300,(M-H)-=298, (2M-H)-=597 Example 186EMI395.1 (#)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-oxo-2-phenyl)ethyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-oxo-2-pyenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- t-butylacetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ester (yield: 5.9 mg, 100%).

1H NMR (DMSO-d6) # 8.62 (d, J= 9.8Hz, 1H), 7.93 (m, 2H), 7.68 (m, 1H), 7.55 (t, J= 7.9Hz, 2H), 5.61 (m, 1H), 5.48 (m, 1H), 5.19 (m, 1H), 4.50 (m, 1H), 3.98 (t, J= 9.8Hz, 1H), 3.30 (m, 1H), 2.38 (m, 1H), 1.73 (m, 1H), 1.71 (s, 3H), 1.59 (m, 3H).

MS: (M+H)+= 331, (M+Na) += 353, (M-H)-= 329.

Example 187 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1- vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.EMI396.1 STDC0236 187A(#)-(2R,3S,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-4- vinyl) butrl-3- (cis-propen-1-vl)-pyrrolidine-5-carboxvlic Acid t-Butvl Ester.

The title compound is prepared according to the method described inExample 84A, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-4-vinyl) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester for ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido-2hydroxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.EMI396.2 STDC0743 187B(#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis- propen-yl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound is prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.

Example 188 ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-methoxy-4-vinyl) butyl-3- (cis-propen-1- yl)-pyrrolidine-5-carboxlic Acid Trifluoroacetic Acid Salt.EMI397.1 STDC0172 188A(#)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-4- vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Ester.

The title compound was prepared according to the method described inExample 84A, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1- acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid for(#)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-ester hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0044 g, 22%).

MS: (M+H) +=481, (M-H)-=479.EMI397.2 STDC0744 1 88B (i)-(2R, 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-methoxv-4-vinyl) butvl-3-(cis- propen-1-vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t butoxycarbonyl-2- (1- acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1 t-butylacetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ester (yield: 0.0031 g, 100%).

1H NMR (DMSO-d6) 8 7.93 (d, J=9.2Hz, 1H), 5.81 (m, 1H), 5.49 (m, 1H), 5.26 (m, 1H), 5.1-4.9 (m, 2H), 4.29 (m 1H), 4.03 (m, 2H), 3.68 (m, 1H), 3.26 (m, 1H), 3.25 (s, 3H), 3.18 (quint., J=8.5Hz, 1H), 2.40 (dt, J=12.7,7.3Hz, 1H), 2.32 (M, 1H), 2.20 (m, 1H), 2.02 (m, 1H), 1.85 (s, 3H), 1.68 (m, 1H), 1.64 (m, 1H), 1.61 (dd, J=6.7,1.8Hz, 3H), 1.55-1.40 (m, 2H).

MS: (M+H) +=325, (M+Na) +=347, (M-H)-=323.

Example 189 (#)-(2R,3R,5R,1'R,2'S)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI398.1 189A ()- (2R, 3R. 5R. 1'S)-1-t-Butoxycarbonvl-2- 1-methanesulfonvloxy-3azido)ethyl-3-t-butyldiphenvlsilyloxymethyl-pvrrolidine-5-carboxylic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 123J substituting ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2-oxiranyl-3-tbutyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (2R, 3S, 5R, 1'S)-2-oxiranyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 9.0 g, 90%).

'H NMR (DMSO-d6) (rotamers) 8 7.62-7.58 (m, 4H), 7.49-7.38 (m 6H), 4.97-4.79 (m, 1H), (m, 2H), 3.79-3.48 (m, 2H), 3.15 and 3.13 (2s, 3H), 2.49-2.39 (m, 2H), 1.98-1.74 (m, 1H), 1.43-1.25 (m, 18H), 1.02 and 1.00 (2s, 9H) MS:STDC0792 (M+H) += 703, (M+Na) + = 725EMI399.1 189B ()- (2R, 3R, 5R. 1'S)-1-t-butoxycarbonyl-2-aziridinyl-3-t- butyldiphenvlsilvioxvmethvl-pyrrolidine-5-carboxylic acid t-butyl ester The title compound was prepared according to the method described inExample 123K substituting ()- (2R, 3R, 5R, 1'S)-1-f-butoxycarbonyl-2- (1- methanesulfonyloxy-3-azido) ethyl-3-t-butyidiphenylsilyloxymethyl-pyrrolidine-5carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-methanesulfonyloxy-3-azido) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 5.9 g, 79%).

'H NMR (DMSO-d6) (rotamers) 8 7.60-7.56 (m, 4H), 7.49-7.39 (m 6H), (m, 1 H), 3.67-3.48 (m, 2H), 3.42-3.30 (m, 1 H), 2.49-2.39 (m, 1H), 2.251.61 (m, 5H), 1.40,1.35,1.33, and 1.27 (4s, 18H), 0.99 and 0.98 (2s, 9H) MS:STDC0638 (M+H) + = 581, (M+Na) + = 603 EMI400.1 189C ()- (2R, 3R. 5R, 1'S)-1-t-Butoxvcarbonvl-2-N-acetylaziridinvl-3-t- butyldiphenvlsilyloxymethyl-pyrrolidine-5-carboxvlic Acid t-Butvl Ester The title compound was prepared according to the method described inExample 123L substituting ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2-aziridinyl-3-tbutyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 3.1 g, 96%).

'H NMR (DMSO-d6) (rotamers) 8 7.60-7.57 (m, 4H), 7.49-7.39 (m 6H), 4.18-4.11 (m, 1H), 3.71-3.51 (m, 3H), 2.76-2.68 (m, 1H), 2.58-2.45 (m, 1H), 2.46 and 2.39 (2d, J=6.1,6.1 Hz, 1 H), 2.40 and 2.47 (2m, 1H), 2.08 and 2.05 (2d,J=3.1,3.1 Hz, 1H), 2.02 and 1.99 (2s, 3H), 1.94-1.79 (m, 1H), 1.41,1.36,1.35 and 1.29 (4s, 18H), 0.99 and 0.98 (2s, 9H) MS:STDC0877 (M+H) + = 623, (M+Na) + = 645EMI400.2 189D(#)-(wR,3R,5R,1'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-acetoxy)ethyl-3-t- bldiphenvlsilvloxvmethyl-pyrrolidine-5-carboxvlic Acid t-Butyl Ester (#)-(2R,3R,5R,1'S)-1-t-butoxycarbonyl-2-N-acetylaziridinyl-3-t- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (2.75g, 4.40 mmole) was reacted with potassium acetate (2.49 g, 25.37 mmole) and acetic acid (1.45 mL, 25.37 mmole) in DMSO (45 mL) at 100 C for 16 hours. The reaction was quenched with 1 N NaHC03 (100 mL) and diluted with ethyl acetate (300 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo.STDC0174 The residue was purified by chromatography on silica gel using 100% dichloromethane to 50% dichloromethane/ethyl acetate to provide the title compound (yield: 2.45g, 81%).

MS: (M+H) +=683, (M+Na) +=705, (M-H)-=681, (M+CI)-=717 EMI401.1 189E ()- (2R. 3R, 5R, 1'R)-1-t-Butoxycarbonyl-2- (1-acetamido-2-hvdroxy) ethyl-3-t- butrldiphenvlsilyloxymethyl-pvrrolidine-5-carboxvlic Acid t-Butvl Ester ()- (2R, 3R, 5R, 1'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-acetoxy)ethyl-3-tbutyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (2.45 g, 3.58 mmole) was reacted with potassium carbonate (1.48 g, 10.73 mmole) in methanol (18 mL) and THF (18mL) at 25 C for 45 minutes. The reaction was quenched with water (100 mL) and diluted with ethyl acetate (200 mL).STDC0307 The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 85% dichloromethane/ethyl acetate to 100% ethyl acetate to provide the title compound (yield: 2.05 g, 90%).

MS: (M+H) +=641, (M+Na) +=663, (2M+Na+H) +=1304, (M-H)-=639, (M+CI)- =675 EMI402.1 189F (?)-(2R. 3R. 5R. 1'R)-1-t-ButoxvcarbonvI-2-(1-acetamido-2-formvl) ethyl-3-t- butyldiphenylsilyloxymethvl-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described inExample 41A substituting ()- (2R, 3R, 5R, 1'R)-1-t-butoxycarbonyl-2- (1-acetamido2-hydroxy) ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t- butyl ester in place of ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl 2- (1-acetamido-2hydroxy) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.

'H NMR (DMSO-d6) (rotamers) 9.49 (d, J=16.3,1H), 8.33 and 8.29 (2d,J=8.8 and 8.8Hz, 1 H), 7.58-7.38 (m, 1 OH), 4.94 and 4.84 (2dd, J=4.4,8.8Hz and 4.4,8.8Hz, 1H), 4.26-3.37 (m, 4H), 2.47-2.30 (m, 1H), 1.97-1.83 (m, 1H), 1.92 (s, 3H), 1.42-1.18 (m, 18H), 1.42-1.18 (m, 1H), 1.00-0.97 (m, 9H).

MS: (M+H) +=639, (M-H)-=637EMI402.2 189G(#)-(2R,3R,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-1-vinyl)methyl-3-t- butvldiDhenvlsilyloxymethvl-pvrrolidine-5-carboxvlic Acid t-Butyl Ester The title compound was prepared according to the method described inExample 118A substituting ()- (2R, 3R, 5R, 1'R)-1-t butoxycarbonyl-2- (1- acetamido-2-formyl) ethyl-3-t-butyidiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl 2-(1- t-butylacetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ester.

'H NMR (DMSO-d6) (rotamers) 7.99-7.74 (m, 1H), 7.59-7.39 (m, 1 OH), 5.80-5.68 (m, 1H), 5.21-5.01 (m, 3H), 3.97-3.31 (m, 1H), 3.78-3.74 (m, 1H), 3.603.46 (m, 2H), 2.53-2.37 (m, 1H), 2.09-1.72 (m, 1H), 1.87 (S, 3H), 1.42-1.23 (m, 19H), 1.00-0.99 (m, 9H).EMI403.1 STDC0858189H (#)-(2R,3R,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-and (1-acetamido-2,3-dihydroxy)propyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5carboxvlic Acid t-Butvl Ester The title compounds were prepared according to the method described inExample 20A substituting ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido- t-butyl2-vinyl)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid ester in place of ()- (2R, 3S, 5R)-1-benzyl-2-vinyl-3-t-butyldimethylsilyloxymethylpyrrolidine-5-carboxylic acid t-butyl ester ()- (2R, 3R, 5R, 1'R, 2'S) isomer (yield: 311mg, 24%) ()- (2R, 3R, 5R, 1'R, 2'R) isomer (yield: 700 mg, 54%).

()- (2R, 3R, 5R, 1'R, 2'S) 1H NMR (DMSO-d6) (rotamers) 7.62-7.39 (m, 11 H), 4.56 and 4.51 (d, J=4.8,1H), (m, 2H), 3.97-3.82 (m, 1 H), 3.743.47 (m, 3H), 3.28-3.21 (m, 2H), 2.89-2.64 (m, 1H), 2.51-2.45 (m, 1H), 2.05-1.8 (m, 1H), 1.87-1.86 (m, 3H), 1.43-1.23 (m, 19H), 0.99-0.98 (m, 9H).

()- (2R, 3R, 5R, 1'R, 2'R)'H NMR (DMSO-d6) (rotamers) 7.63-7.40 (m, 11H), (d, J=4.8,1H), (m, 2H), 3.94-3.80 (m, 1H), 3.85-3.80 (m, 1H), 3.76-3.68 (m, 1H), 3.60-3.51 (m, 1H), 3.44-3.35 (m, 1H), 3.30-3.21 (m, 1H), 2.78-2.62 (m, 1H), 2.46-2.31 (m, 1H), 2.07-1.98 (m 1H), 1.83 (s, 3H), 1.39-1.29 (m, 19H), 1.00-0.99 (m, 9H).EMI404.1 STDC08871891 (#)-(2R,3R,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2,2- dimethyl-1,3-dioxolan-4-vl)) methyl-3-t-butvldiphenvlsilvloxpyrrolidine-5- carboxylic Acid t-Butvl Ester ()- (2R, 3R, 5R, 1'R, 2'R)-1-t-Butoxycarbonyl-2- (1-acetamido-2,3dihydroxy) propyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t- butyl ester was reacted with 2,2-dimethoxypropane (1.1 ml, 9.09 mmole) and pToluenesulfonic acid (4.3 mg, 0.023 mmole) in tetrahydrofuran (4.5 mL) at 25 C for 45 minutes. The reaction was quenched with triethylamine (3 mL). Stirring was continued for an additional 10 minutes. The reaction was then diluted with 10% NaHC03 (15 mL) and extracted with ethyl acetate (45 ml).STDC0351 The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was carried over to the next step. purified by chromatography on silica gel using 100% dichlormethane to 94% dichloromethane/methanol to provide the title compound (yield: 194 mg, 91%). EMI405.1 STDC0711 189J(#)-(2R,34,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2,2dimethvl-1. 3-dioxolan-4-yl)) methyl-3-hvdroxvmethyl-pyrrolidine-5-carboxvlic Acid t-ButylEster The title compound was prepared according to the method described inExample 123G substituting ()- (2R, 3R, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-1-(2, 2-dimethyl-1, 3-dioxolan-4-yl)) methyl-3-tbutyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester for (t)- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2-oxiranyl-3-t-butyldiphenylsilyloxymethyl- pyrrolidine-5-carboxylic acid t-butyl ester.STDC0194 The resulting residue was purified by chromatography on silica gel using 100% dichlormethane to 94% dichloromethane/methanol to provide the title compound (yield: 194 mg, 91%).EMI405.2 STDC0692 189JJ ()- (2R, 3R, 5R, 1'R. 2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2, 2- dimethyl-1, 3-dioxolan-4-vl)) methvl-3-formpvrrolidine-5-carboxvlic Acid t-Butvl Ester The title compound was prepared according to the method described inExample 123H substituting ()- (2R, 3R, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-1- (2,2-dimethyl-1,3-dioxolan-4-yl)) methyl-3-hydroxymethyl-pyrrolidine 5-carboxylic acid t-butyl ester for ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.EMI406.1 STDC0723189K (i)-(2R, 3S, 5R, 1'R, 2'S)-1-t-Butoxvcarbonyl-2-(1-acetamido-1-(2. 2-dimethyl- 1.3-dioxolan-4-vl)) methvl-3- (cis-propen-1-vl)vrrolidine-5-carboxvlic Acid t-ButylEster The title compound was prepared according to the method described inExample 35A substituting ()- (2R, 3R, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-1- (2,2-dimethyl-1, 3-dioxolan-4-yl) methyl-3-formyl-pyrrolidine-5carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2 (1-acetamido-3-methyl) butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 11.5 mg, 59%).

1H NMR (CDCI3) : 8 6.62 (d, 1H), 5.56 (m, 1H), 5.40 (m, 1H), 4.43 (m, 1H), 4.25 (m, 1H), 4.16 (m, 1H), 4.02 (m, 1H), 3.88 (m, 1H), 3.54 (m 1H), 3.14 (m, 1 H), 2.54 (m 1 H), 2.04 (s, 3H), 1.71 (m 1 H), 1.60 (dd, 3H), 1.46 (s, 9H), 1.45 (s, 9H), 1.40 (s, 3H), 1.32 (s, 3H).

MS: (M+H) +=483 EMI407.1 189L (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-1-(2, 2-dimethyl-1, 3-dioxolan-4-yl)) methyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic acid t-butyl ester in place ()- (2R, 3S, 5R, 1'R, 2'S)-1-tbutoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5carboxylic acid t-butyl ester.

1H NMR (DMSO-d6): # 7.84 (d, J=9Hz, 1H), 5.49 (m, 1H), 5.27 (m, 1H), 4.47 (m, 1H), 4.25 (m, 1H), 4.17 (m, 1H), 3.75 (m, 1H), 3.59 (m, 1H), 3.35 (m, 1H), 3.18 (m, 1H), 2.43 (m, 1H), 1.81 (s, 3H), 1.55 (dd, 3H).

MS: (M+H) +=287 Example 190 ()- (2R, 3R. 5R, 1'R. 2'R)-2- (1-Acetamido-2. 3-dihvdroxv) propvl-3- (cis-propen-1-y pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI408.1 190A(#)-(2R,3R,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2,2- dimethyl-1,3-dioxolan-4-yl)methyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described inExample 1891 substituting ()- (2R, 3R, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2,3-dihydroxy) propyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5- carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'R, 2'S)STDC0178-1-tButoxycarbonyl-2- (1-acetamido-2,3-dihydroxy)propyl-3-tbutyidiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester. EMI409.1 STDC0758 190B ()- (2R. 3R. 5R, 1'R, 2'R)-1-t-Butoxvcarbonvl-2- (1-acetamido-1- (2.2dimethyl-1. 3-dioxolan-4-yl)) methyl-3-hydroxymethyl-pvrrolidine-5-carboxvlic Acid t-Butvl Ester The title compound was prepared according to the method described inExample 123G substituting ()- (2R, 3R, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-1- (2,2-dimethyl-1,3-dioxolan4-yl)) methyl-3-tbutyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester for ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2-oxiranyl-3-t-butyldiphenylsilyloxymethylpyrrolidine-5-carboxylic acid t-butyl ester.EMI409.2 STDC0751 190C(#)-(2R,3R,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2,2- dimethvl-1. 3-dioxolan-4-yl)) methvl-3-formyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described inExample 123H substituting ()- (2R, 3R, 5R, 1'R, 2'R)-1-t butoxycarbonyl-2- (1- acetamido-1- (2,2-dimethyl-1,3-dioxolan-4-yl)) methyl-3-hydroxymethyl-pyrrolidine5-carboxylic acid t-butyl ester for ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2- oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester. EMI410.1 STDC0710190D (#)-(2R,3S,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2,2- dimethyl-2,3-dioxolan-4-yl)methyl-3-(cis-propen-1-yl))-pyrrolidine-5-carboxylicAcid Ester The title compound was prepared according to the method described inExample 35A substituting ()- (2R, 3R, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-1- (2,2-dimethyl-1,3-dioxolan-4-yl)) methyl-3-formyl-pyrrolidine-5carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2 (1-acetamido-3-methyl) butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 61%).mg, 1H NMR (CDC13):STDC0295 8 7.88 (d, 1H), 5.52 (m, 1H), 5.34 (m, 1H), 4.33 (m, 1H), 4.21 (m, 1 H), 3.96 (m, 2H), 3.83 (m, 1H), 3.60 (m, 1H), 3.40 (m, 1 H), 2.53 (m, 1 H), 1.98 (s, 3H), 1.66 (dd, 3H), 1.46 (s, 9H), 1.44 (s, 9H), 1.41 (s, 3H), 1.33 (s, 3H).

MS: (M+H) +=483 EMI411.1 190E (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-(cis-propen-1-yl))pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t butoxycarbonyl-2- (1-acetamido-2-hyd roxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester.

'H NMR (DMSO-d6): 6 7.98 (d, J=9Hz, 1H), 5.48 (m, 1H), 5.29 (m, 1H), 4.60 (m, 1H), 4.30 (m, 1H), 4.12 (m, 1H), 3.76 (m, 1H), 3.52 (m, 1H), 3.46 (m, 1H), 3.32 (m, 1H), 3.18 (m, 1H), 2.40 (m, 1H), 1.84 (s, 3H), 1.60 (dd, 3H).

MS: (M+H) +=287 Example 193 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI412.1 193A ()- (2R. 3S. 5R. 1'R. 2'S)-1-t-Butoxycarbonyl-2- (1-acetamido-2- ethoxy) pentyl-3 (cis-propen-1-vl)-pvrrolidine-5-carboxvlic Acid t-Butyl Ester The title compound was prepared according to the method described inExample 88A, substituting ethyl iodide for methyl iodide (yield: 3.6 mg, 28%).

MS: (M+H) += 483, (M+Na) += 505, (M-H)-= 481.EMI412.2 STDC0752 193B(#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1- yl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1acetamido-2-ethoxy) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido-2hydroxy) butyl-3-(cis-propen-1-yl)-pyrroiidine-5-carboxylic acid t-butyl ester. ester (yield: 3.2 mg, 100%).

'H NMR (DMSO-d6) 6 7.92 (d, J= 9.2Hz, 1H), 5.47 (m, 1H), 5.25 (m, 1H), 4.25 (m, 2H), 3.70 (m, 1H), 3.52 (m, 1H), 3.33 (m, 2H), 3.18 (m, 1H), 2.39 (m, 1H), 1.85 (s, 3H), 1.66 (m, 1H), 1.61 (dd, J= 6.7,1.8Hz, 3H), 1.56 (m, 1H), 1.37 (m, 1H), 1.28 (m, 2H), 1.13 (m, 3H), 0.86 (t, J= 7.3Hz, 3H).

MS: (M+H) += 327, (M+Na) += 349, (M-H)-= 325.

Example 194 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-ethox)pentyl-3-(cis-propen-1-yl)- pyrrlidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI413.1 194A(#)-(2R,3S,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2- t-ButlEsterethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid The title compound is prepared according to the method described inExample 88A, substituting ethyl iodide for methyl iodide. EMI414.1 STDC0698 194B(#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-ethoxy)pentyl-3-9cis-propen-1- yl)-pyrrolidine-5-carboxYlic Acid Trifluoroacetic Acid Salt The title compound is prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-ethoxy) pentyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido-2- hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.STDC0645 Example 195 ()- (2R, 3S. 5R. 1'S)-2- (1-Acetamido-2-hvdroxv) ethyl-3-vinvl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid SaltEMI414.2 The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'S)-1-t butoxycarbonyl-2- (1-acetamido- 2-hydroxy) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido-2-hydroxy) butyl-3- (cis<RTI

'H NMR (DMSO-d6) 5 7.80 (d, J= 8.8Hz, 1H), 5.76 (m, 1H), 5.23 (d, J= 17.1Hz, 1H), 5.15 (m, 1H), 4.31 (m, 1H), 4.03 (m, 1H), 3.62 (m, 1H), 3.53 (m, 2H), 2.79 (m, 1H), 2.42 (m, 1H), 1.90 (s, 3H), 1.85 (m, 1H).

MS: (M+H) += 243, (M+Na) += 265, (M-H)-= 241.

Example 196 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-dimethylphosphonyl)propyl- 3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI415.1 196A (#)-(2R,3S,5R,1'R 2'S) and ()- (2R. 3S. 5R, 1'R. 2'R)-1-t-Butoxvcarbonyl-2- (1-acetamido-2-hydroxy-3-dimethylphosphonyl)propyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxvlic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl 2-(1-acetamido-1-formyi) methyl-3(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (78 mg, 0.19 mmol) inTHF (5 mL) was added dropwise to a solution of dimethylphosphonylmethyl lithium (3M) (0.32 mL, 0.95 mmol) in THF (20 mL) at-78 C and reacted for 40 minutes. The reaction was quenched with water (10 mL) and saturated aqueous ammonium chloride (10 mL) followed by extraction using dichloromethane (2 x 50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.STDC0305 The residue was purified by column chromatography on silica gel using 5-10% methanol in dichloromethane to provide the title compounds ()- (2R, 3S, 5R, 1'R, 2'R) isomer (yield: 27 mg, 27%) and ()- (2R, 3S, 5R, 1'R, 2'S) isomer (yield: 5.5 mg, 6%).

()- (2R, 3S, 5R, 1'R, 2'R) ='HNMR (CDC13) # 5. 98 (m, 1H), 5.58 (m, 1H), 5.35 (m, 1H), 4.94 (m, 1H), 4.14 (m, 2H), 3.74 (m, 8H), 3.06 (m, 1H), 2.64 (m, 1H), 2.03 (s, 3H), 1.95 (m, 1H), 1.83 (m, 3H), 1.53 (s, 9H), 1.46 (s, 9H) MS:STDC0867 (M+H) +=535, (M-H)-=533 ()- (2R, 3S, 5R, 1'R, 2'S) MS: (M+H) +=535, (M-H)-=533EMI416.1 196B (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3- dimethylphosphonvl)propyl-3- (cis-propen-1-vl)-pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-dimethylphosphonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)- 1-t- butoxycarbonyl-2- (1-acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)STDC0076-pyrrolidine-5- carboxylic acid t-butyl ester (yield: 3 mg, 96%).

'H NMR (DMSO-d6) 5 7.98 (d, J=9.2 HZ, 1H), 5.48 (M, 1H), 5.28 (m, 1H), 4.36 (m, 1H), 4.30 (m, 1H), 4.08 (m, 2H), 3.70 (m, 2H), 3.60 (m, 6H), 3.18 (m, 1H), 2.40 (m, 1H), 2.05 (m, 1H), 1.85 (s, 3H), 1.60 (dd, J=6.2,1.2 HZ, 3H) MS:STDC0749 (M+H) +=379, (M-H)-=377 Example 197EMI417.1 ()-(2R.3S,5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxv-3-dimethvlphosphonvl)propyl- 3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy-dimethylphosphonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t butoxycarbonyl-2- (1-acetamido-2-hyd roxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester (yield: 13 mg, 96%).

1H NMR (DMSO-d6) 5 7.72 (d, J=9.2 HZ, 1H), 5.48 (m, 1H), 5.24 (m, 1H), 4.44 (m, 1H), 4.15 (m, 2H), 3.62 (m, 7H), 3.54 (m, 1H), 3.15 (m, 1H), 2.40 (m, 1H), 1.95 (m, 1H), 1.82 (s, 3H), 1.72 (m, 1H), 1.54 (dd, J=6.7,1.2 HZ, 3H) MS:STDC0885 (M+H) += 379, (M-H)-= 377 Example 198 ()- (2R. 3S, 5R. 1'S)-2- (1-Acetamido-3-hrdroxy propvl-3- (cis-propen-1-y pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI418.1 198A ( )-(2R. 3S, 5R, 1'S)-1-t-Butoxvcarbonyl-2-(1-acetamido-1-(cis and trans-2t-Butylmethoxyvinyl)methyl-3-9cis-propen-1-yl)-pyrrolidine-5-carboxylicAcidEster ()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl-2-(1-acetamido-1-formyl) methyl-3(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (113 mg, 0.28 mmol) was added to a solution of (methoxymethyl) triphenylphosphonium bromide (240 mg, 0.70 mmol) and potassium t-butoxide (0.56 mL, 0.56 mmol, 1 M in THF) in toluene (3 mL) at 0 C for 15 minutes.STDC0736 The reaction was quenched with saturated aqueous ammonium chloride (3 mL) followed by extraction using dichloromethane (2 X 3 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/4: ethyl acetate/hexane to provide the title compounds 'H NMR (CDC13) 6 8.65 (br d, 1 H) 6.01 (d, J=5.7Hz, 1 H), 5.40 (m, 3H), 5.11 (brt, 1H), 4.15 (m, 2H), 3.72 (m, 1H) 3.61 (s, 3H), 3.00 (m, 1H), 2.42 (m, 1H), 1.94 (s, 3H), 1.64 (dd, 3H), 1.45 (m, 9H), 1.25 (m, 9H) MS: (M+H) += 439. EMI419.1 STDC0834198B (#)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3- (cis-propen-1-vl)-pvrrolidine-5-carboxvlic Acid t-Butvl Ester ()- (2R, 3S, 5R, 1'S)-1-t-Butoxycarbonyl-2- (1-acetamido-2- (cis and trans-2 methoxyvinyl)) methyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (21 mg, 0.048 mmol) was reacted with LiBr (37 mg, 0.43 mmol) and AG50W-X2 ion exchange resin in CH3CN (2 mL) and water (0.1 mL) at room temperature for 45 minutes. The reaction was filtered and quenched with saturated aqueous sodium bicarbonate (1 mL) followed by extraction using dichloromethane (2 X 1 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.STDC0157 The residue was purified by column chromatography on silica gel using 1/4 : ethyl acetate/hexane to provide the title compound.

'H NMR (CDC13) b 9.70 (dd, J=1.3,2.4Hz, 1H), 8.11 (d, J=7.8Hz, 1H), 5.54 (m, 1H), 5.41 (t, J=5.8Hz, 1H), 4.52 (m, 1H), 4.13 (dd, J=4.4,4.8Hz, 1H), 3.75 (dd, J=2.7,3.1Hz, 1H), 2.86 (m, 1H), 2.47 (m, 3H), 1.99 (s, 3H), 1.63 (dd, J=1.6, 5.1 Hz, 3H), 1.46 (s, 9H), 1.45 (m, 1H), 1.44 (s, 9H) MS: (M+H) + = 425; (M-H)-= 423. EMI420.1 STDC0858198C (#)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-hydroxy)propyl-3- t-ButylEster(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid ()- (2R, 3S, 5R, 1'S)-1-t-Butoxycarbonyl-2- (1-acetamido-2-formyl) ethyl-3(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (9 mg, 0.02 mmol) was reacted with sodium borohydride (1 mg, 0.02 mmol) in methanol (0.1 mL) at room temperature for 20 minutes. The reaction was quenched with saturated aqueous ammonium chloride (1 mL) followed by extraction using dichloromethane (2 X 1 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/4: ethyl acetate/hexane to provide the title compound.

'H NMR (CDC13) â 8.45 (d, J=7.5Hz, 1 H), 5.55 (m, 1 H), 5.34 (t, J=7.8Hz, 1H), 4.20 (dd, J=3.0,5.4Hz, 2H), 3.71 (d, J=6.1Hz, 1H), 3.62 (m, 1H), 3.50 (t,J=9.1Hz, 1H), 2.92 (m, 1H), 2.41 (m, 1H), 2.04 (s, 3H), 1.66 (dd, J=2.0,5.1Hz, 3H), 1.62 (m, 1H), 1.47 (s, 9H), 1.45 (m, 1H), 1.43 (s, 9H), 1.22 (m, 2H) MS: (M+H) + = 427; (M-H)-= 425. EMI421.1 STDC0757198D (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-3-hydroxy)propyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'S)-1-t-butoxycarbonyl-2-(1-acetamido2-hydroxy) propyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)- 1-t-butoxycarbonyl-2- (1-acetamido-2hydroxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. ester (yield: 4.6 mg, 100%).

1H NMR (DMSO-dy) # 9. 25 (br s, 1 H), 8.13 (d, J=7.3Hz, 1 H), 5.52 (m, 1H), 5.28 (brt, 1H), 4.32 (brt, 1H), 4.22 (m, 1H), 3.49 (m, 4H), 3.18 (m, 1H), 2.40 (m, 1H), 1.90 (s, 3H), 1.73 (m, 1H), 1.63 (dd, J=1.8,5.5Hz, 3H), 1.57 (m, 1H) MS: (M-H)-= 269; (M+H) + = 271.

Example 199 (#)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI422.1 199A (#)-(2R,3S,5R,1'R,3'R)-1-t-Butoxycarbonyl-2-and (1-acetamido-3-hvdroxv) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid tButyl Ester ()- (2R, 3S, 5R, 1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-formyl) ethyl-3 (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (26 mg, 0.061 mmol) was reacted with ethylmagnesium bromide (3.0 M) (0.122 mL, 0.367 mmol) inTHF (4 mL) at room temperature for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride (10 mL) and water (10 mL) followed by extraction using ethyl acetate (3 X 25 mL).STDC0408 The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/1 ethyl acetate/hexane followed by 2/1 ethyl acetate/hexane to provide the title compounds ()- (2R, 3S, 5R, 1'S, 2'S) (yield: 6.7 mg, 24%) and ()- (2R, 3S, 5R, 1'S, 2'R) (yield: 6.8 mg, 24%).

()- (2R, 3S, 5R, 1'S, 2'S) MS: (M+H) +=455, (M+Na) +=477, (M-H)-=453.

()- (2R, 3S, 5R, 1'S, 2'R) MS: (M+H) +=455, (M+Na) +=477, (M-H)-=453. EMI423.1 STDC0725199B (#)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-3-hydroxy)pentyl-3-(cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting (#)-(2R, 3S, 5R, 1'S, 3'S)-1-t butoxycarbonyl-2- (1- t-acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid butyl ester in place of (#)-(2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido- 2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. ester (yield: 6.2 mg, 100%).

1H NMR (DMSO-d6) # 9.20 (bs, 1H), 8.18 (d, J=7.3 Hz, 1H), 5.51 (m, 1H), 5.27 (m, 1H), 4.30 (m, 1H), 4.25 (m, 1H), 3.58 (m, 1H), 3.41 (m, 1H), 3.18 (m, 1H), 2.39 (m, 1H), 1.90 (s, 3H), 1.75 (m, 1H), 1.64 (dd, J=7.5,1.5Hz, 3H), 1.51 (M, 1H), 1.38 (m, 1H), 1.32 (m, 1H), 0.83 (t, J=7.3Hz, 3H).

MS: (M+H) + = 299, (M+Na) + = 321, (M-H)- = 297, (2M-H)-=595.

Example 200 (#)-(2R,3S,5R,1'S,3'R)-2-(1-Acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI424.1 The title compound was prepared according to the method described in Example 41C, substituting (#)-(2R, 3S, 5R, 1'S, 3'R)-1-t-butoxycarbonyl-2-(1- t-acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidie-5-carboxylicacid butyl ester in place of (#)-(2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido2-hydroxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. ester (yield: 6.5 mg, 100%).

'H NMR (DMSO-d6) 5 9.25 (bs, 1H), 8.15 (d, J=7.3 Hz, 1H), 5.52 (m, 1H), 5.27 (m, 1H), 4.31 (m, 2H), 3.52 (m, 1H), 3.36 (m, 1H), 3.19 (quint., J=8.5Hz, 1H), 2.38 (m, 1H), 1.92 (s, 3H), 1.75 (m, 1H), 1.64 (dd, J=7.3,1.5Hz, 3H), 1.48 (m, 1H), 1.33 (m, 2H), 0.85 (t, J=7.3Hz, 3H).

MS: (M+H) += 299, (M+Na) + = 321, (M-H)- = 297, (2M-H)-=595.

Example 201 (#)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-oxo3,3-difluoro-3-vinyl)propyl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI425.1 The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2-(1Acetamido-2-oxo-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5carboxylic Acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t butoxycarbonyl-2- (1-acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester (yield: 0.0050 g, 100%).

1H NMR (DMSO-d6) # 8.67 (d, J=8.5Hz, 1H), 6.1-5.95 (m, 1H), 5.78 (dd, J=17.1,2.4Hz, 1H), 5.71 (d, 11.0HZ, 1H), 5.45 (m, 1H), 5.12 (m, 1H), 4.94 (t,J=9.2Hz, 1H), 4.51 (dd, J=12.2,6.1Hz, 1H), 3.98 (m, 1H), 3.24 (m, 1H), 2.32 (m, 1H), 1.73 (s, 3H), 1.66 (q, J=11.9Hz, 1H), 1.57 (dd, J=6.7,1.8Hz, 3H).

MS: (M+H)+ = 331, (M+H20) +=349, (M+Na) + = 353, (M-H)-= 329, (2M-H) =659.

Example 202EMI426.1 202A (#)-(2R,3R,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-and (1-acetamido-2-hydroxy)butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5carboxylic Acid Ester The title compounds were prepared according to the method described inExample 41 B substituting ()- (2R, 3R, 5R, 1'R)-1-t butoxycarbonyl-2- (1-acetamido- 2-formyl) ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R)-1-f-butoxycarbonyl-2- (1-acetamido-2formyl) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester to provide (#)-(2R, 3R, 5R, 1'R, 2'S) isomer (yield:STDC0101 370 mg, 17%) and(#)- (2R, 3R, 5R, 1'R, 2'R) isomer (yield: 1.2 g, 55%).

()- (2R, 3R, 5R, 1'R, 2'S) 1 H NMR (d6-DMSO) 8 7.4-7.65 (m, 10H), 4.47 (d, 1 H), 4.32 (m, 1 H), 3.87 (m, 2H), 3.68 (m, 1 H), 3.55 (m, 1 H), 3.25 (m, 1 H), 2.7 (m, 1H), 2.45 (m, 1H), 2.0 (m, 1H), 1.83 (d, 3H), 1.28-1.4 (m, 18H), 0.95 (d, 9H), 0.83 (dt, 3H) MS: (M-H)-= 667, (M+35) + = 703;STDC0543 (M+H) + = 669, (M+Na) + = 691 ()- (2R, 3R, 5R, 1'R, 2'R) 1 H NMR (d6-DMSO) 8 7.4-7.65 (m, 10H), 4.40 (dd, 1H), 4.12-4.32 (m, 1H), 3.82-3.96 (m, 1H), 3.66 (m, 2H), 3.52 (t, 1H), 2.6-2.8 (m, 1H), 2.45 (m, 1H), 1.76-2.0 (m, 1H), 1.87 (d, 3H), 1.25-1.4 (m, 18H), 0.95 (d, 9H), 0.83 (dt, 3H).

MS: (M-H)-= 667, (M+35) + = 703; (M+H) + = 669, (M+Na) + = 691 EMI427.1 202B (#)-(2R,3R,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2- methoxymethvloxv) butyldiphenvlsilvloxrmethvl-pvrrolidine-5-carboxylicAcid t-Butvl Ester ()- (2R, 3R, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2- t-butylhydroxy)butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid ester (0.58 g, 0.87 mmole) was reacted with methoxymethyl chloride (1.15 mL, 10.07 mmole) and diisopropylethylamine (3.5 mL, 20.1 mmole) in dichloromethane (1 mL) at room temperature for 5 hours. The reaction was quenched with saturated NH4CI (100 mL) and diluted with ethyl acetate (200 mL).

The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% methanol/methylene chloride to provide the title compound (yield: 0.64 g, 98%).

1 H NMR (d6-DMSO) 6 7.4-7.65 (m, 1 OH), 4.70 (s, 1 H), 4.62 (s, 1 H), 4.35- 4.55 (m, 2H), 3.75-3.95 (m, 2H), 3.68 (m, 1 H), 3.55 (m, 1 H), 3.25 (m, 1 H), 3.24 (s, 3H), 2.55 (m, 1H), 2.45 (m, 1H), 2.0 (m, 1H), 1.85 (s, 3H), 1.28-1.4 (m, 18H), 0.99 (d, 9H), 0.8 (dt, 3H) MS:STDC0840 (M-H)-= 755, (M+35) + = 791; (M+H) + = 757, (M+Na) + = 779 EMI428.1 202C () (2R. 3R, 5R, 1'R. 2'S)-1-t-Butoxycarbonyl-2- (1-acetamido-2- t-Butylmethoxymethyloxy)butyl-3-hydroxymethyl-pyrrolidine-5-carboxylicAcidEster The title compound was prepared according to the method described inExample 123G substituting ()- (2R, 3R, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-methoxymethyloxy) butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine- 5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl2-oxiranyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.416 g, 95%).

1 H NMR (d6-DMSO) 8 7.45 (t, 1 H), 4.62-4.74 (m, 3H), 4.48 (m, 1 H), 3.85 (m, 2H), 3.55-3.6 (m, 2H), 3.45 (t, 1 H), 3.2-3.4 (m, 2H), 3.25 (d, 3H), 2.4 (m, 2H), 1.82 (d, 3H), 1.58 (m, 3H), 1.32-1.45 (m, 18H), 0.82 (dt, 3H).

MS: (M-H)-= 517, (M+35) + = 553; (M+H) + = 519, (M+Na) + = 541 EMI429.1 202D()- (2R. 3R, 5R, 1'R2'S)-1-t-Butoxycarbonyl-2- (1-acetamido-2methoxymethyloxv) butyl-3-formyl-pvrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described inExample 123H substituting ()- (2R, 3R, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-methoxymethyloxy) butyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2-oxiranyl-3- hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.335 g, 80.8%).

1 H NMR (d6-DMSO) 8 9.55 (d, 1 H), 7.48 (m, 1 H), (m, 4H) 3.9 (d, 1 H), 3.6 (m, 2H), 3.45 (m, 3H), 3.32 (s, 3H), 3.05 (t, 1 H), 2.25-2.45 (m, 4H), 1.83 (s, 3H), 1.58 (m, 3H), 1.30-1.45 (m, 18H), 0.86 (dt, 3H).

MS: (M-H)-= 515, (M+35) += 551; (M+H) + = 517 EMI430.1 202E ()- )-(2R, 3R. 5R. 1'R. 2'S. 1"RS)-1-t-Butoxycarbonyl-2-(1-acetamido-2methoxvmethvloxv) butyl-3- (1-hvdroxv-2-propyn-l vD-pyrrolidine-S-carboxylic Acid t-ButylEster The title compound was prepared according to the method described inExample 38A substituting ()- (2R, 3R, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-methoxymethyloxy) butyl-3-formyl-pyrrolidine-5-carboxylic acid t- butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido-3methyl) butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.27 g, 83%).

MS: (M-H)-= 541, (M+35) + = 577; (M+H)+ = 543, (M+Na) + = 565EMI430.2 202F ()- (2R. 3R. 5R, 1'R. 2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2t-methoxymethyloxy)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylicAcidButylEster The title compound was prepared according to the method described inExample 38B substituting ()- (2R, 3R, 5R, 1'R, 2'S, 1"RS)-1-t butoxycarbonyl-2- (1- acetamido-2-methoxymethyloxy) butyl-3- (1-hydroxy-2-propyn-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S, 1"RS)-1-tbutoxycarbonyl-2- (1-acetamido-3-methyl) butyl-3- (1-hydroxy-2-propyn-1-yl)STDC0077- pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.2 g, 74%).

1 H NMR(d6-DMSO) #7. 49 (br d, 1 H), 5.0 (d, 1 H), 4.7 (br s, 1 H), 4.55-4.7 (m, 3H), 3.88 (br d, 1 H), 3.5-3.7 (m, 2H), 3.43 (t, 2H), 3.2-3.4 (m, 2H), 3.24 (s, 3H), 2.4-2.7 (m, 2H), 1.84 (s, 3H), 1.5-1.7 (m, 2H), 1.30-1.45 (m, 18H), 0.86 (dt, 3H) MS: (M-H)-= 539, (M+35) + = 575;STDC0817 (M+H) + = 541, (M+Na) + = 563EMI431.1 202G-(2R, 3Ra 5R. 1'R. 2'S)-1-t-Butoxvcarbonyl-2-(1-acetamido-2methoxvmethvloxv) butvl-3- (pvrazol-3-vl)-pvrrolidine-5-carboxvlicAcid t-BuM Ester The title compound was prepared according to the method described inExample 38C substituting ()- (2R, 3R, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1- acetamido-2-methoxymethyloxy) butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido-3-methyl) butyl-3- (1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 180 mg, 87%).

1 H NMR (d6-DMSO) 6 7.57 (brt, 2H), 6.1 (d, 1H), (m, 4H) 3.95 (m, 1 H), 3.4-3.6 (m, 3H), 3.3-3.4 (m, 3H), 3.22 (d, 3H), 2.55-2.65 (m, 1 H), 2.2 (m, 1H), 1.85 (s, 3H), 1.5-1.7 (m, 2H), 1.15-1.45 (m, 18H), 0.86 (dt, 3H).

MS: (M-H)-= 553, (M+35) + = 589; (M+H) + = 553, (M+Na) + = 577EMI432.1 202H (#)-(2R,3R,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 1K, substituting ()- (2R, 3R, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-methoxymethyloxy) butyl-3- (pyrazol-3-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3methoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.STDC0193 Chromatography on silica gel with 2-propanol: acetic acid: ethyl acetate: water 1: 1: 3: 1 followed by the addition of 0.1 % trifluoroacetic acid gave the title compound (yield: 15 mg, 55%).

1 H NMR(d6-DMSO) # 7. 95 (d, 1 H), 7.65 (br s, 1 H), 6,18 (d, 1 H), 4.37 (m, 1H), 4.23 (m, 1H), 4.38 (m, 1H), 4.56 (m, 1H), 2.63 (m, 1H), 2.10 (m, 1H), 1.78 (s, 3H), 1.50 (m, 1H), 1.25 (m, 1H), 0.83 (t, J=7.46 Hz, 3H).

MS: (M-H)-= 309, (M+35) + = 345; (M+H) + = 311, (M+Na) + = 333 Example 203 ()- (2R. 3R. 5R. 1'R. 2'R)-2- (1-Acetamido-2-hvdroxv) butvl-3- (pvrazol-3-vh- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI433.1 203B (#)-(2R,3R,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2- methoxymethyloxv) butyl-3-t-butvldiphenylsilvloxvmethvl-pyrrolidine-5-carboxylic Acid t-Butvl Ester The title compounds were prepared according to the method described inExample 202B substituting ()- (2R, 3R, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy)STDC0351 butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5- carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'R, 2'S)-1-tbutoxycarbonl-2-(1-acetamido-2-hydroxy)butyl-3-t-butyldiphenylsilyloxymethylpyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.217 g, 96%).

1 H NMR (d6-DMSO) 7.4-7.65 (m, 10H), 4.70 (s, 1 H), 4.62 (s, 1 H), 4.354.55 (m, 2H), 3.75-3.95 (m, 2H), 3.68 (m, 1H), 3.55 (m, 1 H), 3.25 (m, 1 H), 3.24 (s, 3H), 2.55 (m, 1H), 2.45 (m, 1H), 2.0 (m, 1H), 1.85 (s, 3H), 1.28-1.4 (m, 18H), 0.99 (d, 9H), 0.8 (dt, 3H).STDC0862 MS: (M-H)-= 755, (M+35) + = 791; (M+H) + = 757, (M+Na) + = 779 EMI434.1 203C(s)-(2R, 3R, 5R. 1'R. 2'R)-1-t-Butoxvcarbonvl-2-(1-acetamido-2methoxymethyloxy) butyl-3-hvdroxvmethvl-pvrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described inExample 123G substituting ()- (2R, 3R, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-methoxymethyloxy) butyl-3-t-butyidiphenylsilyloxymethyl-pyrrolidine5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl- t-butyl2-oxiranyl-3-t-butylidphenylsilyloxymethyl-pyrrolidine-5-c EMI435.1 203D (#)-(2R,3R,5R,1'R,2'R)STDC0648-1-t-Butoxycarbonyl-2-(1-acetamido-2- methoxymethyloxy)butyl-3-formyl-pyrrolidine-5-carboxylic Acid t-but Ester The title compound was prepared according to the method described inExample 123H substituting ()- (2R, 3R, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-methoxymethyloxy)butyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2-oxiranyl-3- hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.106 g, 86%).

1 H NMR (d6-DMSO) 89.58 (d, 1 H), 7.58 (dd, 1 H), 4.6-4.72 (m, 3H), 4.48 (d, 1H), 3.88 (d, 1H), 3.4-3.65 (m, 5H), 3.24 (s, 3H), 3.15 (dd, 1H), 2.20-2.48 (m, 4H), 1.86 (s, 3H), 1.58 (m, 3H), 1.30-1.40 (m, 18H), 0.86 (t, 3H).

MS: (M-H)-= 515, (M+35) + = 551; (M+H) + = 517 EMI436.1 203E(#)-(2R,3R,5R,1'R,2'R,1"RS)-1-t-Butoxycarbonyl-2-(1-acetamido-2- methoxymethyloxy)butyl-3-(1-hydroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester The title compound was prepared according to the method described inExample 38A substituting ()- (2R, 3R, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-methoxymethyloxy) butyl-3-formyl-pyrrolidine-5-carboxylic acid tbutyl ester in place of ()- (2R, 3R, 5R, 1'S, 1"RS)-1-t-butoxycarbonyl-2-(1acetamido-3-methyl) butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 32 mg, 76%).

MS: (M-H)-= 541, (M+35) + = 577; (M+H) + = 543, (M+Na) + = 565EMI436.2 203F ()- (2R. 3R. 5R. 1'R. 2'R)-1-t-Butoxvcarbonyl-2- (1-acetamido-2methoxymethyloxy) (l-oxo-2-propvn-1-yl)-pyrrolidine-5-carboxvlic Acid t- ButylEster The title compound was prepared according to the method described inExample 38B substituting ()- (2R, 3R, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1 acetamido-2-methoxymethyloxy) butyl-3- (1-hydroxy-2-propyn-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S, 1"RS)-1-tbutoxycarbonyl-2- (1-acetamido-3-methyl) butyl-3- (1-oxo-2-propyn-1-yl)- pyrroiidine-5-carboxylic acid t-butyl ester (yield: 25 mg, 78%).

1 H NMR (d6-DMSO) 6 7.49 (br d, 1 H), 5.0 (d, 1 H), 4.7 (br s, 1 H), 4.55-4.7 (m, 3H) 3.88 (br d, 1 H), 3.5-3.7 (m, 2H), 3.43 (t, 2H), 3.2-3.4 (m, 2H), 3.24 (s, 3H), 2.4-2.7 (m, 2H), 1.84 (s, 3H), 1.5-1.7 (m, 2H), 1.30-1.45 (m, 18H), 0.86 (dt, 3H).

MS: (M-H)-= 539, (M+35) + = 575; (M+H) + = 541, (M+Na) + = 563EMI437.1 203G(#)-(2R,3R,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2methoxvmethvloxYutyl-3- (pvrazol-3-vl)-yrrolidine-5-carboxvlic Acid t-Butvl Ester The title compound was prepared according to the method described inExample 38C substituting ()- (2R, 3R, 5R, 1'R, 2'R)-1-t-butoxywarbonyl-2-(1- acetamido-2-methoxymethyloxy) butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-t-butoxycarbonyl-2- (1-acetamido-3-methyl) butyl-3- (1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 18 mg, 72%).

1 H NMR (d6-DMSO) 8 7.57 (m, 2H), 6.1 (d, 1H), 4.40-4.7 (m, 4H) 3.93 (m, 1H), 3.4-3.6 (m, 3H), 3.3-3.4 (m, 3H), 3.22 (d, 3H), 2.55-2.65 (m, 1H), 2.2 (m, 1H), 1.85 (s, 3H), 1.5-1.7 (m, 2H), 1.15-1.45 (m, 18H), 0.86 (m, 3H).

MS: (M-H)-= 553, (M+35) + = 589; (M+H) + = 553, (M+Na) + = 577EMI438.1 203H (#)-(2R,3R,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)- pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 15B, substituting ()- (2R, 3R, 5R, 1'R, 2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-methoxymethyloxy) butyl-3- (pyrazol-3-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-acetamido-3ethyl) pentyl-3- (imidazol-2-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.

Chromatography on silica gel with 2-propanol: acetic acid: ethyl acetate: water 1: 1: 3: 1 followed by the addition of 0.1 % trifluoroacetic acid gave the title compound (yield: 4 mg, 45%).

1 H NMR (d6-DMSO) s 7.65 (d, 1 H), 7.64 (d, 1 H), 6,16 (d, 1 H), 4.37 (m, 1H), 4.23 (m, 1H), 4.38 (m, 1H), 4.56 (m, 1H), 2.63 (m, 1H), 2.10 (m, 1H), 1.74 (s, 3H), 1.25-1.40 (m, 2H), 0.83 (t, J=7.46 Hz, 3H).

MS: (M-H)-= 309, (M+35) + = 345; (M+H)+ = 311, (M+Na)+ = 333 Example 204 ()- (2R, 3R, 5R)-2-Acetamidomethyl-3-methoxvcarbonyi-pyrrolidine-5-carbolic AcidHydrochloride.EMI439.1 STDC0567204A (#)-(2R,3R,5R)-1-Benzl-2-aminomethyl-3-t-butyldimethylsilyloxymethyl- pyrrolidine-5-carboxylic Acid Ester The title compound is prepared according to the method described inExample 1 F, substituting ()- (2R, 3R, 5R)-1-benzyl-2-formyl-3-tbutyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R)-1-benzyl-2- (1-oxo-3-ethyl) pentyl-3-t-butyldimethylsilyloxymethyl- pyrrolidine-5-carboxylic acid t-butyl ester.

MS: (M+H) += 435EMI439.2 204B(i)-(2R. 3R, 5R)-1-Benzvl-2-acetamidomethyl-3-tbutyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound is prepared according to the method described inExample 1G, substituting ()- (2R, 3R, 5R)-1-benzyl-2-aminomethyl-3-t- butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t butyl ester in place of ()- (2R, 3R, 5R, 1'R)- and ()- (2R, 3R, 5R, 1'S)-1-benzyl-2- (1-amino-3-ethyl) pentyl-3t-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.

'H NMR (CDC13): s 7.2-7.35 (m, 5H), 6.14 (br, 1H), 3.86 (dd, J=18Hz, 13.5Hz, 2H), 3.67 (m, 1H), 3.60 (m, 1H), 3.49 (m, 1H), 3.28 (m, 1H), 3.06 (m, 1H), 2.19 (m, 2H), 1.95 (s, 3H), 1.45 (s, 9H), 0.91 (s, 9H), 0.07 (s, 6H).

MS: (M+H) += 477EMI440.1 204C ()- (2R, 3R. 5R)-1-Benzyl-2-acetamidomethyl-3-hydroxvmethvvrrolidine- 5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described inExample 1H, substituting (#)-(2R,3R,5R)-1-benzyl-2-acetamidomethyl-3-t- butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-tbutyidimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.EMI440.2 STDC0572 204D()- (2R, 3R. 5R)-1-Benzvl-2-acetamidomethyl-3-formyl-pyrrolidine-5- carboxylic Acid Ester The title compound was prepared according to the method described inExample 2A, substituting ()- (2R, 3R, 5R)-1-benzyl-2-acetamidomethyl-3- hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-hydrxoxymethylpyrrolidine-5-carboxylic acid t-butyl ester.

'H NMR (CDC13): # 9.70 (s, 1H), 7.22-7.36 (m 5H), 5.82 (br, 1H), 3.83 (dd,J= 3.3Hz, 13.5Hz, 2H), 3.74 (m, 1H), 3.56 (d, J= 9Hz, 1H), 3.15 (m, 1H), 2.73 (m, 1H), 2.36-2.10 (m, 2H), 1.98 (s, 3H), 1.45 (s, 9H).

MS: (M+H) += 361EMI441.1 204E (#)-(2R,3R,5R)-1-Benzyl-2-acetamidomethyl-3-methoxycarbonyl- pyrrolidine-5-carboxylic Acid Ester The title compound was prepared according to the method described inExample 2B and 2C, substituting (#)-(2R, 3R, 5R)-1-benzyl-2-acetamidomethyl-3- formyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (#)-(2R, 3R, 5R, 1'S)-1- t-butylbenzyl-2-91-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylicacid ester.

'H NMR (CDC13): S 7.45-7.20 (m, 5H), 5.96 (br, 1H), 3.90-3.73 (m, 4H), 3.71 (s, 3H), 3.52 (dd, J=9Hz, 2Hz, 1H), 3.13 (m, 1H), 2.84 (m, 1H), 2.36 (m, 1H), 2.18 (m, 1H), 1.97 (s, 3H), 1.45 (s, 9H).

MS: (M+H) += 391 EMI442.1 204F()- (2R, 3R. 5R)-2-Acetamidomethvl-3-methoxycarbonyl-pyrrolidine-5- carboxylic Acid Ester The title compound was prepared according to the method described inExample 2D, substituting ()- (2R, 3R, 5R)-1-benzyl-2-acetamidomethyl-3- methoxycarbonyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-1-benzyl-2-(1-acetamido-3-ethyl) pentyl-3-methoxycarbonylpyrrolidine-5-carboxylic acid t-butyl ester.

'H NMR (CDC13): 6 6.19 (br, 1H), 3.72 (m, 2H), 3.70 (s, 3H), 3.43 (m, 1H), 3.28 (m, 1 H), 2.74 (m, 1 H), 2.44 (m 1 H), 2.21 (m, 1 H), 2.00 (s, 3H), 1.48 (s, 9H).

MS: (M+H) += 301EMI442.2 204G ()- (2R. 3R. 5R)-2-Acetamidomethvl-3-methoxvcarbonyl-pyrrolidine-5carboxvlic Acid Hvdrochloride.

The title compound was prepared according to the method described inExample 2E substituting ()- (2R, 3R, 5R)-2-acetamidomethyl-3-methoxycarbonylpyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2- (1acetamido-3-ethyl) pentyl-3-methoxycarbonyi-pyrrolidine-5-carboxylic acid t-butyl ester.

'H NMR (D20): 4.42 (t, J=8.25Hz, 1 H), 4.22 (m, 1 H), 3.83 (m, 1 H), 3.75 (s, 3H), 3.70-3.60 (m, 2H), 3.26 (m, 1H), 2.78 (m, 1H), 2.43 (m, 1 H), 2.03 (s, 3H).

MS: (M+H) += 245 Examples 205-213EMI443.1 <SEP> HO <SEP> ,<tb> N <SEP> n <SEP> N <SEP> ii<tb> <SEP> Boc<tb> <SEP> Example <SEP> 204C<tb> The following title compounds were prepared according to the methods described in Examples 1-39 from the common intermediate prepared as described in Example 204C.

Example 205EMI443.2 ()- (2R. 3R, 5R)-2-Acetamidomethvl-3-ethoxycarbonyl-pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt.

1H NMR (D20) 6 4.30 (t, J=8.2Hz, 1H), 4.21 (m, 3H), 3.62 (dd, J=2.4, 3.4Hz, 2H), 3.23 (m, 1 H), 2.74 (m, 1 H), 2.38 (m, 1 H), 2.02 (s, 3H), 1.26 (m, 3H) MS: (M+H)+ = 259 ; (M-H)-= 257.

Example 206EMI444.1 (#)-(2R,3R,5R)-2-Acetamidomethyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride 'H NMR (D2O) : # 7.46 (s, 2H), 4.53 (dd, J=9.5Hz, J=8.5 Hz, 1H), 4.28 (m, 1H), 3.96 (m, 1H), 3.65 (m, 2H), 3.03 (dt, J=13.5Hz, J=7.6Hz, 1H), 2.46 (m, 1H), 1.94 (s, 3H).

MS: (M-H)-=251 Example 207EMI444.2 (#)-(2R,3S,5R)-2-Acetamidomethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt.

'H NMR (D2O) # 5.74 (m, 1H), 5.24 (m, 2H), 4.20 (dd, J=1.7,8. 1Hz, 1H), 3.65 (m, 2H), 3.50 (m, 1H), 2.84 (m, 1H), 2.61 (m, 1H), 2.03 (s, 3H), 1.95 (m, 1H) MS:213.= Example 208EMI445.1 (#)-(2R,3R,5R)-2-Acetamidomethyl-3-(2,2-dimethyl-vinyl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.

'H NMR (D20) 8 5.01 (br d, 1H), 4.18 (dd, J=2.1,8.1Hz, 1H), 3.53 (m, 3H), 3.04 (m, 1H), 2.55 (m, 1 H), 2.0 (s, 3H), 1.75 (m, 1H), 1.72 (s, 3H), 1.67 (s, 3H) MS: (M+H)+ = 241, (M+Na) + = 263; (M-H)-= 239.

Example 209EMI445.2 (#)-(2R,3R,5R)-2-Acetamidomethyl-3-(N,N-dimethylcarbamoyl)-pyrrolidine-5- carboxviic Acid Trifluoroacetic Acid Salt.

'H NMR (D20) # 4.60 (t, J=8.4Hz, 1H), 4.23 (m, 1H), 3.56 (d, J=5.8Hz, 2H) 3.50 (m, 1H), 3.10 (s, 3H), 2.94 (s, 3H), 2.88 (m, 1H), 2.19 (m, 1H), 2.00 (s, 3H) MS: (M+H) + = 258, (M-H)-= 256.

Example 210 EMI446.1 ((2R, 3R. 5R)-2-Acetamidomethyl-3- (N-methvlcarbamovl)-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt.

'H NMR (D20) 4.49 (t, J=8.5Hz, 1 H), 4.10 (m, 1 H), 3.57 (d, J=5.8Hz, 2H), 3.03 (m, 1H), 2.76 (m, 1 H), 2.74 (s, 3H), 2.29 (m, 1 H), 2.00 (s, 3H) MS: (M+H) + = 244.

Example 211EMI446.2 (#)-(2R,3R,5R)-2-Acetamidomethyl-3-propionyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt.

'H NMR (D2O) 8 4.24 (m, 2H), 3.55 (d, J=4.7Hz, 1 H), 3.40 (m, 1 H), 2.85 (m, 1H), 2.64 (m, 3H), 2.16 (m, 1H), 2.01 (s, 3H), 1.02 (t, J=7.1Hz, 3H) MS: (M+H) + = 243; (M-H)-= 241.

Example 212EMI447.1 (#)-(2R,3R,5R)-2-Acetamidomethyl-3-methoxymethyl-pyrrolidine-5-carboxylic AcidHydrochloride 'H NMR (D20): # 4.44 (t, J=6Hz, 2H), 3.77 (m, 1 H), 3.65-3.48 (m, 3H), 3.35 (s, 3H), 2.64 (m, 1 H), 2.56 (m, 1 H), 2.03 (s, 3H), 2.00 (m, 1H).

MS: (M+H) += 231, (M-H)-= 229 Example 213EMI447.2 ()- (2R, 3S, 5R)-2-Acetamidomethyl-3-methvl-pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt.

'H NMR (D2O? 8 4.30 (m, 1H), 3.64 (m, 1H), 3.48 (m, 1H), 3.20 (m, 1H), 2.64 (m, 1H), 2.03 (s, 3H), 1.76 (m, 1H), 1.32 (brt, 1H), 1.12 (m, 4H) MS: (M+H) + = 201, (M+Na) + = 223.

Example 214 (#)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid SaltEMI448.1 214A (H2R. 3S, 5R. 1'R-1-t-Butoxycarbonyl-2-(1-t-butoxycarbonylamino-2ethylthio) ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

To a solution of ethanethiol (0.047 mL, 0.63 mmol) in THF (2 mL) at 0 C was added 2.5 M n-BuLi/hexane (0.248 mL, 0.62 mmol). The reaction mixture was stirred for 45 minutes and a solution of ()- (2R, 3S, 5R, 1'S)-1-tbutoxycarbonyl-2-(N-t-butoxycarbonylaziridinyl)-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (0.08 g, 0.182 mmole) in THF (0.5 mL) was added followed byDMF (1.5 mL) and stirred at room temperature for 2 hours. The reaction was quenched with 1 N NaHC03 (10 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound (yield: 61 mg, 67%).

1 H NMR (d6-DMSO) 5 6.74 (br d, 1 H), 5.85 (m, 1 H), 4.9-5.0 (m, 2H), 4.20 (m, 1H), 3.95 (m, 1H), 3.75 (d, 1H), 2.8-3.0 (dd, 1H), 2.5 (m, 3H), 1.65 (m, 1H), 1.32-1.45 (m, 27H), 1.17 (dt, 3H).

MS: (M-H)-= 499; (M+H) + = 501, (M+Na) + = 523 EMI449.1 214B(t)- (2R. 3S. 5R, 1'R)-1-t-Butoxvcarbonyl1-N-t-butoxycarbonylacetamido2-ethylthio) ethvl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butvl Ester.

()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl-2- (1-N-t-butoxycarbonylamino-2ethylthio) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (58 mg, 0.116 mmole) was reacted with lithium hexamethyidisilazide (1 M) (1.16 mL, 1.16 mmole) in THF (3 mL) at-78 C. After 0.5 hour at-78 C and 1 hour at-40 C, the above reaction mixture was reacted with acetyl chloride (0.166 mL, 2.33 mmole) at-30 C for 0.3 hours. The reaction was quenched with 1 N NaHC03 (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo.STDC0142 The residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound (yield: 28 mg, 44%).

1 H NMR (d6-DMSO) s 5.88 (m, 1 H), 4.9-5.0 (m, 2H), 4.52 (m, 1 H), 4.33 (m, 1H), 4.1 (m, 1H), 2.78 (dd, 1H), 2.3-2.5 (m, 6H), 1.7 (m, 1H), 1.32-1.5 (m, 27H), 1.11 (t, 3H).

MS: (M+H) + = 543. EMI450.1 STDC0748 214C(#)-(2R,3R,5R,1'R)-2-(1-Acetamido-2-ethylitio)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExampleExample41C, substituting (#)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-N-t- butoxycarbonylacetamido-2-ethylthio) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid tbutyl ester in place of (t)- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1-acetamido- 2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 7 mg, 95%).

1 H NMR (d6-DMSO) 8 8.15 (d, 1H), 5.72 (m, 1H), 5.05-5.2 (m, 2H), 4.2- 4.4 (m, 2H), 4.33 (m, 1H), 2.93 (m, 1 H), 2.7-2.8 (2d, 1 H), 2.3-2.6 (m, 3H), 1.851.95 (m, 1H), 1.93 (s, 3H), 1.17 (t, J=7.46 Hz, 3H) MS: (M+H) + = 287.

Example 215 f (2R, 3S, 5R, 1'R. 3'S)-2- (1-Acetamido-2-ethvisulfinvl) ethvl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid SaltEMI451.1 215A ()- (2R, 3S. 5R. 1'R. 3'S) and (#)-(2R,3S,5R,1'R,3'R)-1-t-Butoxycarbonyl-2 (1-N-t-butoxycarbonylacetamido-2-ethvlsulfinyl) ethyl-3-vinyl-pvrrolidine-5carboxylic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl-2- (1-N-t-butoxycarbonylacetamido- 2-ethylthio) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (72 mg, 0.132 mmole) was reacted with 55% m-chloroperoxybenzoic acid (41 mg, 0.132 mmole) in CHCI3 (1.5 mL) at -40 C for 30 minutes. The reaction was concentrated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate to provide the title compounds ()- (2R, 3S, 5R, 1'R, 3'S) isomer (yield: 14 mg, 18.9%) and ()- (2R, 3S, 5R, 1'R, 3'R) (yield: 45 mg, 60.7%).

(2R, 3S, 5R, 1'R, 3'S) 1H NMR (d6-DMSO) 6 5.88 (m, 1H), 4.9-5.0 (m, 2H), 4.50 (m, 1H), (m, 1H), 2.7-2.9 (m, 3H), 2.55 (m, 1H), 2.37 (s, 3H), 1.7 (m, 1H), 1.32-1.5 (m, 27H), 1.12 (t, 3H) MS: (M+H) + = 559, (M+Na) + = 581 (2R, 3S, 5R, 1'R, 3'R) 1H NMR (d6-DMSO) 6 5.88 (m, 1H), 4.9-5.0 (m, 2H), 4.50 (m, 1H), (m, 1H), 3.2 (m, 1H) 3.1 (dd, 1H), 2.5-2.7 (m, 2H), 2.38 (s, 3H), 1.75 (m, 1H), 1.32-1.5 (m, 27H), 1.12 (t, 3H) MS:STDC0863 (M+H) + = 559, (M+Na) + = 581EMI452.1 215B (i)-(2R. 3S, 5R. 1'R, 3'S)-2-(1-Acetamido-2-ethvisulfinvl) ethvl-3-vinvl- pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 3'S)-1-t-butoxycarbonyl-2- (1-N-tbutoxycarbonylacetamido-2-ethylsulfinyl) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. ester (yield: 9 mg, 86%).

1 H NMR(d6-DMSO) # 8.39 (d, 1 H), 5.72 (m, 1H), 5.15-5.2 (dd, 2H), 4.5 (m, 1 H), 4.37 (m, 1 H), 3.65 (m, 1 H), 2.85-3.04 (m, 3H), 2.6-2.85 (m, 2H), 2.4 (m, 1H), 1.83-1.95 (m, 1H), 1.86 (s, 3H), 1.20 (t, J=7.46 Hz, 3H).

MS: (M-H)-=301; (M+H) + = 303, (M+Na) + = 325 Example 216 (#)-(2R,3S,5R,1'R,3'R)-2-(1-Acetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5- carboxyl Acid Trifluoroacetic Acid SaltEMI453.1 The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 3'R)-1-t-butoxycarbonyl-2- (1-N-tbutoxycarbonylacetamido-2-ethylsulfinyl) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl 2-(1- acetamido-2-hydroxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 12 mg, 94%).

1 H NMR (d6-DMSO) 8 8.39 (d, 1H), 5.72 (m, 1H), 5.15-5.2 (dd, 2H), 4.53 (m, 1 H), 4.41 (t, 1 H), 3.65 (m, 1 H), 3.2 (dd, 1 H), 2.9-3.0 (m, 2H), 2.65-2.9 (m, 2H), 2.4 (m, 1 H), 1.83-1.95 (m, 1 H), 1.83 (s, 3H), 1.20 (t, J=7.46 Hz, 3H) MS: (M-H)-=301; (M+H) + = 303, (M+Na) + = 325 Example 217 ()- (2R. 3S. 5R. 1'R)-2- (1-N--butoxvcarbonvlacetamido-2-ethvlsulfonvl) ethvl-3- vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI454.1 217A ()- (2R, 3S. 5R, 1'R)-1-t-Butoxycarbonvl-2- (1-N-t-butoxvcarbonylacetamido- 2-ethvisulfonvl) ethvl-3-vinyi-pvrrolidine-5-carboxylic Acid t-Butvl Ester.

()- (2R, 3S, 5R, 1'R, 3'R)-1-t-Butoxycarbonyl-2- (1-N-t- butoxycarbonylacetamido-2-ethylsulfinyl) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (25 mg, 0.0448 mmole) was reacted with 55% mchloroperoxybenzoic acid (14 mg, 0.0448 mmole) in CHCI# (1.5 mL) at 0 C for one hour. The reaction was concentrated in vacuo. The residue was purified by chromatography on silica gel using 25% ethyl acetate/hexane to provide the title compound (yield: 23.7 mg, 92%).

1H NMR(d6-DMSO) # 5.88 (m, 1H), 4.85-5.0 (m, 2H), 4.38 (m, 1H), 4.15 (m, 1H), 3.7 (m, 1H) 3.45 (dd, 1 H), 2.9-3.2 (m, 3H), 2.5-2.7 (m, 1 H), 2.3-2.4 (m, 3H), 1.6-2.04 (m, 1H), 1.35-1.55 (m, 27H), 1.15 (t, 3H) MS:STDC0722 (M+H) + = 575 EMI455.1 217B (i)-(2R, 3S, 5R. 1'R)-2-(1-Acetamido-2-ethvlsulfonvl) ethvl-3-vinvl-pyrrolidine- 5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2- (1-N-tbutoxycarbonylacetamido-2-ethylsulfonyl) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-f-butoxycarbonyl-2- (1 acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 12 mg, 94%).

1 H NMR (d6-DMSO) 5 8.34 (d, 1 H), 5.72 (m, 1 H), 5.05-5.25 (dd, 2H), 4.68 (m, 1 H), 4.39 (dd, 1 H), 3.7 (2d, 1 H), 3.48 (dd, 1 H), 3.3-3.4 (dd, 2H), 3.08 (q, 2H), 2.95 (m, 1 H), 2.42 (m, 1 H), 1.9 (m, 1 H), 1.84 (s, 3H), 1.23 (t, J=7.46 Hz, 3H).

MS: (M-H)-= 317, (M+35) + = 353; (M+H) + = 319, (M+Na) + = 341 Examples 220EMI455.2 <tb> <SEP> \. <SEP> ???<tb> <SEP> 1. <SEP> rush<tb> <SEP> AcHN..,OH<tb> <SEP> 2. <SEP> LiHMDSIAcCI'N<tb> BocHN <SEP> H <SEP> goc <SEP> 3. <SEP> TFA/CHzCIz<tb> <SEP> TFA<tb> The following title compounds were prepared in 3 steps according to the methods described in Example 214.

Example 218 (i)-(2R 3S, 5R. 1'R)-2- (1-Acetamido-2-isopropvlthio) ethvl-3-vinyrrolidine-5- carboxylic Acid Trifluoroacetic Acid SaltEMI456.1 218A (#)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2- isopropvlthio) eth l-3-vinyl-pyrrolidine-5-carboxylic Acid t-Bu l Ester.

The title compound was prepared according to the method described inExample 214A, substituting isopropylthiol in place of ethanethiol (yield: 22 mg, 62%).STDC0533 1H NMR(d6-DMSO) # 6. 73 (d, 1H), 5.85 (m, 1H), 4.9-5.0 (m, 2H), 4.18 (m, 1 H), 3.95 (m, 1 H), 3.75 (br d, 1 H), 2.8-3.0 (m, 2H), 1.65 (m, 1 H), 1.32-1.45 (m, 27H), 1.18 (dd, 6H) MS: (M-H)-= 513; (M+H) + = 515, (M+Na) + = 537EMI456.2 218B(#)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-(N-t-butoxycarbonyl-Nacetamido)-2-isopropvlthio) etyvl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 214B, substituting ()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl-2- (1-N-tbutoxycarbonylamino-2-isoproylthio) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t butyl ester in place of ()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl-2- (1-N-t- butoxycarbonylamino-2-ethylthio) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 12 mg, 50%).

1 H NMR (d6-DMSO) â 5.86 (m, 1 H), 4.88-5.0 (m, 2H), 4.54 (m, 1 H), 4.33 (m, 1 H), 4.13 (d, 1H), 3.05 (m, 1H), 2.73-2.84 (m, 2H), 2.38 (br s, 3H), 1.72 (m, 1H), 1.32-1.5 (m, 27H), 1.14 (dd, 6H).

MS: (M+H) + = 557, (M+Na) + = 579EMI457.1 218C(#)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-isopropylthio)ethyl-3-vinyl- pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 15B, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2- (1-N-tbutoxycarbonylacetamido-2-isopropylthio) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t butoxycarbonyl-2- (1- acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 8 mg, 97%).

1H NMR (d6-DMSO) a 8.14 (d, 1H), 5.72 (m, 1H), 5.05-5.2 (dd, 2H), 4.24.4 (m, 2H), 3.68 (dd, 1 H), 2.93 (m, 2H), 2.74 (dd, 1 H), 2.58 (dd, 1 H), 1.93 (m, 1H), 1.87 (s, 3H), 1.2 (t, 6H) MS: (M-H)-= 299; (M+H) + = 301, (M+Na) + = 323 Example 219 ()- (2R. 3S. 5R. 1'R)-2- (1-Acetamido-2-phenvlthio) ethvl-3-vinvl-pyrrolidine-5- carboxylic Acid HvdrochlorideEMI458.1 219A ()- (2R, 3S, 5R, 1'R-1-t-Butoxycarbonvl-2- (1-amino-2-phenvithio) ethyl-3- vinvl-pyrrolidine-5-carboxvlic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'S)-1-t-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5- carboxylic acid t-butyl ester (20.3 mg, 0.06 mmole) was reacted with the phenylthiol (19.9 mg, 0.18 mmol) and triethylamine (0.047 mL, 0.34 mmol) in MeOH (0.06 mL) at ambient temperature for 3.5 hours. The reaction solution was concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel using ethyl acetate/methanol/ammonium hydroxide, 99/0.05/0.05, to provide the title compound (yield: 20.7 mg, 77%).

1H NMR (d6-DMSO) 6 7.31 (m, 4H), 7.17 (m, 1H), 5.87 (m, 1H), 5.03 (d, J=17Hz, 0.4H), 5.01 (d, J=17Hz, 0.6H), 4.91 (d, J=11H, 0.4H), 4.90 (d, J=11Hz, 0.6H), 4.15 (m, 1H), 3.82 (m, 0.6H), 3.76 (m, 0.4H), 3.39 (m, 1H), 2.92 (m, 2H), 2.55 (m, 1 H), 1.64 (m, 2H), 1.42 (s, 5.4H), 1.37 (s, 3.6H), 1.34 (s, 5.4H), 1.22 (s, 3.6H) MS: (M+H) + = 449, (M+Na) + = 471 EMI459.1 219B (i)-(2R, 3S, 5R 1'R)-1-t-Butoxvcarbonvl-2-(1-acetamido-2-shenylthio) ethyl- 3-vinyl-pyrrolidine-5-carboxvlic Acid t-Butyl Ester.

()- (2R, 3S, 5R, 1'R)-l-t-Butoxycarbonyl-2- (l-amino-2-phenylthio) ethyl-3vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (17.2 mg, 0.04 mmole) was reacted with the acetic anhydride (0.011 mL, 0.11 mmol) and triethylamine (0.032 mL, 0. 23 mmol) in CH2CI2 (0.3 mL) at rt for 4.25 hours. The reaction solution was concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel using 5% methanol/dichloromethane to provide the title compound.

'H NMR (d6-DMSO) d 7.75 (d, J=9Hz, 0.6H), 7.73 (d, J=9Hz, 0.4H), 7.32 (m, 4H), 7.19 (m, 1H), 5.87 (m, 1H), 5.04 (d, J=17Hz, 0.4H), 5.00 (d, J=17Hz, 0.6H), 4.95 (d, J=10Hz, 0.6H), 4.93 (d, J=10Hz, 0.4H), 4.59 (m, 0.4H), 4.45 (m, 0.6H), 3.99 (dd, J=10Hz, 2Hz, 0.6H), 3.94 (dd, J=10Hz, 2.5Hz. 0.4H), 3.84 (m, 0.6H), 3.77 (m, 0.4H), 3.07 (dd, 13Hz, 5Hz, 0.6H), 2.95 (m, 1.8H), 2.83 (brt, J=8Hz, 0.6H), 2.48 (m, 1H), 1.84 (s, 1.2H), 1.81 (s, 1.8H), 1.68 (m, 1 H), 1.41 (s, 5.4H), 1.36 (s, 3.6H), 1.34 (s, 5.4H), 1.26 (s, 3.6H) MS:STDC0705 (M-H)-= 489, (M+35)' ; (M+H) + = 490, (M+Na) + = 513 EMI460.1 219C() (2R, 3S, 5R. 1'R)-2- (1-Acetamido-2-phenvlthio) ethvl-3-vinvl-pyrrolidine-5- carboxylic Acid Hydrochloride The title compound was prepared according to the method described inExample 1K, substituting (#)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido- 2-phenylthio) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-ethyl) pentyl-3- (methoxymethyl)-pyrrolidine-5carboxylic acid t-butyl ester (yield:STDC0733 14.6 mg, 100%.) 1H NMR (d4-methanol) 8 7.43 (m, 2H), 7.31 (m, 3H), 5.75 (ddd, J=17Hz, 10Hz, 8Hz, 1H), 5.32 (brd, J=17Hz, 1H), 5.19 (dd, J=10Hz, 1.4Hz, 1H), 4.58 (m, 2H), 3.89 (dd, J=10Hz, 3Hz, 1H), 3.19 (dd, J=14Hz, 6Hz, 1H), 3.09 (dd, J=14Hz, 9Hz, 1H), 3.04 (m, 1H), 2.57 (dt, J=13Hz, 7Hz, 1H), 2.04 (s, 3H), 2.03 (m, 1H) MS: (M-H)-= 333;STDC0596 (M+H) + = 335, (M+Na) + = 357 Example 220 (#)-(2R, 3S, 5R. 1'R)-2- (1-Acetamido-2-benzvlthio) ethvl-3-vinyl-pvrrolidine-5- carboxylic Acid Trifluoroacetic Acid SaltEMI461.1 220A (#)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2- benzvlthio) ethvl-3-vinyl-pyrrolidine-5-carboxvlic Acid t-Bu l Ester The title compound was prepared according to the method described inExample 214A, substituting benzylmercaptan in place of ethanethiol (yield: 28 mg, 72%).

1 H NMR (d6-DMSO) 8 7.2-7.35 (m, 5H), 6.80 (br d, 1 H), 5.84 (m, 1 H), 4.86-4.96 (m, 2H), 4.25 (m, 1 H), 3.95 (m, 1 H), 3.7-3.8 (m, 3H), 2.76-2.94 (m, 1 H), 2.35-2.45 (m, 2H), 1.65 (m, 1 H), 1.32-1.45 (m, 27H) MS: (M-H)-= 561; (M+H) + = 563, (M+Na) + = 585 EMI462.1 220B(ffi)-(2R, 3S. 5R. 1'R)-1-t-Butoxvcarbonvl-2-(1-(N-t-butoxvcarbonylacetamido)-2-benzvlthio) ethvl-3-vinvi-pvrrolidine-5-carboxviic Acid t-Butyl Ester.

The title compound was prepared according to the method described inExample 214B, substituting ()- (2R, 3S, 5R, 1'R)-1-f-Butoxycarbonyl-2- (1-N-t butoxycarbonylamino-2-benzylthio) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid tbutyl ester in place of ()- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl-2- (1-N-tbutoxycarbonylamino-2-ethylthio) ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 3.3 mg, 61%).

1 H NMR(d6-DMSO) # 7.2-7.35 (m, 5H), 5.84 (m, 1 H), (m, 2H), 4.55 (m, 1 H), 4.32 (d, 1 H), 4.05 (d, 1 H), 3.56-3.65 (m, 2H), 2.9 (m, 1 H), 2.3-2.65 (m, 3H), 2.42 (s, 3H), 1.76 (d, 1H), 1.25-1.55 (m, 27H) MS:STDC0756 (M+H) + = 605, (M+Na) + = 627EMI462.2 220C (#)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-benzylthio)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2- (1-N-tbutoxycarbonylacetamido-2-benzylthio) ethyl-3-vinyl-pyrroiidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 2.2 mg, 95%).

1 H NMR (d6-DMSO) 8 8.18 (d, 1H), 7.2-7.32 (m, 5H), 5.68 (m, 1H), 5.02- 5.2 (m, 2H), (m, 2H), 3.76 (s, 2H), 3.68 (dd, 1H), 2.92 (m, 1H), 2.62 (dd, 1 H), 2.32-2.55 (m, 2H), 1.85-1.95 (m, 1 H), 1.89 (s, 3H).

MS: (M-H)-= 347; (M+H) + = 349, (M+Na) + = 371 Example 221EMI463.1 (#)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-(4-pyridinethio)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Dihvdrochloride.

The title compound was prepared according to the method of Example 219A-C substituting 4-thiopyridine for thiophenol as the reagent in Example 219A.

'H NMR (d4-methanol) d 8.57 (d, J=7Hz, 2H), 7.97 (d, J=7Hz, 2H), 5.85 (ddd, J=17Hz, 10Hz, 9Hz, 1 H), 5.40 (br d, J=17Hz, 1H), 5.25 (dd, J=17Hz, 10Hz, 1H), 4.67 (dt, J= OHz, 4Hz, 1 H), 4.47 (dd, J=10Hz, 8Hz, 1H), 4.01 (dd, J=10Hz, 4Hz, 1H), 3.68 (dd, J=14Hz, 5Hz, 1H), 3.45 (dd, J=14Hz, 10Hz, 1H), 3.16 (m, 1H), 2.65 (dt, J=14Hz, 7Hz, 1H), 2.07 (m, 1H), 2.04 (s, 3H) MS: (M-H)-= 334;STDC0267 (M+H) + = 336, (M+Na) + = 358 Example 222EMI464.1 ()- (2R, 3S, 5R. 1'R. 2'S)-2- (1-Acetamido-2-hydroxy) butvl-3- (cis-propen-1-vl)- pyrrolidine-5-carboxvlic Acid Ethyl Ester.

Thionyl chloride (1.49 mL, 20.5 mmol) was reacted with ethanol (25 mL) at 0 C for 10 minutes. ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-hydroxy) butyl-3(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (815 mg, 2.05 mmol) in ethanol (50 mL) was added to the above solution and reacted at room temperature for 17 hours. The reaction was concentrated in vacuo and the residue was purified by chromatography on silica gel with 90/10/0.5 dichloromethane/methanol/ammonium hydroxide to provide the title compound as a white solid (yield: 462 mg, 72%).

'H NMR (DMSO-d6) 8 7.49 (d, J = 9.8 Hz, 1 H), 5.31 (m, 2H) 4.11 (m, 2H), 3.72 (t, J = 7.7 Hz, 1 H), 3.69 (m, 1 H), 3.42 (m, 1 H), 3.07 (m, 1 H), 2.85 (m, 1 H), 2.22 (m, 1 H), 1.76 (s, 3H), 1.54 (d, J = 5.6 Hz, 3H), 1.45 (m, 1 H), 1.39 (m, 1 H), 1.21 (m, 1 H), 1.19 (t, J = 7. 0 Hz, 3H), 0.83 (t, J = 7. 3 Hz, 3H).

MS: (M+H) += 313, (M+Na) += 335, (M-H)-= 311.

Example 223EMI465.1 (#)-(2R,3R,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)pyrrolidine-5-caboxylic Acid Ethyl Ester The title compound is prepared according to the method described inExample 222, substituting ()- (2R, 3R, 5R, 1'R, 2'S)-2- (1-acetamido-2hydroxy) butyl-3- (pyrazol-3-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of (#?-(2R, 3S, 5R, 1'R, 2'S)-2- (1-acetamido-2-hydroxy) butyl-3- (cis-propen- 1-yl)-pyrrolidine-5-carboxylic trifluoroacetic acid salt (yield: 32 mg, 52%).

1H NMR(d?6^-DMSO) # 7.6 (br s, 1H), 6.1 (br s, 1H), 4.08 (q, J=7.12Hz, 2H), 3.78 (m, 1 H), 3.65 (m, 1H), 3.55 (m, 1H), 3.45 (m, 1H), 3.25 (m, 1H), 3.45 (m, 1H), 1.72 (s, 3H), 1.45 (m, 1H), 1.2 (m, 1H), 1.16 (t, J=7.12 Hz, 3H), 0.82 (t,J=7.46 Hz, 3H).

MS: (M-H)-= 337, (M+35) + = 373; (M+H) + = 339, (M+Na) + = 361 Example 224EMI466.1 ()- (2R. 3S, 5R, 1'S, 3'S)-2- (1-Acetamido-2- (N-isopropyl-N-methvlamino-N- oxide)) ethVl-3- (cis-nropen-1-yl)-nyrrolidine-5-carboxylic Acid Ethyl Ester The title compound is prepared according to the method described inExample 222, substituting ()- (2R, 3S, 5R, 1'S, 3'S)-2- (1-acetamido-2- (N-isopropyl)N-methylamino-N-oxide)) ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of ()- (2R, 3S, 5R, 1'R, 2'S)-2- (1-acetamido-2hydroxy) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 25 mg, 34%).

1 H NMR (MeOD-d3) 5 5.51-5.43 (m, 1 H), 5.34-5.27 (m, 1 H), 4.36-4.30 (m, 1H), 4.18 (q, J=7. 1Hz, 2H), 3.88 (dd, J=6.8,8.8Hz, 1H), 3.82-3.67 (m, 2H), 3.493.42 (m, 1H), 3.34 (s, 3H), 3.14-2.96 (m, 1H), 2.42-2.33 (m, 1H), 1.92 (s, 3H), 1.641.52 (m, 1H), 1.63 (dd, J=1.7,6.8Hz, 3H), 1.41-1.24 (m, 1H), 1.39 (d, J=6.4Hz, 3H), 1.31 (d, J=6.4Hz, 3H), 1.26 (t, J=7. 1Hz, 3H).

MS: (M+H) +=356, (M+Na) +=378, (M-H)-=354, (M+35) +=390.

Example 225EMI467.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine- 5-carboxvlic Acid Ethyl Ester The title compound is prepared according to the method described inExample 222, substituting ()- (2R, 3S, 5R, 1'S)-2- (1-acetamido-3-methyl) butyl-3 (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 838 mg, 94%).

1 H NMR (CDC13): # 5.50 (m, 1 H), 5.41 (m, 1 H), 5.28 (m, 1 H), 4.21 (q, J=7. 5Hz, 2H), 4.06 (m, 1H), 3.87 (t, J=7.5Hz, 1H), 3.10 (m, 1H), 2.97 (m, 1H), 2.39 (m, 1H), 1.97 (s, 3H), 1.66 (dd, 3H), 1.60 (m, 1H), 1.40 (m, 2H), 0.94 (d,J=7.5Hz, 3H), 0.93 (d, J=7.5 Hz, 3H).

MS:(M+H)^+?=311 Example 226EMI468.1 ()- 3S, 5R. 1'S)-2-(1-Acetamido-3-methyl) butyl-3-(cis-2-chloro-vin-1-yl)- pyrrolidine-5-carboxylic Acid Ester The title compound is prepared according to the method described inExample 222, substituting ()- (2R, 3S, 5R, 1'S)-2- (1-acetamido-3-methyl) butyl-3 (cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 28 mg, 46%).

1 NMR (CDC13): # 6.05 (d, J=7.5Hz, 1H), 5.90 (dd, J1=9 Hz, J2=6Hz, 1H), 5.31 (d, J=9Hz, 1H), 4.19 (q, J=7.5Hz, 2H), 4.06 (m, 1H), 3.82 (t, J=7.5Hz, 1H), 3.17 (m, 2H), 2.45 (m, 1H), 1.98 (s, 3H), 1.67 (m, 1H), 1.60 (m, 1H), 1.37 (m, 2H), 1.27 (t, J=7.5Hz, 3H), 0.91 (d, J=7.5Hz, 3H), 0.89 (d, J=7.5Hz, 3H).

MS: (M+H) += 331 Example 227Intentionally blank.

Example 228EMI469.1 (#)-(2R,3S,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(2,2-difluoro-vinyl)- pvrrolidine-5-carboxvlic Acid Ethyl Ester The title compound is prepared according to the method described inExample 222, substituting ()- (2R, 3S, 5R, 1'S)-2- (1-acetamido-3-methyl) butyl-3 (2,2-difluoro-vinyl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of ()- (2R, 3S, 5R, 1'R, 2'S)-2-(1-acetamido-2-hydroxy) butyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 28 mg, 57%). aH NMR (CDC13):STDC0297 8 4.22 (q, J=7.5 Hz, 2H), 4.14 (m, 1H), 4.03 (m, 1H), 3.29 (br, 1 H), 2.85 (m, 1 H), 2.52 (m, 1 H), 2.01 (s, 3H), 1.77 (m, 2H), 1.64 (m, 2H), 1.49 (m, 1 H), 1.38 (m, 1 H), 1.29 (t, J=7.5Hz, 3H), 0.93 (d, J=7.5Hz, 3H), 0.90 (d,J=7.5Hz, 3H).

MS: (M+H) += 333 Example 229EMI470.1 (#)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5- carboxylic Acid Ester The title compound is prepared according to the method described inExample 222, substituting ()- (2R, 3R, 5R, 1'S)-2- (1-acetamido-3-methyl) butyl-3 (pyrazol-3-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of(#)- (2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 48 mg, 75.5%).

'H NMR (CDC13): 5 7.49 (d, 1H), 7.26 (s, 1H), 6.18 (d, 1H), 4.18 (q,J=7.5Hz, 2H), 4.12 (m, 1H), 3.91 (t, J=7.5Hz, 1H), 3.51 (t, J=7.5Hz, 1H), 3.40 (q,J=9Hz, 1H), 2.64 (m, 1H), 2.00 (m, 1H), 1.82 (s, 3H), 1.75 (m, 1H), 1.36 (m, 1H), 1.26 (t, J=9Hz, 3H), 0.855 (d, 3H), 0.84 (d, 3H).

MS: (M+H) += 337 Example 230 ()- (2R, 3S. 5R. 1'R)-2- (1-Acetamido-2-ethvl-2-hydroxy) butvl-3- (cis-propen-1-yl pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt.EMI471.1 STDC0730230A ()- (2R. 3S. 5R, 1'R)-1-t-Butoxvcarbonyl-2- (1-acetamido-2-ethyl-2- hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Ester, The title compound was prepared according to the method described inExample 41B, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2-(1-acetamido2-oxo) butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester for ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl 2- (1-acetamido-1-formyl) methyl-3- (cis-propen1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester to provide the title compound (yield: 0.021 g, 51%).

MS: (M+H) += 469, (M+Na) + = 491, (2M+Na) +=959, (M-H)-= 467. EMI471.2 230B (#)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen- 1-yl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2-(1 acetamido-2-ethyl-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1 acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyi ester (yield: 0.0039 g, 100%).STDCDBPG0547* 'H NMR (DMSO-d6) 67. 52 (d, J=10.3Hz, 1H), 5.45 (m, 1H), 5.28 (m, 1H), 4.32 (m, 2H), 3.68 (t, J=8.8Hz, 1H), 3.16 (quint., J=8.5Hz, 1H), 2.41 (dt, J=13.2,8.3Hz, 1H), 1.81 (s, 3H), 1.59 (m, 1H), 1.53 (dd, J=6.8,1.5Hz, 3H), 1.521.42 (m, 3H), 1.30 (m, 1 H), 0.86 (t, J=7.3Hz, 3H), 0.83 (t, J=7.3Hz, 3H).

MS: (M+H) + 313, (M+Na) + = 335, (M-H)-= 311, (2M-H)-= 623.

Example 231 (i)-(2R, 3S, 5R. 1'R, 2'S)-2-(1-Acetamido-2-hydroxv-2-methvl) nentvl-3-(cis-propen- 1-vl)-pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt.EMI472.1 STDC0775 231A(#)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2- t-ButylEster.methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid The title compound was prepared according to the method described inExample 41 B, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2- (1-acetamido2-oxo) pentyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester for(#)- (2R, 3S, 5R, 1'R)-1-t-Butoxycarbonyl 2- (1-acetamido-1-formyl) methyl-3- (cispropen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester and methylmagnesium bromide for ethylmagnesium bromide to provide the title compound (yield: 0.0285 g, 45%).

MS: (M+H)+ = 469, (M+Na) + = 491. EMI473.1 STDC0764 231B(#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis- propen-1-vl)-pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0040 g, 100%).

1H NMR (DMSO-d6) 69.25 (bs, 1H), 8.75 (bs, 1H), 7.54 (d, J=10.3Hz, 1H), 5.45 (m, 1 H), 5.29 (m, 1 H), 4.37 (bt, J=8.3Hz, 1 H), 4.22 (t, J=9.7Hz, 1 H), 3.62 (t,J=8.8Hz, 1H), 3.12 (quint., J=8.5Hz, 1H), 2.41 (dt, J=12.7,7.8Hz, 1H), 1.78 (s, 3H), 1.59 (m, 1H), 1.53 (dd, J=6.8,2. 0Hz, 3H), 1.4-1.25 (m, 4H), 1.17 (s, 3H), 0.81 (t, J=6.5 Hz, 3H).

MS: (M+H) + = 313, (M+Na) + = 335, (M-H)-= 311, (2M-H)-= 623 Example 232 (i)-(2R 3S. 5R. 1'R, 2'S)-2-(1-Acetamido-2-ethvl-2-hvdroxv) nentvl-3-(cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.EMI474.1 STDC0177 232A(i)-(2R, 3S, 5R. 1'R. 2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-ethyl-2- hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Ester.

The title compound was prepared according to the method described in Example 41 B, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2- (1-acetamido t-butylesterfor(#)-2-oxo)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl 2- (1-acetamido-1-formyl) methyl-3- (cis-propen1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester to provide the title compound (yield: 0.0222 g, 33%).

MS: (M+H) + = 483, (M+Na)+ = 505, (M-H)-=481.EMI474.2 STDC0775 232B ()- (2R. 3S, 5R, 1'R, 2'S)-2- (1-Acetamido-2-ethyl-2-hydroxy) pentyl-3- (cis- propen-1-yl)-pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1 acetamido-2-hydroxy)butyl-3- (cis-propen-1-yi)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0035 g, 100%).

1H NMR (DMSO-d6) 6 9. 1 (bs, 1H), 8.75 (bs, 1H), 7.53 (d, J=9.8Hz, 1H), 5.44 (m, 1H), 5.28 (m, 1H), 4.35-4.25 (m, 2H), 3.67 (m, 1H), 3.16 (quint., J=8.5Hz, 1H), 2.41 (dt, J=12.8,7.9Hz, 1H), 1.81 (s, 3H), 1.60 (m, 1H), 1.53 (dd, 8Hz, 3H), 1.46 (m, 2H), 1.4-1.20 (m, 4H), 0.86 (t, J=7.3Hz, 3H), 0.82 (t,J=6.7 Hz, 3H).

MS: (M+H)+ = 327, (M-H)-= 325, (M+CF3COOH)-=439, (2M-H)-= 651 Example 233EMI475.1 (#)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-propyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 232 substituting propyl magnesium bromide for ethyl magnesium bromide.

'H NMR (DMSO-d6): # 0.81 (t, 3H), 0.91 (t, 3H), 1.24-1.49 (m, 8H), 1.54 (dd, 3H), 1.60 (m, 1H), 1.81 (s, 3H), 2.41 (m, 1H), 3.15 (m, 1H), 3.69 (t, 1H), 4.28 (t, 1H), 4.35 (t, 1H), 5.17 (brs, 1H), 5.28 (td, 1H), 5.45 (dq, 1H), 7.54 (d, 1H), 8.80 (br s, 1H), 9.12 (br s, 1 H).

MS: (M+H) += 341.

Example 234 (#)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-ethyl-2-methyoxy)butyl-3-(cis-propen-1-y pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI476.1 234A (#)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-Acetamido-2-ethyl-2- t-(methylthio)methyloxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid But este ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-ethyl-2- methoxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester was reacted with dimethylsufoxide and acetic anhydride according to the method ofMarshall, J. A. in J. Org. Chem. 1979, vol. 44, p 2994 to provide the title compound.EMI476.2 STDC0536 234A()- (2R, 3S, 5R. 1'R, 2'S)-1-t-Butoxvcarbonyl-2- (1-Acetamido-2-ethyl-2- methoxy butvl-3- (cis-propen-1-yl)-pvrrolidine-5-carboxylic Acid t-Bu l Ester ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-Butoxycarbonyl-2- (1-acetamido-2-ethyl-2 (methylthio) methyloxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t- butyl ester is reacted with Raney Nickel according to the procedure of Marshall, J.

A. in J. Org. Chem. 1979, vol. 44, p 2994 to provide the title compound.EMI477.1 STDC0675 ()- 3S, 5R, 1'R, 2'S)-2-(1-Acetamido-2-ethvl-2-methoxy) butvl-3-(cis-propen-1- yl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound is prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1acetamido-2-ethyl-2-methoxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1t-butylacetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ester.

Example 235EMI477.2 ()- (2R, 3S. 5R. 1'R. 2'S)-2- (1-Acetamido-2-ethyl-2-methoxv) Pentvl-3- (cis-propen-1- vl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound is prepared according to the method described inExample 234 substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-ethyl-2-hydroxy) pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester for ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2- (1-acetamido-2 ethyl-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in 234A.

Example 236 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cis- propen-1-yl)-pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid SaltEMI478.1 236A ()- (2R. 3S. 5R. 1'R. 2'S)-1-t-Butoxvcarbonvl-2- (1-Acetamido-2- ( (1- ethoxy ethyloxvyl)-2-hydroxy pentvl-3- (cis-propen-1-vl)-pvrrolidine-5carboxvlic Acid t-Butvl Ester ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-Butoxycarbonyl-2- (1-acetamido-2-oxo) pentyl-3(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (50 mg, 0.11 mmole) was reacted with (ethoxyethyloxymethyl) tributylstannane (260 mg, 0.66 mmole) according to the method of Still, W. C. (J. Am. Chem. Soc., 100,1481 (1978)) to provide the title compound (yield: 26.8 mg, 43.8%).

'H NMR (CDC13): 5 0.89 (t, 3H), 1.19 (m, 3H), 1.29 (dd, 3H), 1.45 (s, 9H), 1.46 (s, 9H), 1.52-1.73 (m, 8H), 1.99 (s, 3H), 2.44 (m, 1 H), 3.24-3.74 (m, 5H), (m, 3H), 4.49 (m, 1H), 4.62 (m, 1H), 5.37 (m, 1H), 5.64 (m, 1H), 5.976.41 (m, 1 H).

MS: (M+H) += 557. EMI479.1 STDC0837236B (i)-(2R, 3S, 5R, 1'R. 2'S)-2-(1-Acetamido-2-hvdroxvmethvl-2-hvdroxv) pentyl- 3- (cis-propen-1-yl)-pyrrolidine-5-carboxic Acid Trifluoroacetic Acid Salt ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-Butoxycarbonyl-2- (1-Acetamido-2- (1-ethoxy-2 ethoxymethyl)-2-hydroxy) pentyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester (13.5 mg, 0.024 mmol) was dissolved in THF (1 mL) and treated with 0.5 N HCI (1 mL) at room temperature for 1 hr. The solvents were removed and the resulting white solid was reacted with trifluoroacetic acid (0.8 mL) in dichloromethane (0.2 mL) at room temperature for 6 hours. The reaction was concentrated in vacuo overnight to provide the title compound (yield: 10.7 mg) as a off white solid.

'H NMR (DMSO-d6): 8 0.81 (t, 3H), 1.24-1.38 (m, 4H), 1.52 (dd, 3H), 1.62 (m, 1H), 1.78 (s, 3H), 2.41 (m, 1H), 3.11 (m, 1H), 3.51 (qAB, 2H), 3.77 (t, 1H), 4.23 (t, 1 H), 4.40 (m, 1 H), 5.27 (t, 1 H), 5.45 (m, 1 H), 7.55 (d, 1 H), 8.87 (br s, 1 H), 9.26 (br s, 1 H).

MS: (M+H) += 329 Example 237 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-alyloxy-2-vinyl)ethyl-3-(cis-propen-1- vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI480.1 237a (#)-(2R,3S,5R,1'R2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-allyloxy-2- vinyl ethyl-3- (cis-propen-1-yl)-pvrrolidine-5-carboxYlic Acid t-Butyl Ester (2R, 3S, 5R, 1'R, 2'S)-1-t-Butoxycarbonyl-2- (1-acetamido-2-hydroxy-2vinyl) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester was reacted according to the method described in Example 84A substituting allyl iodide for methyl iodide (yield: 28 mg, 80%).

MS: (M+H) += 479, (M-H)-= 477EMI480.2 237B (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-allyloxy-2-vinyl)ethyl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1acetamido-2-allyloxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1 t-butylacetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ester. (yield: 4 mg, 100%).

'H NMR (DMSO-d6) 6 7.98 (d, J=7.8 Hz, 1H), 5.90 (m, 1H), 5.55 (m, 1H), 5.48 (m, 1H), 5.32 (m, 2H), 5.26 (m, 2H), 5.16 (m, 1H), 4.28 (m, 2H), 3.96 (m, 1H), 3.79 (m, 1H), 3.73 (m, 1H), 3.66 (m, 1H), 3.26 (m, 1H), 2.40 (m, 1H), 1.81 (s, 3H), 1.70 (m, 1H), 1.64 (dd, J=6.9,1.5 Hz, 3H).

MS: (M+H) += 323, (M-H)- = 321.

Example 238 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-1-(2,5-dihydrofuran-2-yl))methyl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid SaltEMI481.1 238A(tl(2R. 3S. 5R, 1'R. 2'S)-2- 1-Acetamido-1- (2.STDC0806 5-dihydrofuran-2-yl)) methyl-3- (cis-propen-1-vl)-pvrrolidine-5-carboxvlic Acid t-Butyl Ester ()- (2R, 3S, 5R, 1'R, 2'S)-1-tButoxycarbonyl-2-(1-acetamido-2-allyloxy-2vinyl) ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (21 mg, 0.044 mmole) prepared according to the procedure of Example 237A was reacted with bis (tricyclohexylphosphine) benzylidine ruthenium (IV) dichloride [Grubb's catalyst] (7.5 mg, 0.009 mmole) in methylene chloride (5 mL) at 25 C for 2 hours under a nitrogen atmosphere. The reaction was concentrated in vacuo and the resulting residue purified by chromatography on silica gel using 75% ethyl acetate/hexanes to provide the title compound (yield: 18 mg, 90%).

MS: (M+H) += 451, (M-H)-= 449.EMI482.1 STDC0741238B (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-1-(2,5-dihydrofuran-2-yl))methyl-3- TrifluoroaceticAcidSalt(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-Butoxycarbonyl-2-(1- acetamido-1-(2,5-dihydrofuran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl- t-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid butyl ester. (yield: 7 mg, 100%).

1H NMR (DMSO-d6) 5 8.09 (d, J=8.8 Hz, 1H), 6.10 (m, 1H), 5.87 (m, 1H), 5.50 (m, 1H), 5.27 (m, 1 H), 4.68 (m, 2H), 4.58 (m, 1 H), 4.33 (m, 1 H), 4.06 (m, 1H), 3.68 (m, 1H), 3.18 (m, 1H), 2.40 (m, 1H), 1.85 (s, 3H), 1.68 (m, 1H), 1.60 (dd, J=6.8,1.5 Hz, 3H), MS: (M+H) += 295, (M-H)-= 293.

Example 239 ()- -(2R, 3S. 5R, 1'R. 2'S)-2- (1-Acetamido-2-ailyloxy-2-allvll ethvl-3- (cis-propen-1-v pvrrolidine-5-carboxvlicAcid Trifluoroacetic Acid SaltEMI483.1 239A (i)-(2R. 3S. 5R. 1'R. 2'S)-1-t-Butoxvcarbonyl-2-(1-acetamido-2-allvloxy-2- all ll ethyl-3- (cis-propen-1-vl)-pvrrolidine-5-carboxylic Acid t-Butvl Ester (2R, 3S, 5R, 1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2allyl) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester was reacted according to the method described in Example 84A substituting allyl iodide for methyl iodide iodide (yield: 19 mg, 36%).

MS: (M+H) += 493, (M-H)-= 491.EMI483.2 STDC0771239B (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-allyloxy-2-allyl)ethyl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- Acetamid o-2-allyloxy-2-allyl) propyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2- (1 acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. (yield: 5.7 mg, 100%).

1H NMR (DMSO-d6) # 8.06 (dd, J= 8.8 Hz, 1H), 6.92 (m, 1H), 6.77 (m, 1H), 5.50 (m, 1H), 5.29 (m, 2H), 5.17 (m, 1H), 5.05 (m, 2H), 4.27 (m, 2H), 4.10 (dd, J= 12.2,5.4 Hz, 1H), 3.83 (m, 1H), 3.78 (m, 1H), 3.40 (m, 1H), 3.20 (m, 1H), 2.46 (m, 1H), 2.38 (m, 1H), 2.20 (m, 1H), 1.88 (s, 3H), 1.69 (m, 1H), 1.63 (dd, J= 6.8,1. 5 Hz, 3H).

MS: (M-H)-=335.(M+Na)+=359, Example 240 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3- (cis-propen-1-vl)-pyrrolidine-5-carboxviic Acid Trifluoroacetic Acid SaltEMI485.1 240A (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2- vl)) methyl-3 (cis-propen-1-yl,-pyrrolidine-5-carboxylic Acid t-Butvl Ester ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-Butoxycarbonyl-2- (1-Acetamido-2-allyloxy-2-allyl) ethyl3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (11.5 mg, 0.023 mmole) prepared according to the procedure of Example 239A was reacted with bis (tricyclohexylphosphine) benzylidine ruthenium (IV)STDC0386 dichloride [Grubb's catalyst] (3. 8 mg, 0.005 mmole) in methylene chloride (3 mL) at 25 C for 3 hours under a nitrogen atmosphere. The reaction was concentrated in vacuo and the resulting residue purified by chromatography on silica gel using 75% ethyl acetate/hexanes to provide the title compound (yield: 5.7 mg, 53%).

MS: (M+H) += 465, (M+Na) += 487, (M-H)-= 463 EMI485.2 240B (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2- yl) methyl-3- (cis-propen-1-vl)-pvrrolidine-5-carboylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t butoxycarbonyl-2- (1- acetamido-1-(3, 6-dihyd ro-2-H-pyran-2-yl)) propyl-3-(cis-propen-1-yl)-pyrrolidine-5carboxylic acid f-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S-1-t-butroxycarbonylt-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid butyl ester. (yield: 5.9 mg, 100%).

'H NMR (DMSO-d6) 8 8.04 (d, J= 8.8Hz, 1H), 5.77 (m, 2H), 5.50 (m, 1H), 5.25 (m, 1H), 4.21 (m, 2H), 4.14 (m, 1H), 4.04 (m, 1H), 3.81 (m, 1H), 3.40 (m, 1 H), 3.23 (m, 1 H), 2.41 (m, 1 H), 2.09 (m, 1 H), 1.88 (s, 3H), 1.83 (m, 1 H), 1.70 (m, 1 H), 1.63 (d, J= 6.8Hz, 3H).

MS: (M+H) + = 309, (M+Na) + = 331, (M-H)-= 307 The following compounds were synthesized according to the methods previously described in Examples 1-240 Example 241EMI486.1 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))-propyl-3- (cis-propen-1-vl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 1 H NMR (DMSO-d6) 5 7.90 (d, 9.1 Hz, 1 H), 5.79 (m, 2H), 5.48 (m, 1 H), 5.23 (m, 1 H), 4.43 (m, 1 H), 4.24 (m, 2H), 4.17 (m, 2H), 3.73 (m, 1 H), 3.64 (m, 1H), 3.19 (m, 1H), 2.42 (m, 1H), 2.02 (m, 1H), 1.85 (s, 3H), 1.78 (m, 1H),STDC0111 1.75 (m, 1H), 1.56 (dd, J= 7.5,1.5 Hz, 3H).

MS: (M+H) + = 309, (M+Na) + = 331, (M-H)-= 307.

Example 242EMI487.1 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO) 8 7.7 (d, J= 9.8 Hz, 1H), 5.61 (m, 1H), 5.19 (dt, J= 1.8, 11.0 Hz, 1H), 4.33 (dd, J= 6.7,10.3 Hz, 1H), 3.81 (m, 1H), 3.70 (dd, 1.8,10.3 Hz, 1H), 3.54 (q, J= 6.1 Hz, 1H), 3.10 (m, 1H), 2.35 (dt, J= 12.8,6.8 Hz, 1H), 1.90 (s, 3H), 1.7 (m, 1H), 1.59 (dd, J= 0.7,7.3 Hz, 3H), 1.4 (m, 3H), 1.2 (m, 2H), 0.90 (t,J= 6.7 Hz, 3H).

MS: (M+H) += 299 Example 243EMI487.2 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-ethyoxycarbonyl)propyl-3- (cis-propen-1-yl)-pvrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO) 7.75 (m, 1H), 5.60 (m, 1H), 5.29 (m, 1H), (m, 3H), 4.15-4.0 (m, 3H), 3.9-3.6 (m, 3H), 3.15 (m, 1H), 2.45-2.3 (m 2H), 1.9 (s, 3H), 1.8-1.5 (m, 5H), 1.2 (m, 3H).

MS: (M+H) += 343 Example 244EMI488.1 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methyoxy-2-vinyl)ethyl-3-(cis-propen-1- vl)-pvrrolidine-5-carboxvlicAcid Trifluoroacetic Acid Salt 'H NMR (DMSO-d6) d 7.91 (d, J=8.05Hz, 1H), 5.50 (m, 2H), 5.30 (m, 3H), 4.27 (m, 1H), 4.23 (m, 1H), 3.75 (m, 1H), 3.48 (m, 1H), 3.23 (m, 1H), 3.15 (s, 3H), 2.40 (m, 1H), 1.80 (s, 3H), 1.68 (m, 1H), 1.64 (dd, J=1.83,7.32Hz, 3H) MS:STDC0657 (M+H) + = 297, (M-H)- = 295 Example 245EMI488.2 ()- (2R. 3S. 5R. 1'R. 2'S)-2- (1-Acetamido-2-ethoxy-2-vinyl) ethyl-3- (cis-propen-1-v pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-d6) d 7.90 (d, J=7.85Hz, 1H), 5.57 (m, 2H), 5.48 (m, 3H), 4.27 (m, 1 H), 4.22 (m, 1 H), 3.77 (m, 1 H), 3.60 (m, 1 H), 3.46 (m, 1 H), 3.23 (m, 2H), 2.39 (m, 1H), 1.80 (s, 3H), 1.70 (m, 1H), 1.64 (dd, J=1.47,6.73Hz, 3H), 1.12 (t,J=6.83 Hz, 3H) MS:STDC0720311,(M-H)-=309= Example 246EMI489.1 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-(propeny-2-yl))ethyl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 1H NMR (DMSO-d6) b 7.69 (d, J=9.75Hz, 1H), 5.47 (m, 1H), 5.28 (m, 1H), 5.03 (m, 1H), 4.86 (m, 1H), 4.40 (m, 1H), 4.30 (m, 1H), 4.18 (m, 1H), 3.97 (m, 1H), 3.68 (m, 1H), 3.21 (m, 1H), 2.43 (m, 1H), 1.82 (m, 1H), 1.73 (s, 3H), 1.64 (s, 3H), 1.59 (m, 3H) MS:STDC0624 (M+H)+ = 297, (M-H)-= 295 Example 247EMI489.2 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-(propeny-2-yl)-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 1H NMR (DMSO-d6) 8 7.65 (d, J=9.80 HZ, 1H), 5.48 (m, 1H), 5.23 (m, 1H), 4.99 (s, 1H), 4.88 (s, 1H), 4.46 (m, 1H), 4.30 (m, 1H), 4.19 (m, 1H), 3.55 (m, 1H), 3.22 (m, 1H), 2.44 (m, 1H), 1.78 (s, 3H), 1.75 (m, 1H), 1.65 (s, 3H), 1.58 (dd, J=1.23, 6.70HZ, 3H) MS:STDC0694 (M+H) += 297, (M-H)-=295 Example 248EMI490.1 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methyox-2-(propeny-2-yl))ethyl-3-(cis- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 1H NMR (DMSO-d6) d 7.77 (d, J=9.8 Hz, 1H), 5.49 (m, 1H), 5.25 (m, 1H), 5.07 (m, 1H), 4.94 (m, 1H), 4.32 (m, 1H), 4.25 (m, 1H), 3.75 (m, 1), 3.48 (m, 1H), 3.25 (m, 1H), 3.08 (s, 3H), 2.40 (m, 1H), 1.77 (s, 3H), 1.68 (m, 1H), 1.64 (dd, J=1.22, 6.71 Hz, 3H), 1.56 (s, 3H) MS:STDC0641 (M+H) + =311, (M-H)- =309 Example 249EMI491.1 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5- carboxvlic Acid Trifluoroacetic Acid Salt 1H NMR (DMSO-d6) # 7.62 (d, J=9. 21Hz, 1H), 5.58 (m, 1H), 5.28 (m, 1H), 4.37 (m, 1H), 3.98 (m, 1H), 3.57 (m, 1H), 3.10 (m, 1H), 2.45 (m, 1H), 1.92 (s, 3H), 1.76 (m, 1H), 1.62 (dd, J=1.83,6.72Hz, 3H), 1.24 (m, 5H), 0.84 (t, J=7. 61Hz, 3H), 0.77 (t, J=7. 61Hz, 3H) MS:STDC0671 (M+H) +=297, (M-H)-=295 Example 250EMI491.2 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5- carboxvlic Acid Trifluoroacetic Acid Salt 1H, NMR (DMSO-d6) 6 7.76 (d, J=9.2 Hz, 1H), 5.46 (m, 1H), 5.29 (m, 1H), 4.23 (m, 1H), 3.63 (m, 1H), 3.15 (m, 1H), 3.01 (m, 1H), 2.38 (m, 1H), 1.87 (s, 3H), 1.71 (m, 1H), 1.60 (m, 3H), 1.36 (m, 1H), 1.20 (m, 4H), 0.83 (t, J=7.3Hz, 6H) MS:STDC0813 (M+H) +=297, (M-H)-=295 Example 251EMI492.1 (-)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5carboxylic Acid Ethyl Ester and (+L (2S, 3S. 5S. 1'R)-2- (1-Acetamido-2-ethvl) butvl- 3- (cis-propen-1-yl)-pyrrolidine-5-carboxvlic Acid Ethvl Ester ()- (2R, 3S, 5R, 1'S)-2-(1-Acetamido-2-ethyl) butyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic acid ethyl ester (100 mg) was chromatographed in one injection on a chiral HPLC column of dimensions 5 x 30 cm. The column was packed with Chiralpak AD chiral stationary phase packing from ChiralTechnologies. The mobile phase consisted of 1: 9 ethanol: hexanes at a flow rate of 117 mL/min.STDC0168 Two peaks were observed at (24-36) minutes (-)- (2R, 3S, 5R, 1'S) (yield: 45 mg) and at (66-96) min (+)- (2S, 3S, 5S, 1'R) (yield: 45 mg).

(-)- (2R, 3S, 5R, 1'S) D=-26 (c=0.78, dichloromethane) Example 252 (-)- (2R. 3S. 5R, 1'S)-2- (1-Acetamido-2-ethvl) butvl-3- (c/'s-propen-1-vl)-Dvrrolidine-5- carboxylate Ammonium SaltEMI493.1 (-)- (2R, 3S, 5R, 1'S)-2- (1-Acetamido-2-ethyl) butyl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxylic acid ethyl ester (4.9 mg, 0.0157 mmole) prepared according to the procedure of Example 251 was reacted with lithium hydroxide (0.75 mg, 0.0314 mmole) in a mixture of methanol (0.75 mL) and water (0.25 mL) at 0 C for 7 hours. Then 0.1 N aqueous Hydrochloric acid (1 mL) was added, the reaction was concentrated in vacuo and the resulting residue purified by ion exchange chromatography on Aldrich Dowex 50WX8-400 strongly acidic resin.STDC0310 The residue was placed on the column and washed with water (5 mL) followed by elution using 0.5 N aqueous Ammonium hydroxide to provide the title compound as a colorless solid (yield: 3.9 mg, 83%). o =-40 , c=0.08 (water).

1 H NMR (DMSO-d6) 8 7.71 (d, J= 9.2 Hz, 1 H), 5.38 (m, 1 H), 5.29 (m, 1 H), 3.92 (m, 1 H), 3.65 (t, J= 8.5 Hz, 1 H), 3.43 (m, 1 H), 3.33 (m, 1 H), 2.98 (m, 1 H), 2.23 (m, 1H), 1.76 (s, 3H), 1.54 (dd, J= 6.7,1.8 Hz, 3H), 1.46 (m, 2H), 1.23 (m, 1 H), 0.84 (t, J= 7. 3 Hz, 3H).

MS: (M+H) = 285, (M+Na) += 307, (M-H)-= 283.

o =-40 , (c=0.08, water).

Example 253 EMI494.1 (#)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (MeOD-d3) 8.7.8 (d, J=9.3Hz, 1H), 5.49-5.43 (m, 1H), 5.25 (dd,J=1.95,9.3Hz, 1H), 4.38-4.31 (m, 2H), 3.57-3.50 (m, 1H), 3.46 (dd, J=4.9,10.3Hz, 1H), 3.42 (s, 3H), 3.35-3.32 (m, 2H), 3.27 (s, 3H), 3.16-3.09 (m, 1H), 2.46-2.40 (m, 1H), 1.80 (s, 3H), 1.72-1.65 (m, 1H), 1.55 (d, J=6.8Hz, 3H).

MS: (M+H) +=315, (M+Na) +=337, (M-H)-=313, (M+CI)-=349, (2M-H)-=627.

Example 254EMI494.2 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2,3-dimethyoxy)proxyl-3-(cis-propen-1-yl)- pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt 'H NMR (MeOD-d3) # 8.04 (d, J=8.5Hz, 1H), 5.52-5.48 (m, 1H), 5.275.22 (m, 1H), 4.32-4.25 (m, 2H), 3.74-3.71 (m, 1H), 3.53 (dd, J=2.4,10.1 Hz, 1H), 3.33-3.25 (m, 2H), 3.31 (s, 3H), 3.25 (s, 3H), 3.21-3.17 (m, 1H), 2.42-2.36 (m, 1H), 1.86 (s, 3H), 1.71-1.63 (m, 1H), 1.62 (d, J=7.3Hz, 3H).

MS: (M+H) +=315, (M+Na) +=337, (M-H)-=313, (M+CI)-=349, (2M-H)-=627 Example 255EMI495.1 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxyethyl-2-hydroxy)pentyl-3-(cis- propen-1-vl)-pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-d6): # 7.60 (m, 1H), 5.46 (m, 1H), 5.30 (m, 1H), 4.54 (m, 1H), 4.35 (m, 1H), 4.03 (m, 1H), 3.96 (m, 1H), 3.69 (m, 1H), 3.15 (m, 1H), 2.40 (m, 1H), 1.98 (m, 2H), 1.80 (s, 3H), 1.70-1.50 (m, 5H), 1.38 (m, 3H), 0.83 (m, 3H).

MS: (M+H) +=343, (M-H)-=341 Example 256EMI495.2 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-(3-pentyloxy))ethyl-3-(cis-proen-1-yl)- pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt 1H NMR (MeOD-d3) # 5.69-5.59 (m, 1H), 5.33-5.25 (m, 1H), 4.39 (m, 1H), 4.34 (dd, J=7.8,10.2Hz, 1H), 3.73 (dd, J=4.8,10.2Hz, 1H), 3.58-3.47 (m, 2H), 3.38-3.24 (m, 1 H), 3.27-3.20 (m, 1 H), 2.61-2.52 (m, 1H), 2.02 (s, 3H), 1.90-1.78 (m, 1 H), 1.70 (dd, J=1.7,6.8Hz, 3H), 1.60-1.50 (m, 4H), 0.92 (t, J=7.5Hz, 6H) (M+H) + = 327, (M+Na) + = 349 Example 257EMI496.1 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-(3-pentyloxy))ethyl-3-(cis-propen-1-yl)- pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt 'H NMR (MeOD-d3)STDC0884 5 5.73-5.66 (m, 1H), 5.32-5.25 (m, 1H), 4.36 (dd,J=7.8,10.2Hz, 1H), 4.09 (m, 1H), 3.68 (dd, J=6.1,10.2Hz, 1H), 3.61 (d, J=4.4Hz, 2H), 3.35-3.23 (m, 1H), 3.24-3.16 (m, 1H), 2.65-2.55 (m, 1H), 2.03 (s, 3H), 1.921.80 (m, 1 H), 1.70 (dd, J=2.0,7.1 Hz, 3H), 1.59-1.47 (m, 4H), 0.94-0.88 (m, 6H) (M+H) + = 327, (M+Na) + = 349 Example 258EMI497.1 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 1H NMR (DMSO-d6) 5 8.01 (d, J= 8.6Hz, 1H), 5.76 (m, 1H), 5.49 (m,STDC0586 1H), 5.25 (m, 1H), 5.05 (m, 2H), 4.28 (m, 1H), 4.02 (m, 1H), 3.77 (m, 1H), 3.62 (m, 1H), 3.36 (m, 1H), 3.29 (m, 1H), 3.18 (m, 1H), 2.43 (m, 1H), 2.38 (m, 1H), 2.16 (m, 1H), 1.87 (s, 3H), 1.69 (m, 1H), 1.63 (dd, J=6.7,1.2 Hz, 3H), 1.12 (t, J=6.7Hz, 3H).

MS: (M+H) = 325, (M-H)-= 323 Example 259EMI497.2 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-allyloxy)ethyl-3-(cis-proent-1-yl)- pvrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-d6) # 9.16 (m, 2H), 8.13 (d, J=7.5Hz, 1H), 5.88 (m, 1H), 5.50 (m, 1H), 5.15-5.32 (m, 3H), 4.35 (m, 2H), 3.95 (m, 2H), 3.61 (m, 1H), 3.40 (m, 2H), 3.20 (m, 1H), 2.40 (m, 1H), 1.87 (s, 3H), 1.72 (m, 1H), 1.62 (d, J=6.2,3H) MS:STDC0735 (M+1) =297, (M+23) =319, (2M+23) =615 Example 260EMI498.1 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-2-(2-ethoxycarbonyl))pentyl- 3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-d6): 5 7.57 (d, J=10Hz, 1H), 5.45 (m, 1H), 5.29 (m, 1H), 4.35 (m, 1H), 4.09 (m, 1H), 3.68 (m, 1H), 3.44 (m, 1H), 3.17 (m, 1H), 2.87 (m, 1 H), 2.64 (m, 1 H), 2.39 (m, 1 H), 1.80 (s, 3H), 1.65-1.56 (m, 2H), 1.53 (m, 3H), 1.50-1.30 (m, 3H), 1.21 (t, J=7.5Hz, 3H), 0.80 (t, J=7.5Hz, 3H).

MS: (M+H) +=385, (M-H)-=383 Example 261EMI498.2 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-3,4-dihydroxy)butyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (CD30D) 8 5.58-5.70 (m, 1H), 5. 24-5.38 (m, 1H), 4.34-4.50 (m, 2H), 3.58-3.72 (m, 2H), 3.42-3.48 (d, 2H), 2.50-2.63 (m, 1 H), 2.04 (s, 3H), 1.771.95 (m, 1 H), 1.65-1.76 (m, 4H), 1.50-1.63 (m, 1 H).

MS: (M+H) += 301 Example 262EMI499.1 ()- (2R. 3S. 5R. 1'S. 3'S)-2- (1-Acetamido-3. 4-dihvdroxv) butvl-3- (c/s-proDen-1-vl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (CD30D) 8 5.58-5.72 (m, 1 H), 5.25-5.37 (m, 1 H), 4.30-4.45 (m, 2H), 3.63-3.77 (m, 2H), 3.44-3.49 (d, 2H), 2.50-2.63 (m, 1 H), 2.03 (s, 3H), 1.761.95 (m, 2H), 1.65-1.75 (m, 4H).

MS: (M+H) += 301 Example 263 ()- (2R. 3S. 5R. 1'R)-2- (1-Acetamido-2-methoxy) ethyl-3- (cis-propen-1-v pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.EMI500.1 STDC0198263A (#)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-methoxy)ethyl-3- (cis-propen-1-yl)-pvrrolidine-5-carboxvlic Acid t-Bu l Ester.

The title compound was prepared according to the method described inExample 84A, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2- (1-acetamido2-hydroxy) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester for ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy) butyl-3-(cispropen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4.2 mg, 20%).

MS: (M+H)+=427, (M+Na)+=449 (M-H)-=425.EMI500.2 STDC0194 263B ()- (2R. 3S. 5R. 1'R)-2- 1-Acetamido-2-methoxv) ethvl-3- (cis-propen-1-yl)- pyrrolidine-5-carboxvlic Acid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-methoxy) ethyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid tbutyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1-acetamido- 2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0031 g, 100%).

1H NMR (DMSO-d6) s 8.12 (d, J=7.9Hz, 1H), 5.50 (m, 1H), 5.23 (m, 1H), 4.33 (m 1H), 3.56 (dd, J=9.7,8. 0Hz, 1H), 3.4-3.3 (m, 2H), 3.26 (s, 3H), 3.19 (m, 1H), 2.39 (dt, J=12.8,7.3Hz, 1H), 1.86 (s, 3H), 1.71 (m, 1H), 1.61 (dd,J=6.7,1.8Hz, 3H).

MS: (M+H) +=271, (M+Na) +=293.

Example 264 (#)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen- 1-vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.EMI501.1 STDC0214264A (#)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3- dimethyl) butyl-3- (cis-propen-1-vl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41 B, substituting t-butyl lithium for ethyl magnesium bromide to provide ()- (2R, 3S, 5R, 1'R, 2'S-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3dimethyl) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 2.5 mg, 11 %) ()- (2R, 3S, 5R, 1'R, 2'S) MS: (M+H) + = 469; (M-H)-= 467. EMI502.1 STDC0771 264B ()- (2R. 3S, 5R. 1'R. 2'S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis- propen-1-vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described inExample 41 C, substituting ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-dimethyl) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of ()- (2R, 3S, 5R, 1'R, 2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy) butyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 2.3 mg, 100%).

'H NMR (D2O) 8 5.40 (m, 1H), 5.10 (t, J=5.5Hz, 1H), 4.13 (t, J=9.2Hz, 1H), 3.46 (m, 1H), 3.22 (d, J=7.3Hz, 1H), 3.00 (m, 1H), 2.41 (m, 1H), 1.70 (s, 3H), 1.45 (m, 1 H), 1.39 (d, J=4.9Hz, 3H), 1.07 (t, J=5.5Hz, 1 H), 0.70 (s, 9H)MS: (M+H) +=313.

Using the methods described above and the general knowledge of one skilled in the art, compounds of the invention can be prepared which are represented by taking one core from Table 1 (wherein Ac is acetyl), one Y substituent from Table 2, one R substituent from Table 3 and one R3 substituent from Table 4a, 4b, 4c, 4d, 4e, 4f or 4g.

Table 1 EMI503.1 Table 2EMI503.2 EMI504.1 EMI505.1 EMI506.1 EMI507.1 EMI508.1 EMI509.1 Table 4aEMI510.1 EMI511.1 Table 4bEMI512.1 EMI513.1 EMI514.1 EMI515.1 EMI516.1 EMI517.1 EMI518.1 EMI519.1 EMI520.1 EMI521.1 EMI522.1 EMI523.1 EMI524.1 EMI525.1 Table 4dEMI525.2 EMI526.1 Table 4eEMI527.1 EMI528.1 EMI529.1 Table 4fEMI530.1 EMI531.1 EMI532.1 EMI533.1 EMI534.1 Table 4g EMI534.2 EMI535.1 EMI536.1 EMI537.1 EMI538.1 EMI539.1 EMI540.1 EMI541.1 EMI542.1 The ability of the compounds of the invention

to inhibit neuraminidase in vitro can be determined according to the method described below.

Neuraminidase Inhibition Assav: Influenza virus A/N1/PR/8/34 was grown in the allantoic cavity of fertilized eggs and purified by sucrose density gradient centrifugation (Laver, W. G. (1969) in"Fundamental Techniques in Virology" (K. Habel and N. P. Salzman, eds.) pp.

92-86, Academic Press, New York). Influenza virus A/N2/Tokyo/3/67 was obtained from the tissue culture supernatents of virus grown on MDCK cells.

Neuraminidase from B/Memphis/3/89 virus was prepared by digestion of the virus with TPCK-trypsin followed by centrifugation and then purification of the neuraminidase catalytic fragment using sucrose density gradient centrifugation and dialysis as described previously (Air, G. M., Laver, W. G., Luo, M., Stray,S. J., Legrone, G., and Webster, R. G. (1990) Virology 177,578-587).

The neuraminidase inhibition assays used the neuraminidase enzymatic activity associated with the A/N1/PR/8/34 or A/N2/Tokyo/3/67 whole virus, or theB/Memphis/3/89 catalytic head fragment. The whole virus or catalytic fragment was diluted appropriately with 20 mM N-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer on the day of the experiment. Neuraminidase inhibition assays were conducted in 20 mM N-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer with 5% DMSO. Reaction mixtures included neuraminidase, inhibitor (test compound) and 20-30, uM 4-methylumbelliferyl sialic acid substrate in a total volume of 200, uL and were contained in white 96-well U-shaped plates. Typically, five to eight concentrations of inhibitor were used for each Ki value measurement.

The reactions were initiated by the addition of enzyme and allowed to proceed for 30-60 minutes at room temperature. The fluorescence for each well of the plate was measured once each minute during the reaction period by a Fluoroskan II plate reader (ICN Biomedical) equipped with excitation and emission filters of 355 +/-35 nm and 460 +/-25 nm, respectively. The plate reader was under the control of DeltaSoft II software (Biometallics) and a Macintosh computer. If the compound exhibited linear reaction velocities during the reaction period, then the reaction velocities for the dose-response study were fit to equation 1 using a nonlinear regression program (Kaleidagraph) to determine the overall Ki value (Segel, I. H. (1975) in Enzyme Kinetics, pp. 105-106, Wiley-lnterscience, NewYork).

(1-ViNo) =/ {[I] + Ki (1 +/Km)} eqn 1In equation 1, Vi and Vo represent inhibited and uninhibited reaction velocities, respectively, and Km = 16-40AM depending on the neuraminidase strain tested. For those compounds exhibiting slow-binding inhibition (Morrison, J. F.

(1982) Trends Biochem. Sci. 7,102-105), a second experiment was performed in a manner identical to the first except that neuraminidase and inhibitor were preincubated in the absence of substrate for 2 hours at room temperature prior to initiating the reactions with substrate. Data analysis for the resulting linear velocities was conducted as described above.

Equation 2 was used to measure Ki values in the sub-nanomolar range (Morrison, J. F. And Stone, S. R. (1985) Comments Mol. Cell Biophys. 2,347- 368).

V = A {sqrt { (Ki' + It-Et) ^2 + 4Ki'Et}- (Ki'+ It-Et)] eqn. 2 In equation 2, V = velocity; A = akcat/2 (Km +); a is a factor to convert fluorescence units to molar concentrations; Ki'= Ki (1 +/Km); It = total inhibitor concentration and Et = total active concentration of neuraminidase.

The compounds of the invention inhibit influenza A neuraminidase and influenza B neuraminidase with Kj values between about 0.1 nanomolar and about 500 micromolar. Preferred compounds of the invention invention inhibit influenza A neuraminidase and influenza B neuraminidase with Kj values between about 0.1 nanomolar and about 3.5 micromolar.

The ability of the compounds of the invention to inhibit plaque formation in cell culture can be determined by the method described below.

Cell Culture Plaque Formation Inhibition AssavCell Cultures: MDCK cells obtained from the American Type Culture Collection were grown in Dulbecco's Modified Eagle Medium (DMEM) high glucose (GibcoBRL) supplemented with 10% fetal calf serum (JRH Biosciences), 40 mMHEPES buffer (GibcoBRL) and antibiotics (GibcoBRL). Cells were routinely cultured in flasks or roller bottles at 37 C and 5% C02. At confluence cells were reduced to a density of 500,000 cells in a ml using trypsin/EDTA (GibcoBRL) treatment of the monolayer followed by cell centrifugation, resuspension, and dilution into growth media. Cells were planted at a volume to surface area ratio of 1 ml over 1 cm2 of growth surface.

Plaque Assay Protocol: On MDCK cell confluent 6 well plates growth media was removed and the cells were overlaid with 1.5 ml of assay media (DMEM with 1% fetal calf serum, 40 mM HEPES buffer and antibiotics) containing pre-mixed virus (influenza A/Tokyo/3/67 ) (40-100 plaque forming units) and 2x concentration test compound. The plates were placed on a rocker and incubated for 2 hours at room temperature. During the virus adsorption period agar overlay media was prepared. In a microwave oven 2X agarose (final concentration of 0.6% agarose) in overlay media (DMEM with 40 mM HEPES buffer) was melted and then placed in a 48 C water bath for temperature equilibration.STDC0160 After the virus adsorption period was completed 1.5 ml agar over media was added and mixed with the 1.5 mi virus and test compound containing media per well.

Cultures were incubated at 35 C for the period required for plaque development, usually several days. Plaques were fixed with 3.7% formalin inPBS for 20 minutes followed by removal of the agar overlay and staining with 0.1% crystal violet in distilled water for 15 minutes. Plaques were counted andEC 50 concentration determined from multiple concentrations of the tested compound using regression analysis.

Viral Stocks: Stocks were prepared in MDCK confluent roller bottles incubated at 37 C in DMEM supplemented with 1% FCS, 40mM HEPES buffer, and antibiotics. Bottles were inoculated with a multiplicity of infection of approximately 0.1 plaque forming unit for each cell. Roller bottles were harvested after the cytopathic effect of the virus was observed to be complete. Stocks were prepared from the supernatant resulting from the low speed centrifugation of the media and cell lysate. Stocks were titered and stored at-80 C.

Compounds of the invention provided plaque formation inhibition for influenza virus A/N2/Tokyo in MDCK cells with EC50 values between about 100 micromolar and about 1 nanomolar. Preferred compounds of the invention provided plaque formation inhibition for influenza virus A/N2/Tokyo in MDCK cells with EC50 values between about 1 micromolar and about 1 nanomolar.

The compounds of the invention can be tested for in vivo antiviral activity using the method described below.

In Vivo Antiviral Efficacy Method Female BALB/c mice were placed under anesthesia (sevoflurane) and inoculated intranasally (IN) with 0.1 ml of influenza A VR-95 (Puerto Rico PR834) at 10-2 (diluted from frozen stock). This viral concentration consistently produced disease in mice within 5 days of inoculation. Animals were treated 4h. pre-infection and 4h. post-infection, andperiodically thereafter, with one of the following therapies: no treatment; test compound (100,25,6.25,1.39 mg/kg/dayBID, PO); or vehicle (sterile water BID, PO). A group of ten animals (designated as control) was inoculated with 0.9% saline. Percent survival was determined.

On day five, lungs were harvested, weighed and assigned scores of 0,1,2,3 or 4 based on percentage consolidation (0; 10-20; 25-50; 50-75; 75-100%, respectively). In addition, each lung pair was image analyzed to determine objective lung consolidation percentages.

The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2 naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, ptoluenesulfonate and undecanoate.STDC0500 Also, basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.

Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, lithium, calcium or magnesium or with ammonium or N (R**) 4+ salts (where R** is loweralkyl).

In addition, salts of the compounds of this invention with one of the naturally occurring amino acids are also contemplated.

Preferred salts of the compounds of the invention include hydrochloride, methanesulfonate, sulfonate, phosphonate and isethionate.

The compounds of the formula 1, II and III of this invention can have a substituent which is an acid group (for example,-C02H,-S03H,-S02H,-P03H2, -P02H). Compounds of the formula 1, II and III of this invention having a substituent which is an ester of such an acidic group are also encompassed by this invention. Such esters may serve as prodrugs. The prodrugs of this invention are metabolized in vivo to provide the above-mentioned acidic substituent of the parental compound of formula 1, II or III. Prodrugs may also serve to increase the solubility of these substances and/or absorption from the gastrointestinal tract.STDC0486 These prodrugs may also serve to increase solubility for intravenous administration of the compounds. Prodrugs may also serve to increase the hydrophobicity of the compounds. Prodrugs may also serve to increase the oral bioavailability of the compounds by increasing absorption and/or decreasing first-pass metabolism. Prodrugs may also serve to increase tissue penetration of the compounds, thereby leading to increased activity in infected tissues and/or reduced rate of clearance.

Such esters contemplated by this invention include: alkyl esters, especially loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like; alkoxyalkyl esters, especially, loweralkoxyloweralkyl esters, including, but not limited to, methoxymethyl, 1-ethoxyethyl, 2-methoxyethyl, isopropoxymethyl, t-butoxymethyl esters and the like; alkoxyalkoxyalkyl esters, especially, alkoxyalkoxy-substituted loweralkyl esters, including, but not limited to, 2-methoxyethoxymethyl esters and the like; aryloxyalkyl esters, especially, aryloxy-substituted loweralkyl esters, including, but not limited to, phenoxymethyl esters and the like, wherein the aryl group is unsubstituted or substituted as previously defined herein;STDC0833 haloalkoxyalkyl esters, especially, haloalkoxy-substituted loweralkyl esters, including, but not limited to, 2,2,2-trichloroethoxymethyl esters and the like; alkoxycarbonylalkyl esters, especially, loweralkoxycarbonyl-substituted loweralkyl esters, including, but not limited to, methoxycarbonylmethyl esters and the like; cyanoalkyl esters, especially, cyano-substituted loweralkyl esters, including, but not limited to, cyanomethyl, 2-cyanoethyl esters and the like; thioalkoxymethyl esters, especially, lowerthioalkoxy-substituted methyl esters, including, but not limited to, methylthiomethyl, ethylthiomethyl esters and the like; alkylsulfonylalkyl esters, especially, loweralkyisulfonyl-substituted loweralkyl esters, including, but not limited to, 2-methanesulfonylethyl esters and the like;STDC0786 arylsulfonylalkyl esters, especially, arylsulfonyl-substituted loweralkyl esters, including, but not limited to, 2-benzenesulfonylethyl and 2toluenesulfonylethyl esters and the like; acyloxyalkyl esters, especially, loweralkylacyloxy-substituted loweralkyl esters, including, but not limited to, formyloxymethyl, acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, pivaloyloxyethyl esters and the like; cycloalkylcarbonyloxyalkyl esters including, but not limited to, cyclopentanecarbonyloxymethyl, cyclohexanecarbonyloxymethyl, cyclopentanecarbonyloxyethyl, cyclohexanecarbonyloxyethyl esters and the like; arylcarbonyloxyalkyl esters including, but not limited to, benzoyloxymethyl esters and the like;STDC0605 (alkoxycarbonyloxy) alkyl esters, especially, (loweralkoxycarbonyloxy)substituted loweralkyl esters, including, but not limited to, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 1 (methoxycarbonyloxy) ethyl, 2- (ethoxycarbonyloxy) ethyl esters and the like; (cycloalkyloxycarbonyloxy) alkyl esters, especially, (cycloalkyloxycarbonyloxy)-substituted loweralkyl esters, including, but not limited to, cyclohexyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxyethyl, cyclohexyloxycarbonyloxypropyl esters and the like;STDC0723 oxodioxolenylmethyl esters including, but not limited to, (5-phenyl-2-oxo1,3-dioxolen-4-yl) methyl, [5- (4-methylphenyl)-2-oxo-1, 3-dioxolen-4-yl] methyl, [5 (4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-fluorophenyl)-2-oxo-1,3- dioxolen-4-yl] methyl, [5- (4-chlorophenyl)-2-oxo-1, 3-dioxolen-4-yl] methyl, (2-oxo1,3-dioxolen-4-yl) methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-ethyl-2oxo-1,3-dioxolen-4-yl) methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5isopropyl-2-oxo-1, 3-dioxolen-4-yl) methyl, (5-butyl-2-oxo-1,3-dioxolen-4-yl) methyl esters and the like;STDC0653 phthalidyl esters wherein the phenyl ring of the phthalidyl group is unsubstituted or substituted as defined previously herein, including, but not limited to, phthalidyl, dimethylphthalidyl, dimethoxyphthalidyl esters and the like; aryl esters including, but not limited to, phenyl, naphthyl, indanyl esters and the like; arylalkyl esters, especially, aryi-substitued loweralkyl esters, including, but not limited to, benzyl, phenethyl, 3-phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined herein;STDC0726 dialkylaminoalkyl esters, especially dialkylamino-substituted loweralkyl esters, including, but not limited to, 2- (N, N-dimethylamino) ethyl, 2- (N, Ndiethylamino) ethyl ester and the like (heterocyclic) alkyl esters, especially, heterocyclic-substituted loweralkyl esters wherein the heterocycle is a nitrogen-containing heterocycle, including, but not limited to, (heterocyclic) methyl esters and the like, wherein the heterocyclic part of the (heterocyclic) alkyl group is unsubstituted or substituted as previously defined herein; and carboxyalkyl esters, especially, carboxy-substituted loweralkyl esters, including, but not limited to carboxymethyl esters and the like; and the like.

Preferred prodrug esters of acid-containing compounds of the Formula I, II or III are loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and benzyl esters wherein the phenyl ring is unsubstituted or substituted as previously defined herein.

Methods for the preparation of prodrug esters of compounds of theFormula I, II or III are well-known in the art and include: reacting the acid with the corresponding halide (for example, chloride or acyl chloride) and a base (for example, triethylamine, DBU, N, Ndimethylaminopyridine and the like) in an inert solvent (for example, DMF, acetonitrile, N-methylpyrrolidone and the like); reacting an activated derivative of the acid (for example, an acid chloride, sulfonyl chloride, monochlorophosphonate and the like) with the corresponding alcohol or alkoxide salt; and the like.

Other examples of prodrugs of the present invention include esters of hydroxyl-substituted compounds of formula 1, II or III which have been acylated with a blocked or unblocked amino acid residue, a phosphate function, a hemisuccinate residue, an acyl residue of the formula R' C (O)-or R' C (S)- wherein R' is hydrogen, lower alkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formula Ra-C (Rb) (Rd)-C (O)- or Ra-C (Rb) (Rd)-C (S)- wherein Rb and Rd are independently selected from hydrogen or lower alkyl and Ra is-N (Re) (Rf),-oRe or-SRe wherein Re and Rf are independently selected from hydrogen, lower alkyl and haloalkyl,STDC0788 or an amino-acyl residue having the formula R NH (CH2) 2NHCH2C (O)-or R' 'NH (CH2) 2OCH2C (O)-wherein R' 'is hydrogen, lower alkyl, (aryl) alkyl, (cycloalkyl) alkyl, acyl, benzoyl or an a-amino acyl group. The amino acid esters of particular interest are of glycine and lysine; however, other amino acid residues can also be used, including any of the naturally occuring amino acids and also including those wherein the amino acyl group is-C (O) CH2NR'02R'03 wherein R'02 and R'03 are independently selected from hydrogen and lower alkyl, or the group -NR102 R'03, where R102 and R'03, taken together, forms a nitrogen containing heterocyclic ring.

Other prodrugs include a hydroxyl-substituted compound of formula I, II orIII wherein the hydroxyl group is functionalized with a substituent of the formula -CH (R'04) OC (o) R 05 or-CH (Rr04) OC (S) RX05 wherein R105 is lower alkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy and R104 is hydrogen, lower alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl.

Such prodrugs can be prepared according to the procedure of Schreiber (Tetrahedron Lett. 1983,24,2363) by ozonolysis of the corresponding methallyl ether in methanol followed by treatment with acetic anhydride.

The preparation of esters of hydroxyl-substituted compounds of formula formula I, II or III is carried out by reacting a hydroxyl-substituted compound of formula formula I, II or III, with an activated amino acyl, phosphoryl, hemisuccinyl or acyl derivative.

Prodrugs of hydroxyl-substituted-compounds of the invention can also be prepared by alkylation of the hydroxyl substituted compound of formula formula I,II or III, with (halo) alkyl esters, transacetalization with bis- (alkanoyl) acetals or condensation of the hydroxyl group with an activated aldehyde followed by acylation of the intermediate hemiacetal.

In preparing prodrugs it often is necessary to protect other reactive functional groups, in order to prevent unwanted side reactions. After protection of the reactive groups the desired group can be functionalized. The resulting functionalized product is then deprotected, to remove the protecting groups that were added to prevent unwanted side reactions. This will provide the desired prodrug. Suitable reaction conditions for preparing protecting groups are well known in the art. One source for reaction conditions is found in T. H. Greene andP. G. M. Wuts, Protective Groups in Oraanic Synthesis. 2nd edition, John Wiley & Sons, New York (1991).STDC0332 This invention also encompasses compounds of the Formula I, II or III which are esters or prodrugs and which are also salts. For example, a compound of the invention can be an ester of a carboxylic acid and also an acid addition salt of an amine or nitrogen-containing substituent in the same compound.

The compounds of the present invention are useful for inhibiting neuraminidase from disease and influenza B viral infections; and, in particular, the prophylaxis of influenza A and influenza B viral infections in human subjects who are at high risk of developing other respiratory diseases concurrent with or as a consequence of influenza virus infections, or who suffer from chronic respiratory illness, such as asthma, emphysema, or cystic fibrosis.

Total daily dose administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 10 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.

Administration of a compound of this invention will begin before or at the time of infection or after the appearance of established symptoms and/or the confirmation of infection.

The compounds of the present invention may be administered orally, parenterally, sublingually, intranasally, by intrapulmonary administration, by inhalation or insufflation as a solution, suspension or dry powder (for example, in a spray), or rectally, in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.

Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e. g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium.

Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y. (1976), p. 33 et seq.

While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more anti-infective agents and/or other agents used to treat other acute or chronic respiratory ailments. Other agents to be administered in combination with a compound of the present invention include: an influenza vaccine; other influenza inhibitors such as, for example, amantadine, rimantadine, ribavirin, and the like; another influenza neuraminidase inhibitor, such as, for example, zanamivir or GS 4104 and the like; agents used to treat respiratory bacterial infections and bronchitis, such as, for example, erythromycin, clarithromycin, azithromycin and the like;STDC0438 and agents used to treat asthma, such as, for example, zileuton, albuterol (salbutamol), salmeterol, formoterol, ipratropium bromide, inhaled steroids and the like, or anti-inflammatory agents for treating asthma such as, for example, beclomethasone dipropionate, fluticasone propionate, budesonide, triamcinolone acetonide, flunisolide, cromolyn, zafirlukast, montelukast used in combination with a compound of the present invention.

When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.