benzyl (4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-3-oxohexanoate -Drug Synthesis Database

【结构式】

【分子编号】50790

【品名】benzyl (4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-3-oxohexanoate

【CA登记号】

【分子式】C₂₀H₃₂O₄Si

【分子量】364.55718

【元素组成】C 65.89% H 8.85% O 17.55% Si 7.7%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XXIII)

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).

参考文献中间体

合成目标

【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：(LVII)

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)

参考文献中间体

合成目标

【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	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