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 -Drug Synthesis Database

【结构式】

【分子编号】17381

【品名】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

【CA登记号】

【分子式】C₈₀H₁₂₃NO₁₆Si₂

【分子量】1411.02476

【元素组成】C 68.1% H 8.79% N 0.99% O 18.14% Si 3.98%

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：(XIII)

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

合成路线2

该中间体在本合成路线中的序号：(XIII)

Ester (XIII) was submitted to cyclization by means of triethylsilyl triflate and 2-chloro-1-methylpyridinium iodide (MCPI) in dichloromethane/methanol gaving the macrocyclic compound (XIV). Elimination of the p-methoxybenzyl group of (XIV) with dichlorodicyanobenzoquinone (DDQ) in dichloromethane yielded the alcohol (XV), which was converted into the iodo derivative (XVI) with I2, triphenylphosphine and imidazole in hot toluene. The reductive fragmentation of the spiroketal rings of (XVI) with zinc/silver-graphite in THF afforded compound (XVII) with the adequate configuration in the C21-C24 fragment.

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
(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
(XIV)	17382	(10S,12S,13R,14S,16R,28S,31S,32R)-13-[[tert-butyl(dimethyl)silyl]oxy]-31-[(E)-2-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-12,14-dimethoxy-4-[(4-methoxybenzyl)oxy]-8,10,16,19,19,32,35,35-octamethyl-2,18,20,30,34,36-hexaoxa-23-azapentacyclo[31.3.1.0(1,6).0(17,21).0(23,28)]heptatriaconta-7,17(21)-diene-22,29-dione	C₈₀H₁₂₁NO₁₅Si₂	详情	详情
(XV)	17383	(10S,12S,13R,14S,16R,28S,31S,32R)-13-[[tert-butyl(dimethyl)silyl]oxy]-31-[(E)-2-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-4-hydroxy-12,14-dimethoxy-8,10,16,19,19,32,35,35-octamethyl-2,18,20,30,34,36-hexaoxa-23-azapentacyclo[31.3.1.0(1,6).0(17,21).0(23,28)]heptatriaconta-7,17(21)-diene-22,29-dione	C₇₂H₁₁₃NO₁₄Si₂	详情	详情
(XVI)	17384	(10S,12S,13R,14S,16R,28S,31S,32R)-13-[[tert-butyl(dimethyl)silyl]oxy]-31-[(E)-2-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-4-iodo-12,14-dimethoxy-8,10,16,19,19,32,35,35-octamethyl-2,18,20,30,34,36-hexaoxa-23-azapentacyclo[31.3.1.0(1,6).0(17,21).0(23,28)]heptatriaconta-7,17(21)-diene-22,29-dione	C₇₂H₁₁₂INO₁₃Si₂	详情	详情
(XVII)	17385	(9aS,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-allyl-24-[[tert-butyl(dimethyl)silyl]oxy]-12-[(E)-2-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-14-hydroxy-23,25-dimethoxy-2,2,13,19,21,27-hexamethyl-7,8,9,9a,12,13,14,15,20,21,22,23,24,25,26,27-hexadecahydro-4H-[1,3]dioxolo[4,5-f]pyrido[2,1-c][1,4]oxazacyclotricosine-4,10,16(6H,17H)-trione	C₆₉H₁₀₇NO₁₂Si₂	详情	详情

Extended Information