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【结 构 式】

【分子编号】50792

【品名】benzyl (2S)-1-[(2S)-2-amino-4-methylpentanoyl]-2-pyrrolidinecarboxylate

【CA登记号】

【 分 子 式 】C18H26N2O3

【 分 子 量 】318.41612

【元素组成】C 67.9% H 8.23% N 8.8% O 15.07%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(XXVII)

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:(XV)

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3

该中间体在本合成路线中的序号:(XV)

Similarly, (S)-2-hydroxy-3-methylbutyric acid (LV) was protected as the silyl ether (LVI) and then condensed with benzyl acetate, via activation with CDI, to afford keto ester (LVII). Subsequent methylation of (LVII) using iodomethane and NaH provided (XVI) as a diastereomeric mixture. The unstable keto acid (XVII), obtained in situ by catalytic hydrogenolysis of (XVI), was then coupled to the dipeptide ester (XV) to afford, after desilylation, the hydroxy keto amide (XIX). Esterification of alcohol (XIX) with the isostatine derivative (XI) as in Scheme 3, followed by acidic cleavage of the O-silyl and N-Boc protecting groups led to depsipeptide (XXI)

1 Edge, A. (Diacrin, Inc.); Method for improving graft acceptance in a recipient by administration of a cytokine profile altering agent. WO 0051630 .
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) 50802 (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-methylheptanoic acid C19H39NO5Si 详情 详情
(XV) 50792 benzyl (2S)-1-[(2S)-2-amino-4-methylpentanoyl]-2-pyrrolidinecarboxylate C18H26N2O3 详情 详情
(XVI) 62563 benzyl (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
(XIX) 62564 benzyl (2S)-1-((2S)-2-{[(4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino}-4-methylpentanoyl)-2-pyrrolidinecarboxylate C26H38N2O6 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
(LV) 37829 (2S)-2-hydroxy-3-methylbutyric acid C5H10O3 详情 详情
(LVI) 52726 (2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3-methylbutanoic acid C11H24O3Si 详情 详情
(LVII) 50790 benzyl (4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-3-oxohexanoate C20H32O4Si 详情 详情
Extended Information