(E,3S,4S)-4-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]-1-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-2-methyl-1-penten-3-ol -Drug Synthesis Database

【结构式】

【分子编号】17369

【品名】(E,3S,4S)-4-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]-1-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-2-methyl-1-penten-3-ol

【CA登记号】

【分子式】C₆₀H₉₂O₉Si₂

【分子量】1013.55608

【元素组成】C 71.1% H 9.15% O 14.21% Si 5.54%

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：(I)

Subsequent reduction of the ketonic group of (XV) with L-selectride in THF afforded the enantiomerically pure alcohol (XVI), which was treated with p-methoxybenzyl trichloroacetimide (XVII) and a catalytic amount of triphenylmethyl tetrafluoroborate to give the expected p-methoxybenzyl ether (XVIII). The desilylation of (XVIII) with tetrabutylammonium fluoride (TBAF) in THF gives the diol (XIX), which was selectively resilylated at the primary OH group yielding the se-condary alcohol (XX). The selective debenzylation of (XX) with H2 over W-2 RaNi in ethanol afforded the vicinal diol (XXI), which was submitted to cleavage with sodium per-iodate in THF to obtain the aldehyde (XXII). Finally, this compound is condensed with the vinyl bromide (XXIII) by means of butyllithium and magnesium bromide in THF to afford the desired C16-C34 fragment of FK-506, the key intermediate in the total synthesis described in Tetrahedron 1997, 53(39): 13257.

参考文献中间体

合成目标

【1】 Liu, L.B.; Roper, T.D.; Ireland, R.E.; Total synthesis of FK-506. 1. Construction of the C16-C34 fragment. Tetrahedron 1997, 53, 39, 13221.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	17369	(E,3S,4S)-4-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]-1-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-2-methyl-1-penten-3-ol	C₆₀H₉₂O₉Si₂	详情	详情
(XV)	17357	4-((1R,2S)-3-(benzyloxy)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methylpropyl)-11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undecan-9-one	C₄₀H₇₀O₇Si₂	详情	详情
(XVI)	17363	4-((1R,2S)-3-(benzyloxy)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methylpropyl)-11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undecan-9-ol	C₄₀H₇₂O₇Si₂	详情	详情
(XVII)	17358	(2R)-3-methoxy-2-methylpropyl 4-methylbenzenesulfonate	C₁₂H₁₈O₄S	详情	详情
(XVIII)	17359	(4S)-5-methoxy-4-methyl-1-pentyne; methyl (2S)-2-methyl-4-pentynyl ether	C₇H₁₂O	详情	详情
(XIX)	17364	(2S,4E)-5-[4-[(1S,2S)-3-(benzyloxy)-2-hydroxy-1-methylpropyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-2,4-dimethyl-4-penten-1-ol	C₃₆H₅₂O₈	详情	详情
(XX)	17365	(2S,3S)-1-(benzyloxy)-3-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]-2-butanol	C₄₂H₆₆O₈Si	详情	详情
(XXI)	17366	(2S,3S)-3-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]-1,2-butanediol	C₃₅H₆₀O₈Si	详情	详情
(XXII)	17367	(2R)-2-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]propanal	C₃₄H₅₆O₇Si	详情	详情
(XXIII)	17368	(1R,2R,5R)-5-[(E)-2-bromo-1-propenyl]-2-[[tert-butyl(diphenyl)silyl]oxy]cyclohexyl methyl ether; ([(1R,2R,4R)-4-[(E)-2-bromo-1-propenyl]-2-methoxycyclohexyl]oxy)(tert-butyl)diphenylsilane	C₂₆H₃₅BrO₂Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The completion of the total synthesis of FK-506, starting with the key intermediate C16-C34 fragment obtained as described in Tetrahedron 1997, 53(39): 13221, has been presented: 1) The silyl ether (I) was partially deprotected with tetrabutylammonium fluoride (TBAF) in THF giving the diol (II), which is selectively tosylated with tosyl chloride at the primary OH group yielding the monotosylate (III). The protection of the secondary alcohol of (III) with triethylsilyl chloride (TES-Cl) affords the protected tosylate (IV), which by treatment with lithium iodide and sodium benzenesulfinate is converted into the sulfone (V). The condensation of (V) with aldehyde (VI) by means of butyllithium followed by Dess-Martin oxidation gives a nonisolated ketosulfone intermediate, which was treated with tri-butyltin hydride and azobis(isobutyronitrile) (AIBN) yielding ketone (VII).

参考文献中间体

合成目标

【1】 Liu, L.B.; Roper, T.D.; Gleason, J.L.; Ireland, R.E.; Total synthesis of FK-506. 2. Completion of the synthesis. Tetrahedron 1997, 53, 39, 13257.
【2】 Liu, L.B.; Roper, T.D.; Ireland, R.E.; Total synthesis of FK-506. 1. Construction of the C16-C34 fragment. Tetrahedron 1997, 53, 39, 13221.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	17369	(E,3S,4S)-4-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]-1-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-2-methyl-1-penten-3-ol	C₆₀H₉₂O₉Si₂	详情	详情
(II)	17370	(2S,4E)-5-[4-[(1S,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-2-hydroxy-1,3-dimethyl-3-butenyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-2,4-dimethyl-4-penten-1-ol	C₅₄H₇₈O₉Si	详情	详情
(III)	17371	(2S,4E)-5-[4-[(1S,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-2-hydroxy-1,3-dimethyl-3-butenyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-2,4-dimethyl-4-pentenyl 4-methylbenzenesulfonat	C₆₁H₈₄O₁₁SSi	详情	详情
(IV)	17372	(2S,4E)-5-[4-[(1R,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1,3-dimethyl-2-[(triethylsilyl)oxy]-3-butenyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-2,4-dimethyl-4-pentenyl 4-methylbe	C₆₇H₉₈O₁₁SSi₂	详情	详情
(V)	17373	(2S,4E)-5-[4-[(1R,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1,3-dimethyl-2-[(triethylsilyl)oxy]-3-butenyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-2,4-dimethyl-4-pentenyl benzenesul	C₆₆H₉₆O₁₁SSi₂	详情	详情
(VI)	17374	ethyl (4R,5S,7S,8S,10R)-7-formyl-8-methoxy-2,2,10-trimethyl-1,3,6-trioxaspiro[4.5]decane-4-carboxylate	C₁₅H₂₄O₇	详情	详情
(VII)	17375	ethyl (4R,5S,7S,8S,10R)-7-((3S,5E)-6-[4-[(1R,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1,3-dimethyl-2-[(triethylsilyl)oxy]-3-butenyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-3,5-dimethyl-5-hexenoyl)-8-methoxy-2,2,10-trimethyl-1,3,6-trioxaspiro[4.5]decane-4-carboxylate	C₇₅H₁₁₄O₁₅Si₂	详情	详情

Extended Information