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【结 构 式】

【分子编号】46158

【品名】(3S,6R,7S,8S,9Z,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-9,12,16-heptadecatrienoic acid

【CA登记号】

【 分 子 式 】C39H69NO6SSi2

【 分 子 量 】736.217

【元素组成】C 63.63% H 9.45% N 1.9% O 13.04% S 4.36% Si 7.63%

与该中间体有关的原料药合成路线共 8 条

合成路线1

该中间体在本合成路线中的序号:(XXVIII)

The condensation of the known ketone (XVII) with aldehyde (XVIII) by means of LDA in THF gives the hydroxyketone (XIX), which is silylated with Tbdms-OTf and TEA in dichloromethane, yielding the silyl ether (XX). The terminal vinyl group of (XX) is cleaved oxidatively by means of OsO4 and NaIO4 in THF/water, affording the aldehyde (XXI), which is oxidized to acid (XXII) by means of NaClO2 in t-butanol/water. Acid (XXII) is esterified to methyl ester (XXIII), which is selectively deprotected at the Pmb group by hydrogenation with H2 over Pd/C in ethanol to provide the primary alcohol (XXIV). The oxidation of (XXIV) with tetrapropylammonium perruthenate (TPAP) furnishes the aldehyde (XXV), which is submitted to a Wittig condensation with the intermediate phosphonium salt (XVI) by means of LiHMDS in THF to give the adduct (XXVI). The hydrolysis of the ester group of (XXVI) with NaOH in warm isopropanol yields the carboxylic acid (XXVII), which is selectively deprotected by means of TBAF in THF to afford the hydroxyacid (XXVIII).

1 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407.
2 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684.
3 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVI) 46148 [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide C38H49BrNOPSSi 详情 详情
(XVII) 44451 (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one C16H32O2Si 详情 详情
(XVIII) 42656 (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanal C12H16O3 详情 详情
(XIX) 46149 (2S,3S,4R,7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6,6-tetramethyl-9-decen-5-one C28H48O5Si 详情 详情
(XX) 46150 (5S,8R,9S)-5-allyl-9-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-4,10-dioxa-3,11-disilatridecan-7-one C34H62O5Si2 详情 详情
(XXI) 46151 (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanal C33H60O6Si2 详情 详情
(XXII) 46152 (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanoic acid C33H60O7Si2 详情 详情
(XXIII) 46153 methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanoate C34H62O7Si2 详情 详情
(XXIV) 46154 methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-hydroxy-4,4,6,8-tetramethyl-5-oxononanoate C26H54O6Si2 详情 详情
(XXV) 46155 methyl (3S,6R,7S,8R)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5,9-dioxononanoate C26H52O6Si2 详情 详情
(XXVI) 46156 methyl (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoate C46H85NO6SSi3 详情 详情
(XXVII) 46157 (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid C45H83NO6SSi3 详情 详情
(XXVIII) 46158 (3S,6R,7S,8S,9Z,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-9,12,16-heptadecatrienoic acid C39H69NO6SSi2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XXVIII)

The macrolactonization of (XXVIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF provides the protected macrolactone (XXIX), which is deprotected with TFA in dichloromethane to give the trienic macrolactone (XXX). Selective hydrogenation of the disubstituted double bond of (XXX) by means of potassium azodicarboxylate (DKAD) and AcOH in dichloromethane yields the precursor (XXXI), which is finally epoxidized with dimethyldioxirane (XXXII) in dichloromethane to afford the target epothilone B.

1 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407.
2 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXVIII) 46158 (3S,6R,7S,8S,9Z,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-9,12,16-heptadecatrienoic acid C39H69NO6SSi2 详情 详情
(XXIX) 46159 (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-10,13-cyclohexadecadiene-2,6-dione C39H67NO5SSi2 详情 详情
(XXX) 46160 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-10,13-cyclohexadecadiene-2,6-dione C27H39NO5S 详情 详情
(XXXI) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-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 C27H41NO5S 详情 详情
(XXXII) 31501 3,3-dimethyl-1,2-dioxirane C3H6O2 详情 详情

合成路线3

该中间体在本合成路线中的序号:(VIII)

The reaction of chiral aldehyde (I) with dimethyl diazomethylphosphonate (II) by means of tBu-OK in THF gives the acetylenic ester (III), which is condensed with ally bromide derivative (IV) by means of CuI and TEA in DMF/ethyl ether to yield the dienyne (V). The partial hydrogenation of (V) over a Lindlar catalyst in hexane affords the trienoic ester (VI). The hydrolysis of (VI) with NaOH in warm isopropanol provides the corresponding carboxylic acid (VII), which is selectively desilylated with TBAF in THF to give the hydroxyacid (VIII). The macrolactonization of (VIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in benzene/THF yields the protected macrolactone (IX), which is deprotected with TFA in dichloromethane to afford the trienic macrolactone (X). Selective hydrogenation of the disubstituted double bond of (X) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane provides the precursor (XI), which is finally epoxidated with dimethyldioxirane (XII) in dichloromethane to furnish the target epothilone B.

1 White, J.D.; et al.; Improved synthesis of epothilone B employing alkylation of an alkyne for assembly of subunits. Org Lett 1999, 1, 9, 1431.
2 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 46155 methyl (3S,6R,7S,8R)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5,9-dioxononanoate C26H52O6Si2 详情 详情
(II) 42709 Diazomethylphoshonic acid dimethyl ester 27491-70-9 C3H7N2O3P 详情 详情
(III) 46161 methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-9-decynoate C27H52O5Si2 详情 详情
(IV) 46147 4-((1E,3S,5Z)-7-bromo-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; (1S,3Z)-5-bromo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl tert-butyl(dimethyl)silyl ether C19H32BrNOSSi 详情 详情
(V) 46162 methyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadien-9-ynoate C46H83NO6SSi3 详情 详情
(VI) 46156 methyl (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoate C46H85NO6SSi3 详情 详情
(VII) 46157 (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid C45H83NO6SSi3 详情 详情
(VIII) 46158 (3S,6R,7S,8S,9Z,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-9,12,16-heptadecatrienoic acid C39H69NO6SSi2 详情 详情
(IX) 46159 (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-10,13-cyclohexadecadiene-2,6-dione C39H67NO5SSi2 详情 详情
(X) 46160 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-10,13-cyclohexadecadiene-2,6-dione C27H39NO5S 详情 详情
(XI) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-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 C27H41NO5S 详情 详情
(XII) 31501 3,3-dimethyl-1,2-dioxirane C3H6O2 详情 详情

合成路线4

该中间体在本合成路线中的序号:(XLI)

The oxidation of (XXXVIII) with TPAP and NMO in acetonitrile gives the carbaldehyde (XXXIX), which is condensed with the intermediate phosphonium bromide (XVII) by means of LiHMDS in THF to yield the heptadecadienoic ester (XL). The regioselective deprotection of (XL) by means of Tms-OTf in dichloromethane affords the hydroxyacid (XLI), which is submitted to a macrocyclization by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF to provide the protected didehydro precursor (XLII). The desilylation of (XLII) by means of TFA in dichloromethane yields the free didehydro precursor (XLIII), which is hydrogenated by means of 2,4,6-tri-isopropylbenzenesulfonyl hydrazide and TEA in refluxing ethyl ether to afford epothilone D (XLIII). Finally, this compound is epoxidated by means of dimethyldioxirane (DMDO) in dichloromethane.

1 Potier, P.; Ermolenko, M.S.; Synthesis of epothilones B and D from D-glucose. Tetrahedron Lett 2002, 43, 16, 2895.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVII) 46148 [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide C38H49BrNOPSSi 详情 详情
(XXXVIII) 54362 tert-butyl (3S,6R,7S,8S)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-9-hydroxy-4,4,6,8-tetramethyl-5-oxononanoate C29H60O6Si2 详情 详情
(XXXIX) 54363 tert-butyl (3S,6R,7S,8R)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8-tetramethyl-5,9-dioxononanoate C29H58O6Si2 详情 详情
(XL) 54364 tert-butyl (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoate C49H91NO6SSi3 详情 详情
(XLI) 46158 (3S,6R,7S,8S,9Z,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-9,12,16-heptadecatrienoic acid C39H69NO6SSi2 详情 详情
(XLII) 46159 (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-10,13-cyclohexadecadiene-2,6-dione C39H67NO5SSi2 详情 详情
(XLIII) 46160 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-10,13-cyclohexadecadiene-2,6-dione C27H39NO5S 详情 详情
(XLIV) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-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 C27H41NO5S 详情 详情

合成路线5

该中间体在本合成路线中的序号:(XXVIII)

The condensation of the known ketone (XVII) (2) with aldehyde (XVIII) by means of LDA in THF gives the hydroxyketone (XIX), which is silylated with Tbdms-OTf and TEA in dichloromethane, yielding the silyl ether (XX). The terminal vinyl group of (XX) is cleaved oxidatively by means of OsO4 and NaIO4 in THF/water, affording the aldehyde (XXI), which is oxidized to acid (XXII) by means of NaClO2 in t-butanol/water. Acid (XXII) is esterified to methyl ester (XXIII), which is selectively deprotected at the Pmb group by hydrogenation with H2 over Pd/C in ethanol to provide the primary alcohol (XXIV). The oxidation of (XXIV) with tetrapropylammonium perruthenate (TPAP) furnishes the aldehyde (XXV), which is submitted to a Wittig condensation with the intermediate phosphonium salt (XVI) by means of LiHMDS in THF to give the adduct (XXVI). The hydrolysis of the ester group of (XXVI) with NaOH in warm isopropanol yields the carboxylic acid (XXVII), which is selectively deprotected by means of TBAF in THF to afford the hydroxyacid (XXVIII).

1 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407.
2 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684.
3 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVI) 46148 [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide C38H49BrNOPSSi 详情 详情
(XVII) 44451 (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one C16H32O2Si 详情 详情
(XVIII) 42656 (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanal C12H16O3 详情 详情
(XIX) 46149 (2S,3S,4R,7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6,6-tetramethyl-9-decen-5-one C28H48O5Si 详情 详情
(XX) 46150 (5S,8R,9S)-5-allyl-9-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-4,10-dioxa-3,11-disilatridecan-7-one C34H62O5Si2 详情 详情
(XXI) 46151 (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanal C33H60O6Si2 详情 详情
(XXII) 46152 (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanoic acid C33H60O7Si2 详情 详情
(XXIII) 46153 methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanoate C34H62O7Si2 详情 详情
(XXIV) 46154 methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-hydroxy-4,4,6,8-tetramethyl-5-oxononanoate C26H54O6Si2 详情 详情
(XXV) 46155 methyl (3S,6R,7S,8R)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5,9-dioxononanoate C26H52O6Si2 详情 详情
(XXVI) 46156 methyl (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoate C46H85NO6SSi3 详情 详情
(XXVII) 46157 (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid C45H83NO6SSi3 详情 详情
(XXVIII) 46158 (3S,6R,7S,8S,9Z,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-9,12,16-heptadecatrienoic acid C39H69NO6SSi2 详情 详情

合成路线6

该中间体在本合成路线中的序号:(XXVIII)

The macrolactonization of (XXVIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF provides the protected macrolactone (XXIX), which is deprotected with TFA in dichloromethane to give the trienic macrolactone (XXX). Finally, the selective hydrogenation of the disubstituted double bond of (XXX) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane yields the target epothilone D.

1 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407.
2 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXVIII) 46158 (3S,6R,7S,8S,9Z,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-9,12,16-heptadecatrienoic acid C39H69NO6SSi2 详情 详情
(XXIX) 46159 (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-10,13-cyclohexadecadiene-2,6-dione C39H67NO5SSi2 详情 详情
(XXX) 46160 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-10,13-cyclohexadecadiene-2,6-dione C27H39NO5S 详情 详情

合成路线7

该中间体在本合成路线中的序号:(VIII)

The reaction of chiral aldehyde (I) with dimethyl diazomethylphosphonate (II) by means of tBu-OK in THF gives the acetylenic ester (III), which is condensed with ally bromide derivative (IV) by means of CuI and TEA in DMF/ethyl ether to yield the dienyne (V). The partial hydrogenation of (V) over a Lindlar catalyst in hexane affords the trienoic ester (VI). The hydrolysis of (VI) with NaOH in warm isopropanol provides the corresponding carboxylic acid (VII), which is selectively desilylated with TBAF in THF to give the hydroxyacid (VIII). The macrolactonization of (VIII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in benzene/THF yields the protected macrolactone (IX), which is deprotected with TFA in dichloromethane to afford the trienic macrolactone (X) (1). Finally, the selective hydrogenation of the disubstituted double bond of (X) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane provides the target epothilone D.

1 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684.
2 White, J.D.; et al.; Improved synthesis of epothilone B employing alkylation of an alkyne for assembly of subunits. Org Lett 1999, 1, 9, 1431.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 46155 methyl (3S,6R,7S,8R)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5,9-dioxononanoate C26H52O6Si2 详情 详情
(II) 42709 Diazomethylphoshonic acid dimethyl ester 27491-70-9 C3H7N2O3P 详情 详情
(III) 46161 methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-9-decynoate C27H52O5Si2 详情 详情
(IV) 46147 4-((1E,3S,5Z)-7-bromo-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; (1S,3Z)-5-bromo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl tert-butyl(dimethyl)silyl ether C19H32BrNOSSi 详情 详情
(V) 46162 methyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadien-9-ynoate C46H83NO6SSi3 详情 详情
(VI) 46156 methyl (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoate C46H85NO6SSi3 详情 详情
(VII) 46157 (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid C45H83NO6SSi3 详情 详情
(VIII) 46158 (3S,6R,7S,8S,9Z,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-9,12,16-heptadecatrienoic acid C39H69NO6SSi2 详情 详情
(IX) 46159 (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-10,13-cyclohexadecadiene-2,6-dione C39H67NO5SSi2 详情 详情
(X) 46160 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-10,13-cyclohexadecadiene-2,6-dione C27H39NO5S 详情 详情

合成路线8

该中间体在本合成路线中的序号:(XLI)

The oxidation of (XXXVIII) with TPAP and NMO in acetonitrile gives the carbaldehyde (XXXIX), which is condensed with the intermediate phosphonium bromide (XVII) by means of LiHMDS in THF to yield the heptadecadienoic ester (XL). The regioselective deprotection of (XL) by means of Tms-OTf in dichloromethane affords the hydroxyacid (XLI), which is submitted to a macrocyclization by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF to provide the protected didehydro precursor (XLII). The desilylation of (XLII) by means of TFA in dichloromethane yields the free didehydro precursor (XLIII), which is finally hydrogenated by means of 2,4,6-tri-isopropylbenzenesulfonyl hydrazide and TEA in refluxing ethyl ether to afford the target epothilone D.

1 Potier, P.; Ermolenko, M.S.; Synthesis of epothilones B and D from D-glucose. Tetrahedron Lett 2002, 43, 16, 2895.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVII) 46148 [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide C38H49BrNOPSSi 详情 详情
(XXXVIII) 54362 tert-butyl (3S,6R,7S,8S)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-9-hydroxy-4,4,6,8-tetramethyl-5-oxononanoate C29H60O6Si2 详情 详情
(XXXIX) 54363 tert-butyl (3S,6R,7S,8R)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8-tetramethyl-5,9-dioxononanoate C29H58O6Si2 详情 详情
(XL) 54364 tert-butyl (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7,15-tris{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoate C49H91NO6SSi3 详情 详情
(XLI) 46158 (3S,6R,7S,8S,9Z,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-9,12,16-heptadecatrienoic acid C39H69NO6SSi2 详情 详情
(XLII) 46159 (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-10,13-cyclohexadecadiene-2,6-dione C39H67NO5SSi2 详情 详情
(XLIII) 46160 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-10,13-cyclohexadecadiene-2,6-dione C27H39NO5S 详情 详情
Extended Information