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 -Drug Synthesis Database

【结构式】

【分子编号】17375

【品名】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

【CA登记号】

【分子式】C₇₅H₁₁₄O₁₅Si₂

【分子量】1311.89216

【元素组成】C 68.67% H 8.76% O 18.29% Si 4.28%

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：(VII)

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

合成路线2

该中间体在本合成路线中的序号：(VII)

The diastereoselective reduction of (VII) with NaBH4/CeCl3 in methanol/ethyl ether affords alcohol (VIII), which was methylated with trimethyloxonium tetrafluoroborate in dichloromethane giving the methyl ether (IX). The treatment of (IX) with lithium bis(trimethylsilyl)amide (Li-HMDS) and Mg(HMDS)2 causes enolization and ring opening affording alcohol (X), which was protected with tert-butyldimethylsilyl triflate yielding the fully silylated compound (XI). The hydrolysis of the ester group of (XI) with NaOH, followed by a selective elimination of the triethylsilyl group with trifluoroacetic acid and esterification of the resulting alcohol with piperidine-2(S)-carboxylic acid (XII) by means of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) afforded ester (XIII).

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	CAS号	分子式	供应商	用于合成
(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
(VIII)	17376	ethyl (4R,5S,7R,8S,10R)-7-((1S,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]-1-hydroxy-3,5-dimethyl-5-hexenyl)-8-methoxy-2,2,10-trimethyl-1,3,6-trioxaspiro[4.5]decane-4-carboxylate		C₇₅H₁₁₆O₁₅Si₂	详情	详情
(IX)	17377	ethyl (4R,5S,7R,8S,10R)-7-((1S,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]-1-methoxy-3,5-dimethyl-5-hexenyl)-8-methoxy-2,2,10-trimethyl-1,3,6-trioxaspiro[4.5]decane-4-carboxylate		C₇₆H₁₁₈O₁₅Si₂	详情	详情
(X)	17378	ethyl 5-((1R,3S,4R,5S,7S,9E)-10-[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]-4-hydroxy-3,5-dimethoxy-1,7,9-trimethyl-9-decenyl)-2,2-dimethyl-1,3-dioxole-4-carboxylate		C₇₆H₁₁₈O₁₅Si₂	详情	详情
(XI)	17379	ethyl 5-((1R,3S,4R,5S,7S,9E)-4-[[tert-butyl(dimethyl)silyl]oxy]-10-[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-dimethoxy-1,7,9-trimethyl-9-decenyl)-2,2-dimethyl-1,3-dioxole-4-carboxylate		C₈₂H₁₃₂O₁₅Si₃	详情	详情
(XII)	17380	(2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid	3105-95-1	C₆H₁₁NO₂	详情	详情
(XIII)	17381	5-((1R,3S,4R,5S,7S,9E)-4-[[tert-butyl(dimethyl)silyl]oxy]-10-[4-((1R,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1,3-dimethyl-2-[[(2S)piperidinylcarbonyl]oxy]-3-butenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-3,5-dimethoxy-1,7,9-trimethyl-9-decenyl)-2,2-dimethyl-1,3-dioxole-4-carboxylic acid		C₈₀H₁₂₃NO₁₆Si₂	详情	详情

Extended Information