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【结 构 式】

【分子编号】51457

【品名】(8S,10Z,15S,16S,17R,20S)-16-[[tert-butyl(dimethyl)silyl]oxy]-20-(2-hydroxyethyl)-2,2,11,15,17,19,19,22,22,23,23-undecamethyl-8-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,7,21-trioxa-2lambda(4)-thia-22-sila-10-tetracosen-18-one

【CA登记号】

【 分 子 式 】C45H87NO6S2Si2

【 分 子 量 】858.49192

【元素组成】C 62.96% H 10.21% N 1.63% O 11.18% S 7.47% Si 6.54%
与该中间体有关的原料药合成路线共 4 条
合成路线1合成路线2合成路线3合成路线4

合成路线1

该中间体在本合成路线中的序号：(XII)

Synthesis of the target epothilone: The condensation of the iodinated dioxolane (XI) with the phenylsulfone (XII) by means of BuLi and DMPU gives the adduct (XIII), which is deprotected with Amberlyst 15 to yield the diol (XIV). Regioselective silylation of (XIV) with Tbdms-Cl and imidazole affords the monosilylated diol (XV), which is fully protected with Sem-Cl and DIEA, providing compound (XVI). The reaction of (XVI) with tributyltin hydride gives the stannane (XVII), which is condensed with the chiral aldehyde (XVIII) by means of SnBr4 to yield the 4-decanol derivative (XIX). The elimination of The OH group of (XIX) is performed via its reaction with Cl-C(S)-OPh (XX) to afford the thiocarbonate (XXI), which is then treated with tributyltin hydride to provide the dehydroxylated compound (XXII). Selective deprotection of (XXII) with DDQ gives the primary alcohol (XXIII), which is esterified with pivaloyl chloride, yielding the pivaloyl ester (XXIV). The selective desilylation of the Tbdms group of (XXIV) with TBAF gives the primary alcohol (XXV), which is oxidized to the corresponding aldehyde (XXVI) by means of DMP. The Grignard reaction of aldehyde (XXVI) with methylmagnesium bromide yields the secondary alcohol (XXVII).

参考文献 中间体
合成目标
【1】 Martin, N.; Thomas, E.J.; Total syntheses of epothilones B and D: Applications of allylstannanes in organic synthesis. Tetrahedron Lett 2001, 42, 47, 8373.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 51436 (4R)-4-(iodomethyl)-2,2-dimethyl-1,3-dioxolane C6H11IO2 详情 详情
(XII) 51457 (8S,10Z,15S,16S,17R,20S)-16-[[tert-butyl(dimethyl)silyl]oxy]-20-(2-hydroxyethyl)-2,2,11,15,17,19,19,22,22,23,23-undecamethyl-8-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,7,21-trioxa-2lambda(4)-thia-22-sila-10-tetracosen-18-one C45H87NO6S2Si2 详情 详情
(XIII) 51438 1-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-2-methyl-2-propenyl phenyl sulfone; (4S)-2,2-dimethyl-4-[3-methyl-2-(phenylsulfonyl)-3-butenyl]-1,3-dioxolane C16H22O4S 详情 详情
(XIV) 51439 (2S)-5-methyl-4-(phenylsulfonyl)-5-hexene-1,2-diol C13H18O4S 详情 详情
(XV) 51440 (2S)-1-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-4-(phenylsulfonyl)-5-hexen-2-ol C19H32O4SSi 详情 详情
(XVI) 51441 1-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]propyl)-2-methyl-2-propenyl phenyl sulfone; (8S)-2,2,11,11,12,12-hexamethyl-8-[3-methyl-2-(phenylsulfonyl)-3-butenyl]-5,7,10-trioxa-2lambda(4)-thia-11-silatridecane C25H46O5S2Si 详情 详情
(XVII) 51442 tert-butyl(dimethyl)silyl (2S,4E)-5-methyl-6-(tributylstannyl)-2-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-4-hexenyl ether; (8S)-2,2,11,11,12,12-hexamethyl-8-[(E)-3-methyl-4-(tributylstannyl)-2-butenyl]-5,7,10-trioxa-2lambda(4)-thia-11-silatridecane C31H68O3SSiSn 详情 详情
(XVIII) 51443 (3S)-4-[(4-methoxybenzyl)oxy]-3-methylbutanal C13H18O3 详情 详情
(XIX) 51444 (8S,10Z,15S)-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-18-(4-methoxyphenyl)-2,2,11,15-tetramethyl-5,7,17-trioxa-2lambda(4)-thia-10-octadecen-13-ol C32H60O6SSi 详情 详情
(XX) 25805 1-[(chlorocarbothioyl)oxy]benzene; Phenylchlorothioformate 1005-56-7 C7H5ClOS 详情 详情
(XXI) 51445 O-((Z,6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-1-[(2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropyl]-3-methyl-6-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-3-heptenyl) O-phenyl carbonothioate C39H64O7S2Si 详情 详情
(XXII) 51446 tert-butyl(dimethyl)silyl (2S,4Z,9S)-10-[(4-methoxybenzyl)oxy]-5,9-dimethyl-2-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-4-decenyl ether; (8S)-8-[(Z,7S)-8-[(4-methoxybenzyl)oxy]-3,7-dimethyl-2-octenyl]-2,2,11,11,12,12-hexamethyl-5,7,10-trioxa-2lambda(4)-thia-11-silatridecane C32H60O5SSi 详情 详情
(XXIII) 51447 (2S,6Z,9S)-10-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6-decen-1-ol C24H52O4SSi 详情 详情
(XXIV) 51448 (2S,6Z,9S)-10-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6-decenyl pivalate C29H60O5SSi 详情 详情
(XXV) 51449 (2S,6Z,9S)-10-hydroxy-2,6-dimethyl-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6-decenyl pivalate C23H46O5S 详情 详情
(XXVI) 51450 (2S,6Z,9S)-2,6-dimethyl-10-oxo-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6-decenyl pivalate C23H44O5S 详情 详情
(XXVII) 51451 (2S,6Z,9S)-10-hydroxy-2,6-dimethyl-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6-undecenyl pivalate C24H48O5S 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XXXIV)

The oxidation of the secondary OH group of (XXVII) with DMP gives the methyl ketone (XXVIII), which is condensed with the phosphonate (XXIX) to yield the diene (XXX). Reductive removal of the pivalate group of (XXX) by means of DIBAL affords the primary alcohol (XXXI), which is oxidized with DMP to provide the corresponding aldehyde (XXXII). The aldol condensation between aldehyde (XXXII) and the already reported intermediate, the ketone (X), by means of LDA gives the aldol (XXXIII), which is silylated with Tbdms-OTf and deprotected at the primary dimethoxyltrityl group by means of dichloroacetic acid to give the primary alcohol (XXXIV). The oxidation of (XXXIV) with DMP and NaClO2, followed by elimination of the Sem protecting group with MgBr2 and Bu-SH, yields the hydroxyacid (XXXV), which is submitted to macrocyclization under the modified Yamaguchi conditions (2,4,6-trichlorobenzoyl chloride and DMAP) to afford the silylated epothilone derivative (XXXVI). Finally, this compound is desilylated by means of TFA and epoxidized with DMDO to furnish the target epothilone B.

参考文献 中间体
合成目标
【1】 Martin, N.; Thomas, E.J.; Total syntheses of epothilones B and D: Applications of allylstannanes in organic synthesis. Tetrahedron Lett 2001, 42, 47, 8373.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 51435 (5S)-7-[bis(4-methoxyphenyl)(phenyl)methoxy]-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone C36H50O5Si 详情 详情
(XXVII) 51451 (2S,6Z,9S)-10-hydroxy-2,6-dimethyl-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6-undecenyl pivalate C24H48O5S 详情 详情
(XXVIII) 51452 (2S,6Z,9S)-2,6-dimethyl-10-oxo-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6-undecenyl pivalate C24H46O5S 详情 详情
(XXIX) 44442 diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C9H16NO3PS 详情 详情
(XXX) 51453 (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6,10-undecadienyl pivalate C29H51NO4S2 详情 详情
(XXXI) 51454 (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6,10-undecadien-1-ol C24H43NO3S2 详情 详情
(XXXII) 51455 (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6,10-undecadienal C24H41NO3S2 详情 详情
(XXXIII) 51456 (8S,10Z,15S,16S,17R,20S)-20-[2-[bis(4-methoxyphenyl)(phenyl)methoxy]ethyl]-16-hydroxy-2,2,11,15,17,19,19,22,22,23,23-undecamethyl-8-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,7,21-trioxa-2lambda(4)-thia-22-sila-10-tetracosen-18-one C60H91NO8S2Si 详情 详情
(XXXIV) 51457 (8S,10Z,15S,16S,17R,20S)-16-[[tert-butyl(dimethyl)silyl]oxy]-20-(2-hydroxyethyl)-2,2,11,15,17,19,19,22,22,23,23-undecamethyl-8-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,7,21-trioxa-2lambda(4)-thia-22-sila-10-tetracosen-18-one C45H87NO6S2Si2 详情 详情
(XXXV) 40835 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(XXXVI) 40836 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H69NO5SSi2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XII)

Synthesis of the target epothilone: The condensation of the iodinated dioxolane (XI) with the phenylsulfone (XII) by means of BuLi and DMPU gives the adduct (XIII), which is deprotected with Amberlyst 15 to yield the diol (XIV). Regioselective silylation of (XIV) with Tbdms-Cl and imidazole affords the monosilylated diol (XV), which is fully protected with Sem-Cl and DIEA, providing compound (XVI). The reaction of (XVI) with tributyltin hydride gives the stannane (XVII), which is condensed with the chiral aldehyde (XVIII) by means of SnBr4 to yield the 4-decanol derivative (XIX). The elimination of The OH group of (XIX) is performed via its reaction with Cl-C(S)-OPh (XX) to afford the thiocarbonate (XXI), which is then treated with tributyltin hydride to provide the dehydroxylated compound (XXII). Selective deprotection of (XXII) with DDQ gives the primary alcohol (XXIII), which is esterified with pivaloyl chloride, yielding the pivaloyl ester (XXIV). The selective desilylation of the Tbdms group of (XXIV) with TBAF gives the primary alcohol (XXV), which is oxidized to the corresponding aldehyde (XXVI) by means of DMP. The Grignard reaction of aldehyde (XXVI) with methylmagnesium bromide yields the secondary alcohol (XXVII).

参考文献 中间体
合成目标
【1】 Martin, N.; Thomas, E.J.; Total syntheses of epothilones B and D: Applications of allylstannanes in organic synthesis. Tetrahedron Lett 2001, 42, 47, 8373.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 51436 (4R)-4-(iodomethyl)-2,2-dimethyl-1,3-dioxolane C6H11IO2 详情 详情
(XII) 51457 (8S,10Z,15S,16S,17R,20S)-16-[[tert-butyl(dimethyl)silyl]oxy]-20-(2-hydroxyethyl)-2,2,11,15,17,19,19,22,22,23,23-undecamethyl-8-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,7,21-trioxa-2lambda(4)-thia-22-sila-10-tetracosen-18-one C45H87NO6S2Si2 详情 详情
(XIII) 51438 1-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-2-methyl-2-propenyl phenyl sulfone; (4S)-2,2-dimethyl-4-[3-methyl-2-(phenylsulfonyl)-3-butenyl]-1,3-dioxolane C16H22O4S 详情 详情
(XIV) 51439 (2S)-5-methyl-4-(phenylsulfonyl)-5-hexene-1,2-diol C13H18O4S 详情 详情
(XV) 51440 (2S)-1-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-4-(phenylsulfonyl)-5-hexen-2-ol C19H32O4SSi 详情 详情
(XVI) 51441 1-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]propyl)-2-methyl-2-propenyl phenyl sulfone; (8S)-2,2,11,11,12,12-hexamethyl-8-[3-methyl-2-(phenylsulfonyl)-3-butenyl]-5,7,10-trioxa-2lambda(4)-thia-11-silatridecane C25H46O5S2Si 详情 详情
(XVII) 51442 tert-butyl(dimethyl)silyl (2S,4E)-5-methyl-6-(tributylstannyl)-2-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-4-hexenyl ether; (8S)-2,2,11,11,12,12-hexamethyl-8-[(E)-3-methyl-4-(tributylstannyl)-2-butenyl]-5,7,10-trioxa-2lambda(4)-thia-11-silatridecane C31H68O3SSiSn 详情 详情
(XVIII) 51443 (3S)-4-[(4-methoxybenzyl)oxy]-3-methylbutanal C13H18O3 详情 详情
(XIX) 51444 (8S,10Z,15S)-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-18-(4-methoxyphenyl)-2,2,11,15-tetramethyl-5,7,17-trioxa-2lambda(4)-thia-10-octadecen-13-ol C32H60O6SSi 详情 详情
(XX) 25805 1-[(chlorocarbothioyl)oxy]benzene; Phenylchlorothioformate 1005-56-7 C7H5ClOS 详情 详情
(XXI) 51445 O-((Z,6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-1-[(2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropyl]-3-methyl-6-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-3-heptenyl) O-phenyl carbonothioate C39H64O7S2Si 详情 详情
(XXII) 51446 tert-butyl(dimethyl)silyl (2S,4Z,9S)-10-[(4-methoxybenzyl)oxy]-5,9-dimethyl-2-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-4-decenyl ether; (8S)-8-[(Z,7S)-8-[(4-methoxybenzyl)oxy]-3,7-dimethyl-2-octenyl]-2,2,11,11,12,12-hexamethyl-5,7,10-trioxa-2lambda(4)-thia-11-silatridecane C32H60O5SSi 详情 详情
(XXIII) 51447 (2S,6Z,9S)-10-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6-decen-1-ol C24H52O4SSi 详情 详情
(XXIV) 51448 (2S,6Z,9S)-10-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6-decenyl pivalate C29H60O5SSi 详情 详情
(XXV) 51449 (2S,6Z,9S)-10-hydroxy-2,6-dimethyl-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6-decenyl pivalate C23H46O5S 详情 详情
(XXVI) 51450 (2S,6Z,9S)-2,6-dimethyl-10-oxo-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6-decenyl pivalate C23H44O5S 详情 详情
(XXVII) 51451 (2S,6Z,9S)-10-hydroxy-2,6-dimethyl-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6-undecenyl pivalate C24H48O5S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XXXIV)

The oxidation of the secondary OH group of (XXVII) with DMP gives the methyl ketone (XXVIII), which is condensed with the phosphonate (XXIX) to yield the diene (XXX). Reductive removal of the pivalate group of (XXX) by means of DIBAL affords the primary alcohol (XXXI), which is oxidized with DMP to provide the corresponding aldehyde (XXXII). The aldol condensation between aldehyde (XXXII) and the already reported intermediate, the ketone (X), by means of LDA gives the aldol (XXXIII), which is silylated with Tbdms-OTf and deprotected at the primary dimethoxyltrityl group by means of dichloroacetic acid to give the primary alcohol (XXXIV). The oxidation of (XXXIV) with DMP and NaClO2, followed by elimination of the Sem protecting group with MgBr2 and Bu-SH, yields the hydroxyacid (XXXV), which is submitted to macrocyclization under modified Yamaguchi conditions (2,4,6-trichlorobenzoyl chloride and DMAP) to afford the silylated epothilone derivative (XXXVI). Finally, this compound is desilylated by means of TFA to furnish the target epothilone D.

参考文献 中间体
合成目标
【1】 Martin, N.; Thomas, E.J.; Total syntheses of epothilones B and D: Applications of allylstannanes in organic synthesis. Tetrahedron Lett 2001, 42, 47, 8373.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 51435 (5S)-7-[bis(4-methoxyphenyl)(phenyl)methoxy]-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone C36H50O5Si 详情 详情
(XXVII) 51451 (2S,6Z,9S)-10-hydroxy-2,6-dimethyl-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6-undecenyl pivalate C24H48O5S 详情 详情
(XXVIII) 51452 (2S,6Z,9S)-2,6-dimethyl-10-oxo-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6-undecenyl pivalate C24H46O5S 详情 详情
(XXIX) 44442 diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C9H16NO3PS 详情 详情
(XXX) 51453 (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6,10-undecadienyl pivalate C29H51NO4S2 详情 详情
(XXXI) 51454 (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6,10-undecadien-1-ol C24H43NO3S2 详情 详情
(XXXII) 51455 (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6,10-undecadienal C24H41NO3S2 详情 详情
(XXXIII) 51456 (8S,10Z,15S,16S,17R,20S)-20-[2-[bis(4-methoxyphenyl)(phenyl)methoxy]ethyl]-16-hydroxy-2,2,11,15,17,19,19,22,22,23,23-undecamethyl-8-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,7,21-trioxa-2lambda(4)-thia-22-sila-10-tetracosen-18-one C60H91NO8S2Si 详情 详情
(XXXIV) 51457 (8S,10Z,15S,16S,17R,20S)-16-[[tert-butyl(dimethyl)silyl]oxy]-20-(2-hydroxyethyl)-2,2,11,15,17,19,19,22,22,23,23-undecamethyl-8-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,7,21-trioxa-2lambda(4)-thia-22-sila-10-tetracosen-18-one C45H87NO6S2Si2 详情 详情
(XXXV) 40835 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(XXXVI) 40836 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H69NO5SSi2 详情 详情
Extended Information