(1E,3S,4S,5S,7R,8R,9E,12S,14S,15R,16S,18R)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16,19,19-tetramethoxy-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-5-[(triisopropylsilyl)oxy]-1,9-nonadecadien-3-ol -Drug Synthesis Database

【结构式】

【分子编号】57363

【品名】(1E,3S,4S,5S,7R,8R,9E,12S,14S,15R,16S,18R)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16,19,19-tetramethoxy-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-5-[(triisopropylsilyl)oxy]-1,9-nonadecadien-3-ol

【CA登记号】

【分子式】C₆₈H₁₃₈O₁₀Si₄

【分子量】1228.17972

【元素组成】C 66.5% H 11.33% O 13.03% Si 9.15%

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：(XLV)

The condensation of (XL) with the intermediate 14-iodo-10-tetradecenal dimethylacetal (XXI) by means of BuLi in THF/HMPA gives the adduct (XLI), which is desulfurized by means of NCS and AgNO3 in acetone/THF/water to yield the ketonic product (XLII). The cleavage of the 4-methoxybenzyl group of (XLII) by means of DDQ in dichloromethane affords the beta-hydroxyketone (XLIII). The reduction of the ketonic group of (XLIII) with LiAlH4 and LiI in ethyl ether provides the dihydroxy compound (XLIV), which is selectively monoprotected with Tips-OTf and 2,6-lutidine in dichloromethane to give the intermediate (XLV).

参考文献中间体

合成目标

【1】 Smith, A.B. III; et al.; Formal total synthesis of FK506. Concise construction of the C(10)-C(34) segment via an effective coupling tactic. Tetrahedron Lett 1994, 35, 25, 4271.
【2】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXI)	57344	(1S,2R,3E,6S,8S,9R,10S,12R)-2-allyl-9-{[tert-butyl(dimethyl)silyl]oxy}-1-(iodomethyl)-8,10,13,13-tetramethoxy-4,6,12-trimethyl-3-tridecenyl tert-butyl(dimethyl)silyl ether; (5S,6R,7E,10S,12S,13R)-6-allyl-5-(iodomethyl)-12-methoxy-2,2,3,3,8,10,15,15,16,16-decamethyl-13-[(1S,3R)-1,4,4-trimethoxy-3-methylbutyl]-4,14-dioxa-3,15-disila-7-heptadecene	C₃₆H₇₃IO₆Si₂	详情	详情
(XL)	57356	[((1R,2R,4R)-4-{(E,3S,4S)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-pentenyl}-2-methoxycyclohexyl)oxy](triisopropyl)silane; (1S,2E)-1-[(1S)-1-(1,3-dithian-2-yl)ethyl]-3-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2-methyl-2-propenyl 4-methoxybenzyl ether	C₃₄H₅₈O₄S₂Si	详情	详情
(XLI)	57359	4-{[((1S,2E)-1-{(1S)-1-[2-((2R,3R,4E,7S,9S,10R,11S,13R)-3-allyl-2,10-bis{[tert-butyl(dimethyl)silyl]oxy}-9,11,14,14-tetramethoxy-5,7,13-trimethyl-4-tetradecenyl)-1,3-dithian-2-yl]ethyl}-3-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2-methyl-2-propenyl)oxy]methyl}phenyl methyl ether	C₇₀H₁₃₀O₁₀S₂Si₃	详情	详情
(XLII)	57360	(1E,3S,4S,7R,8R,9E,12S,14S,15R,16S,18R)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16,19,19-tetramethoxy-3-[(4-methoxybenzyl)oxy]-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-1,9-nonadecadien-5-one	C₆₇H₁₂₄O₁₁Si₃	详情	详情
(XLIII)	57361	(1E,3S,4S,7R,8R,9E,12S,14S,15R,16S,18R)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-14,16,19,19-tetramethoxy-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-1,9-nonadecadien-5-one	C₅₉H₁₁₆O₁₀Si₃	详情	详情
(XLIV)	57362	(1E,3S,4R,5S,7R,8R,9E,12S,14S,15R,16S,18R)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16,19,19-tetramethoxy-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-1,9-nonadecadiene-3,5-diol	C₅₉H₁₁₈O₁₀Si₃	详情	详情
(XLV)	57363	(1E,3S,4S,5S,7R,8R,9E,12S,14S,15R,16S,18R)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16,19,19-tetramethoxy-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-5-[(triisopropylsilyl)oxy]-1,9-nonadecadien-3-ol	C₆₈H₁₃₈O₁₀Si₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XLV)

The silylation of the remaining OH group of (XLV) with Tes-OTf and lutidine in dichloromethane gives the fully silylated intermediate (XLVI), which is treated with a mild acid in order to cleave the 1,3-dithiane ring and yield the carbaldehyde (XLVII). The condensation of (XLVII) with the chiral piperidine carboxylic acid (XLVIII) by means of LDA in THF affords the adduct (XLIX). The oxidation of the OH group of (XLIX) provides the beta dioxo compound (L), which is treated with Ac-OH in THF/water to selectively cleave the triethylsilyl protecting group and yield the secondary alcohol (LI).

参考文献中间体

合成目标

【1】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XLV)	57363	(1E,3S,4S,5S,7R,8R,9E,12S,14S,15R,16S,18R)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16,19,19-tetramethoxy-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-5-[(triisopropylsilyl)oxy]-1,9-nonadecadien-3-ol	C₆₈H₁₃₈O₁₀Si₄	详情	详情
(XLVI)	57364	(1S,2R,3S,5S,7E,9R,10R,12S,13S,14S,15E)-9-allyl-2,10-bis{[tert-butyl(dimethyl)silyl]oxy}-1-[(2R)-3,3-dimethoxy-2-methylpropyl]-3-methoxy-16-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-5,7,13,15-tetramethyl-14-[(triethylsilyl)oxy]-12-[(triisopropylsilyl)oxy]-7,15-hexadecadienyl methyl ether	C₇₄H₁₅₂O₁₀Si₅	详情	详情
(XLVII)	57365	(2R,4S,5R,6S,8S,10E,12R,13R,15S,16S,17S,18E)-12-allyl-5,13-bis{[tert-butyl(dimethyl)silyl]oxy}-4,6-dimethoxy-19-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,8,10,16,18-pentamethyl-17-[(triethylsilyl)oxy]-15-[(triisopropylsilyl)oxy]-10,18-nonadecadienal	C₇₂H₁₄₆O₉Si₅	详情	详情
(XLVIII)	57366	(2S)-1-{2-[(4-methoxybenzyl)oxy]acetyl}-2-piperidinecarboxylic acid	C₁₆H₂₁NO₅	详情	详情
(XLIX)	57367	(2S)-1-{(4R,6S,7R,8S,10S,12E,14R,15R,17S,18S,19S,20E)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-19-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid	C₈₈H₁₆₇NO₁₄Si₅	详情	详情
(L)	57368	(2S)-1-{(4R,6S,7R,8S,10S,12E,14R,15R,17S,18S,19S,20E)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-3-oxo-19-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid	C₈₈H₁₆₅NO₁₄Si₅	详情	详情
(LI)	57369	(2S)-1-{(4R,6S,7R,8S,10S,12E,14R,15R,17S,18S,19S,20E)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-19-hydroxy-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-3-oxo-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid	C₈₂H₁₅₁NO₁₄Si₄	详情	详情

Extended Information