【结 构 式】 |
【分子编号】20930 【品名】benzyl (2S)-2-pyrrolidinecarboxylate 【CA登记号】16652-71-4 |
【 分 子 式 】C12H15NO2 【 分 子 量 】205.25664 【元素组成】C 70.22% H 7.37% N 6.82% O 15.59% |
合成路线1
该中间体在本合成路线中的序号:(XXV)Protection of 2-hydroxyisovaleric acid (XIX) with tert-butyldimethylsilyl chloride and imidazole in DMF, followed by condensation with Meldrum's acid (XX) by use of diethyl phosphorocyanidate (DEPC) and Et3N in THF, furnishes derivative (XXI), which is then subjected to reaction with benzyl alcohol (XXII) in refluxing benzene to afford beta-keto ester (XXIII). Next, derivative (XXIII) is methylated with MeI and NaH and its benzyl group is removed by hydrogenation over Pd/C in THF to yield carboxylic acid (XXIV). Coupling between H-Pro-OBzl.HCl (XXV) and Boc-Leu-OH (XXVI) by means of DEPC and Et3N in DMF affords dipeptide (XXVII), which is then converted into fragment (XXVIII) by first condensation with carboxylic acid (XXIV) by means of DCC, HOBt and NMM in THF/DMF and treatment with tetrabutylammonium fluoride for TBDMS protecting group removal. Coupling of fragment (XXVIII) with fragment (XVIII) by means of DCC and DMAP in CH2Cl2 furnishes linear peptide (XXIX), which is hydrogenated over Pd/C in THF and then subjected to cyclization by means of BOPCl and Et3N in CH2Cl2 to give macrolide (XXX). Next, deprotection of (XXX) with TMSOTf affords intermediate (XXXI) (didemnin A).
【1】 Harris, B.D.; et al.; Synthetic studies of didemnins. II. Approaches to statine diastereomers. Tetrahedron Lett 1987, 28, 25, 2837. |
【2】 Hamada, Y.; Shioiri, T.; Anti-tumor active cyclic peptide derived from marine organism: Synthesis, conformation and bioactivity. Kagaku Zokan 1990, 118, 31. |
【3】 Hamada, Y.; et al.; Efficient total synthesis of didemnins A and B. J Am Chem Soc 1989, 111, 2, 669. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XVIII) | 50786 | (5S,8R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-5-(4-methoxybenzyl)-4,8-dimethyl-9-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oic acid | C44H70N4O10Si | 详情 | 详情 | |
(XIX) | 37829 | (2S)-2-hydroxy-3-methylbutyric acid | C5H10O3 | 详情 | 详情 | |
(XX) | 17938 | 8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C18H20ClN3 | 详情 | 详情 | |
(XXI) | 50789 | 5-((2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-3-methylbutylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione | C17H30O6Si | 详情 | 详情 | |
(XXII) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
(XXIII) | 50790 | benzyl (4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-3-oxohexanoate | C20H32O4Si | 详情 | 详情 | |
(XXIV) | 50791 | (2S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2,5-dimethyl-3-oxohexanoic acid | C14H28O4Si | 详情 | 详情 | |
(XXV) | 20930 | benzyl (2S)-2-pyrrolidinecarboxylate | 16652-71-4 | C12H15NO2 | 详情 | 详情 |
(XXVI) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid;N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
(XXVII) | 50792 | benzyl (2S)-1-[(2S)-2-amino-4-methylpentanoyl]-2-pyrrolidinecarboxylate | C18H26N2O3 | 详情 | 详情 | |
(XXVIII) | 50793 | benzyl (2S)-1-((2S)-2-[[(2S,4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino]-4-methylpentanoyl)-2-pyrrolidinecarboxylate | C26H38N2O6 | 详情 | 详情 | |
(XXIX) | 50794 | benzyl (2S)-1-[(2S,5S,7S,11S,12R,15S,16R,19S)-11-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-7-isopropyl-19-(4-methoxybenzyl)-5,16,20-trimethyl-15-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-4,6,9,14,18,21-hexaoxo-23-phenyl-8,17,22-trioxa-3,13,20-triazatricos-1-anoyl]-2-pyrrolidinecarboxylate | C70H106N6O15Si | 详情 | 详情 | |
(XXX) | 50795 | (2R)-N-[(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-[[tert-butyl(dimethyl)silyl]oxy]-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-yl]-4-methyl-2-(methylamino)pentanamide | C55H92N6O12Si | 详情 | 详情 | |
(XXXI) | 50796 | (2R)-N-[(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-yl]-4-methyl-2-(methylamino)pentanamide | C49H78N6O12 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(IV)This compound can be obtained by two related ways: 1) The reaction of L-lysine (I) with NaNO2 - H2SO4 in water gives 6-amino-2(S)-hydroxyhexanoic acid (II), which is protected with benzyl chloroformate as usual yielding the N-benzyloxycarbonyl compound (III). The condensation of (III) with L-proline benzyl ester (IV) by means of hydroxybenzotriazole (HBT) and dicyclohexylcarbodiimide (DCC) affords the acylated proline ester (V), which is esterified with 4-phenylbutylphosphonous acid (VI) by means of DCC and dimethylaminopyridine (DMAP), and oxidized with NaIO4 to give the protected phosphonic ester (VIII). Finally, this compound is debenzylated by hydrogenation of Pd/C in methanol. The phosphonous acid (VI) is obtained by reaction of 4-phenyl-1-butene (VII) with sodium hypophosphite by means of azobisisobutyronitrile (AIBN). 2) The condensation of acylated proline ester (V) with dibenzyl 4-phenylbutylphosphonate (IX) by means of PCl5, triethylamine and DMAP also gives the protected phosphonic ester (VIII). The dibenzyl phosphonate (IX) is obtained by condensation of 4-phenylbutyl chloride (X) with dibenzyl phosphite (XI) by means of NaH in DMF.
【1】 Karanewsky, D.S.; Petrillo, E.W. Jr. (E.R. Squibb & Sons, Inc.); Orally active phosphonyl hydroxyacyl prolines and processes for preparing phosphonyl hydroxyacyl prolines. AU 8666133; EP 0229520; JP 1987164691; US 4745196 . |
【2】 Prous, J.; Castaner, J.; SQ-29852. Drugs Fut 1989, 14, 6, 533. |
【3】 Powell, J.R.; Karanewsky, D.S.; Dejneka, T.; DeForrest, J.M.; Petrillo, E.W. Jr.; Perri, M.G.; Badia, M.C.; Loots, M.J.; Cushman, D.W.; (Phosphinyloxy)acyl amino acid inhibitors of angiotensin converting enzyme (ACE). 1. Discovery of (S)-1-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline, a novel orally acting inhibitor of ACE. J Med Chem 1988, 31, 1, 204. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 20927 | L-lysine | 56-87-1 | C6H14N2O2 | 详情 | 详情 |
(II) | 20928 | (2S)-6-amino-2-hydroxyhexanoic acid | C6H13NO3 | 详情 | 详情 | |
(III) | 20929 | (2S)-6-[[(benzyloxy)carbonyl]amino]-2-hydroxyhexanoic acid | C14H19NO5 | 详情 | 详情 | |
(IV) | 20930 | benzyl (2S)-2-pyrrolidinecarboxylate | 16652-71-4 | C12H15NO2 | 详情 | 详情 |
(V) | 20931 | benzyl (2S)-1-((2S)-6-[[(benzyloxy)carbonyl]amino]-2-hydroxyhexanoyl)-2-pyrrolidinecarboxylate | C26H32N2O6 | 详情 | 详情 | |
(VI) | 20932 | 4-phenylbutylphosphinic acid | C10H15O2P | 详情 | 详情 | |
(VII) | 20933 | 1-(3-butenyl)benzene | 768-56-9 | C10H12 | 详情 | 详情 |
(VIII) | 20934 | benzyl (2S)-1-((2S)-6-[[(benzyloxy)carbonyl]amino]-2-[[hydroxy(4-phenylbutyl)phosphoryl]oxy]hexanoyl)-2-pyrrolidinecarboxylate | C36H45N2O8P | 详情 | 详情 | |
(IX) | 20935 | dibenzyl 4-phenylbutylphosphonate | C24H27O3P | 详情 | 详情 | |
(X) | 20936 | 1-(4-chlorobutyl)benzene | 4830-93-7 | C10H13Cl | 详情 | 详情 |
(XI) | 12507 | dibenzyl phosphonate; Dibenzyl phosphite | 17176-77-1 | C14H15O3P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XII)The protected dipeptide (XIV) was prepared by coupling between L-proline benzyl ester (XII) and N-Boc-L-leucine (XIII) in the presence of DCC and HOBt. Acidic Boc group cleavage in (XIV) then gave amine (XV). The unstable keto acid (XVII) was obtained by hydrogenolysis of the epimeric benzyl esters (XVI), and subsequently coupled to the dipeptide ester (XV) by means of HBTU to afford the keto amide (XVIII) as a diastereomeric mixture. Desilylation of (XVIII) with tetrabutylammonium fluoride furnished the deprotected alcohol (XIX), which was further esterified with the protected isostatine (XI) leading to depsipeptide (XX). Then, removal of the O-silyl and N-Boc protecting groups of (XX) under acidic conditions provided intermediate (XXI)
【1】 Jou, G.; Gonzalez, I.; Albericio, F.; Lloyd-Williams, P.; Giralt, E.; Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution. J Org Chem 1997, 62, 2, 354. |
【2】 Giralt Lledo, E.; Albericio Palomera, F.; Lloyd-Williams, P.; Gonzalez Valcarcel, I.; Jou Prat, G.; Gomez Gonzalez, A.; Manzanares Secades, I. (PharmaMar, SA); Process for the preparation of didemnine A. ES 2102322 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XI) | 50793 | benzyl (2S)-1-((2S)-2-[[(2S,4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino]-4-methylpentanoyl)-2-pyrrolidinecarboxylate | C26H38N2O6 | 详情 | 详情 | |
(XII) | 20930 | benzyl (2S)-2-pyrrolidinecarboxylate | 16652-71-4 | C12H15NO2 | 详情 | 详情 |
(XIII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid;N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
(XIV) | 52728 | benzyl (2S)-1-{(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate | C23H34N2O5 | 详情 | 详情 | |
(XV) | 50792 | benzyl (2S)-1-[(2S)-2-amino-4-methylpentanoyl]-2-pyrrolidinecarboxylate | C18H26N2O3 | 详情 | 详情 | |
(XVI) | 52727 | benzyl (2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,5-dimethyl-3-oxohexanoate | C21H34O4Si | 详情 | 详情 | |
(XVII) | 50791 | (2S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2,5-dimethyl-3-oxohexanoic acid | C14H28O4Si | 详情 | 详情 | |
(XVIII) | 52729 | benzyl (2S)-1-{(2S)-2-[((2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,5-dimethyl-3-oxohexanoyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate | C32H52N2O6Si | 详情 | 详情 | |
(XX) | 62535 | benzyl (2S)-1-{(2S,7S,11S,12R)-11-{[tert-butyl(dimethyl)silyl]oxy}-2-isobutyl-7-isopropyl-5,16,16-trimethyl-12-[(1S)-1-methylpropyl]-4,6,9,14-tetraoxo-8,15-dioxa-3,13-diazaheptadec-1-anoyl}-2-pyrrolidinecarboxylate | C45H75N3O10Si | 详情 | 详情 | |
(XXI) | 62536 | benzyl (2S)-1-{(2S)-2-[((4S)-4-{[(3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoyl]oxy}-2,5-dimethyl-3-oxohexanoyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate | C34H53N3O8 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(XII)Keto amide (XXXI) was obtained by acylation of L-proline benzyl ester (XII) with pyruvic acid (XXX). Subsequent hydrogenolysis of the benzyl ester group provided pyruvyl proline (XXXII). The target dehydrodidemnin B was then prepared by coupling of didemnin A (XXIX), from either natural or synthetic sources, with pyruvyl proline (XXXII)
【1】 Jou, G.; Gonzalez, I.; Albericio, F.; Lloyd-Williams, P.; Giralt, E.; Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution. J Org Chem 1997, 62, 2, 354. |
【2】 Rinehart, K.L.; Lithgow-Bertelloni, A.M. (PharmaMar, SA); Dehydrodidemnin B. WO 9104985 . |
【3】 Giralt Lledo, E.; Albericio Palomera, F.; Lloyd-Williams, P.; Gonzalez Valcarcel, I.; Jou Prat, G.; Gomez Gonzalez, A.; Manzanares Secades, I. (PharmaMar, SA); Process for the preparation of didemnine A. ES 2102322 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XII) | 20930 | benzyl (2S)-2-pyrrolidinecarboxylate | 16652-71-4 | C12H15NO2 | 详情 | 详情 |
(XXIX) | 50796 | (2R)-N-[(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-yl]-4-methyl-2-(methylamino)pentanamide | C49H78N6O12 | 详情 | 详情 | |
(XXX) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
(XXXI) | 62541 | benzyl (2S)-1-pyruvoyl-2-pyrrolidinecarboxylate | C15H17NO4 | 详情 | 详情 | |
(XXXII) | 62542 | (2S)-1-pyruvoyl-2-pyrrolidinecarboxylic acid | C8H11NO4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(II)N-Boc-L-Valine N-hydroxysuccinimidyl ester (I) was coupled to L-proline benzyl ester (II), and the resulting Boc dipeptide (III) was subsequently deprotected with trifluoroacetic acid in CH2Cl2 to afford (IV). This was condensed with N-Boc-L-aspartic acid gamma-benzyl 1-N-hydroxysuccinimidyl diester (V) to give (VI). After Boc deprotection of (VI) with trifluoroacetic acid, tripeptide (VII) was coupled with N-Boc-L-leucine N-hydroxysuccinimidyl ester (VIII) to yield tetrapeptide (IX). Further Boc deprotection of (IX) with trifluoroacetic acid furnished peptide intermediate (X).
【1】 Ateeq, H.S.; Lin, K.-C.; Hsiung, S.H.; et al.; Selective, tight-binding inhibitors of integrin alpha4beta1 that inhibit allergic airway responses. J Med Chem 1999, 42, 5, 920. |
【2】 Lin, K.-C.; Adams, S.P.; Castro, A.C.; Zimmerman, C.N.; Cuervo, J.H.; Lee, W.-C.; Hammond, C.E.; Carter, M.B.; Almquist, R.G.; Ensinger, C.L. (Biogen, Inc.); Cell adhesion inhibitor. EP 0842196; JP 1999511124; WO 9703094 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 27097 | tert-butyl (1S)-1-[[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)oxy]carbonyl]-2-methylpropylcarbamate | C14H20N2O6 | 详情 | 详情 | |
(II) | 20930 | benzyl (2S)-2-pyrrolidinecarboxylate | 16652-71-4 | C12H15NO2 | 详情 | 详情 |
(III) | 27098 | benzyl (2S)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]-2-pyrrolidinecarboxylate | C22H32N2O5 | 详情 | 详情 | |
(IV) | 27099 | benzyl (2S)-1-[(2S)-2-amino-3-methylbutanoyl]-2-pyrrolidinecarboxylate | C17H24N2O3 | 详情 | 详情 | |
(V) | 27100 | benzyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)oxy]-4-oxobutanoate | C20H22N2O8 | 详情 | 详情 | |
(VI) | 27101 | benzyl (2S)-1-[(2S)-2-([(2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoyl]amino)-3-methylbutanoyl]-2-pyrrolidinecarboxylate | C33H43N3O8 | 详情 | 详情 | |
(VII) | 27102 | benzyl (2S)-1-((2S)-2-[[(2S)-2-amino-4-(benzyloxy)-4-oxobutanoyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylate | C28H35N3O6 | 详情 | 详情 | |
(VIII) | 27103 | tert-butyl (1S)-1-[[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)oxy]carbonyl]-3-methylbutylcarbamate | C15H22N2O6 | 详情 | 详情 | |
(IX) | 27104 | benzyl (2S)-1-[(2S,5S,8S)-5-[2-(benzyloxy)-2-oxoethyl]-8-isobutyl-2-isopropyl-12,12-dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatridec-1-anoyl]-2-pyrrolidinecarboxylate | C39H54N4O9 | 详情 | 详情 | |
(X) | 27105 | benzyl (2S)-1-((2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-4-(benzyloxy)-4-oxobutanoyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylate | C34H46N4O7 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号:(VII)Synthesis of the dipeptide intermediate (IX): The esterification of D-cyclohexylalanine (I) by means of SOCl2 and methanol gives the methyl ester (II), which is condensed with tert-butyl bromoacetate (III) by means of DIEA in acetonitrile to yield the N-substituted cyclohexylalanine (IV). The reaction of (IV) with Boc2O and DIEA in DMF affords the N-protected compound (V), which is hydrolyzed with NaOH in dioxane/water to provide the free N-substituted cyclohexylalanine (VI). The condensation of (VI) with L-proline benzyl ester (VII) by means of HOBT and DCC in DMF gives the dipeptide (VIII), which is finally debenzylated by means of H2 over Pd/C in methanol to yield the target dipeptide intermediate (IX).
【1】 Adang, A.E.P.; De Man, A.P.A.; Vogel, G.M.T.; Grootenhuis, P.D.J.; Smit, M.J.; Peters, C.A.M.; Visser, A.; Rewinkel, J.B.M.; van Dinther, T; Lucas, H.; Kelder, J.; van Aelst, S.; Meuleman, D.G.; van Boeckel, C.A.A.; Unique overlap in the prerequisites for thrombin inhibition and oral bioavailability resulting in potent oral antithrombotics. J Med Chem 2002, 45, 20, 4419. |
【2】 Adang, A.E.P.; Peters, J.A.M.; Van Boeckel, C.A.A.; Rewinkel, J.B.M. (Akzo Nobel N.V.); Thrombin inhibitors. WO 9807308 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 39357 | (2S)-2-amino-3-cyclohexylpropionic acid; L-Cyclohexylalanine | 27527-05-5 | C9H17NO2 | 详情 | 详情 |
(II) | 60226 | methyl 2-amino-3-cyclohexylpropanoate | C10H19NO2 | 详情 | 详情 | |
(III) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
(IV) | 60227 | methyl 3-cyclohexyl-2-({2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoate | C16H29NO4 | 详情 | 详情 | |
(V) | 60228 | methyl 3-cyclohexyl-2-({[(1,1-dimethylethyl)oxy]carbonyl}{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoate | C21H37NO6 | 详情 | 详情 | |
(VI) | 60229 | 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-N-{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}alanine | C20H35NO6 | 详情 | 详情 | |
(VII) | 20930 | benzyl (2S)-2-pyrrolidinecarboxylate | 16652-71-4 | C12H15NO2 | 详情 | 详情 |
(VIII) | 60230 | phenylmethyl 1-[3-cyclohexyl-2-({[(1,1-dimethylethyl)oxy]carbonyl}{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoyl]-2-pyrrolidinecarboxylate | C32H48N2O7 | 详情 | 详情 | |
(IX) | 23165 | (2S)-1-((2R)-2-[(tert-butoxycarbonyl)[2-(tert-butoxy)-2-oxoethyl]amino]-3-cyclohexylpropanoyl)-2-pyrrolidinecarboxylic acid | C25H42N2O7 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号:(XIII)For the preparation of tripeptide intermediate (XVIII), N-Cbz-threonine (XII) was coupled with proline benzyl ester (XIII) to give dipeptide (XIV). Subsequent hydrogenolysis of the benzyl groups of (XIV) in the presence of Pd/C furnished threonyl proline (XV). Coupling of (XV) with the succinimidyl ester (XVII) prepared from the protected ornithine (XVI) then provided tripeptide intermediate (XVIII).
【1】 Chen, H.-J.; Klein, L.L.; Li, L.; et al.; Total synthesis and antifungal evaluation of cyclic aminohexapeptides. Bioorg Med Chem Lett 2000, 8, 7, 1677. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XII) | 43420 | (2S,3R)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxybutyric acid | 19728-63-3 | C12H15NO5 | 详情 | 详情 |
(XIII) | 20930 | benzyl (2S)-2-pyrrolidinecarboxylate | 16652-71-4 | C12H15NO2 | 详情 | 详情 |
(XIV) | 43421 | benzyl (2S)-1-((2S,3R)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxybutanoyl)-2-pyrrolidinecarboxylate | C24H28N2O6 | 详情 | 详情 | |
(XV) | 43422 | (2S)-1-[(2S,3R)-2-amino-3-hydroxybutanoyl]-2-pyrrolidinecarboxylic acid | C9H16N2O4 | 详情 | 详情 | |
(XVI) | 43423 | (2S)-2-[(tert-butoxycarbonyl)amino]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]pentanoic acid | C25H30N2O6 | 详情 | 详情 | |
(XVII) | 43424 | 9H-fluoren-9-ylmethyl (4S)-4-[(tert-butoxycarbonyl)amino]-5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-5-oxopentylcarbamate | C29H33N3O8 | 详情 | 详情 | |
(XVIII) | 43425 | (2S)-1-[(2S,3R)-2-[((2S)-2-[(tert-butoxycarbonyl)amino]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]pentanoyl)amino]-3-hydroxybutanoyl]-2-pyrrolidinecarboxylic acid | C34H44N4O9 | 详情 | 详情 |