(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 -Drug Synthesis Database

【结构式】

【分子编号】57344

【品名】(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

【CA登记号】

【分子式】C₃₆H₇₃IO₆Si₂

【分子量】785.04749

【元素组成】C 55.08% H 9.37% I 16.17% O 12.23% Si 7.16%

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：(XXI)

Synthesis of the intermediate 14-iodo-10-tetradecenal dimethylacetal (XXI): The reaction of the chiral trihydroxy compound (XI) with 2,4-dimethyl-3-pentanone dimethyl acetal (XII) by means of TsOH in THF gives the ketal (XIII), which is treated with TsCl, TEA and DMAP in dichloromethane to yield the silyl ether (XIV). The condensation of (XIV) with ethynyl lithium (XV) in DMSO affords the propargyl derivative (XVI). The reduction of (XVI) with H2 over Lindlar catalyst in hexane containing quinoline provides the allyl derivative (XVII), which is condensed with propane-1,3-dithiol and BF3/Et2O in dichloromethane to give the chiral hydroxy dithiane (XVIII). The cleavage of the ketal group of (XVIII) by means of TsOH in methanol, followed by reaction of the intermediate diol with TsCl and pyridine yields the primary monotosylate (XIX), which is treated with Tbdms-OTf and lutidine in dichloromethane to afford the bis silyl ether (XX). Finally, this compound is iodinated by means of NaI, Cu and AgNO3 in hot acetonitrile/methanol to provide the desired intermediate 14-iodo-10-tetradecenal dimethylacetal (XXI).

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.
【2】 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.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XI)	57298	(2S,3S)-3-{(E,4S,6S)-6-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-6-methoxy-2,4-dimethyl-1-hexenyl}-1,2,4-butanetriol	C₂₁H₄₀O₇	详情	详情
(XII)	57336	3,3-dimethoxy-2,4-dimethylpentane; 1-isopropyl-1-methoxy-2-methylpropyl methyl ether	C₉H₂₀O₂	详情	详情
(XIII)	57337	(2S,3E,6S,8S)-2-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-8-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-8-methoxy-4,6-dimethyl-3-octen-1-ol	C₂₈H₅₂O₇	详情	详情
(XIV)	57338	(2S,3E,6S,8S)-2-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-8-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-8-methoxy-4,6-dimethyl-3-octenyl 4-methylbenzenesulfonate	C₃₅H₅₈O₉S	详情	详情
(XV)	17461	ethynyllithium	C₂HLi	详情	详情
(XVI)	57339	(2R,3S,5R,6S)-2-{(1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-methoxy-3,5-dimethyl-5-decen-9-ynyl}-3,6-dimethoxy-5-methyltetrahydro-2H-pyran; (1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-3,5-dimethyl-5-decen-9-ynyl methyl ether	C₃₀H₅₂O₆	详情	详情
(XVII)	57340	(2R,3S,5R,6S)-2-{(1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-methoxy-3,5-dimethyl-5,9-decadienyl}-3,6-dimethoxy-5-methyltetrahydro-2H-pyran; (1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-3,5-dimethyl-5,9-decadienyl methyl ether	C₃₀H₅₄O₆	详情	详情
(XVIII)	57341	(2R,4S,5R,6S,8S,10E,12R)-12-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-2-(1,3-dithian-2-yl)-4,6-dimethoxy-8,10-dimethyl-10,14-pentadecadien-5-ol	C₃₂H₅₈O₅S₂	详情	详情
(XIX)	57342	(2S,3R,4E,7S,9S,10R,11S,13R)-3-allyl-13-(1,3-dithian-2-yl)-2,10-dihydroxy-9,11-dimethoxy-5,7-dimethyl-4-tetradecenyl 4-methylbenzenesulfonate	C₃₂H₅₂O₇S₃	详情	详情
(XX)	57343	(2S,3R,4E,7S,9S,10R,11S,13R)-3-allyl-2,10-bis{[tert-butyl(dimethyl)silyl]oxy}-13-(1,3-dithian-2-yl)-9,11-dimethoxy-5,7-dimethyl-4-tetradecenyl 4-methylbenzenesulfonate	C₄₄H₈₀O₇S₃Si₂	详情	详情
(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

合成路线2

该中间体在本合成路线中的序号：(XXI)

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

Extended Information