(3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid -Drug Synthesis Database

【结构式】

【分子编号】44453

【品名】(3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid

【CA登记号】

【分子式】C₂₃H₄₄O₅Si

【分子量】428.68486

【元素组成】C 64.44% H 10.35% O 18.66% Si 6.55%

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：(VIII)

The synthesis of intermediate tridecenoic acid (VIII) has been performed as follows: The reaction of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether gives the chiral beta-hydroxy ketone (III), which is protected with Tbdms-OTf, yielding the silyl ether (IV). The ozonolysis of the double bond of (IV) affords the aldehyde (V), which is oxidized with NaClO2 to the carboxylic acid (VI). Finally, this compound is condensed with 2(S)-methyl-6-heptenal (VII) by means of LDA in THF to provide the intermediate tridecenoic acid (VIII).

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960.
【2】 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	分子式	供应商	用于合成
(I)	44448	2,2-dimethyl-3-oxopentanal	C₇H₁₂O₂	详情	详情
(II)	44449	allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane	C₂₃H₃₉B	详情	详情
(III)	44450	(5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one	C₁₀H₁₈O₂	详情	详情
(IV)	44451	(5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one	C₁₆H₃₂O₂Si	详情	详情
(V)	44452	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal	C₁₅H₃₀O₃Si	详情	详情
(VI)	43166	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid	C₁₅H₃₀O₄Si	详情	详情
(VII)	27185	(2S)-2-methyl-6-heptenal	C₈H₁₄O	详情	详情
(VIII)	44453	(3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid	C₂₃H₄₄O₅Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (IX) with DIBAL in dichloromethane gives the corresponding aldehyde (X), which is condensed with the phosphorane (XI) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XII). The alkylation of (XII) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether affords the chiral secondary alcohol (XIII) (1), which is esterified with the intermediate tridecenoic acid (VIII) by means of EDC and DMAP in dichloromethane to provide the ester (XIV). Ring-closing metathesis of (XIV) catalyzed by a Ru catalyst gives the macrolactone (XV), which is desilylated by means of TFA in dichloromethane, yielding the dihydroxymacrolactone (XVI). Finally, the double bond of (XVI) is epoxidized by means of dimethyldioxirane (DMDO) or MCPBA in chloroform.

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	44449	allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane		C₂₃H₃₉B	详情	详情
(VIII)	44453	(3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid		C₂₃H₄₄O₅Si	详情	详情
(IX)	44454	ethyl 2-methyl-1,3-thiazole-4-carboxylate	6436-59-5	C₇H₉NO₂S	详情	详情
(X)	44455	2-methyl-1,3-thiazole-4-carbaldehyde		C₅H₅NOS	详情	详情
(XI)	39940	2-(triphenylphosphoranylidene)propanal		C₂₁H₁₉OP	详情	详情
(XII)	44456	(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal		C₈H₉NOS	详情	详情
(XIII)	43171	(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol		C₁₁H₁₅NOS	详情	详情
(XIV)	44457	(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate		C₃₄H₅₇NO₅SSi	详情	详情
(XV)	43176	(4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione		C₃₂H₅₃NO₅SSi	详情	详情
(XVI)	44447	(4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione		C₂₆H₃₉NO₅S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960.
【2】 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	分子式	供应商	用于合成
(I)	44448	2,2-dimethyl-3-oxopentanal	C₇H₁₂O₂	详情	详情
(II)	44449	allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane	C₂₃H₃₉B	详情	详情
(III)	44450	(5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one	C₁₀H₁₈O₂	详情	详情
(IV)	44451	(5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one	C₁₆H₃₂O₂Si	详情	详情
(V)	44452	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal	C₁₅H₃₀O₃Si	详情	详情
(VI)	43166	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid	C₁₅H₃₀O₄Si	详情	详情
(VII)	27185	(2S)-2-methyl-6-heptenal	C₈H₁₄O	详情	详情
(VIII)	44453	(3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid	C₂₃H₄₄O₅Si	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VIII)

The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (IX) with DIBAL in dichloromethane gives the corresponding aldehyde (X), which is condensed with the phosphorane (XI) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XII). The alkylation of (XII) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether affords the chiral secondary alcohol (XIII) (1), which is esterified with the intermediate tridecenoic acid (VIII) by means of EDC and DMAP in dichloromethane to provide the ester (XIV). Ring-closing metathesis of (XIV) catalyzed by a Ru catalyst gives the macrolactone (XV), which is finally desilylated by means of TFA in dichloromethane, yielding the target epothilone C.

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	44449	allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane		C₂₃H₃₉B	详情	详情
(VIII)	44453	(3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid		C₂₃H₄₄O₅Si	详情	详情
(IX)	44454	ethyl 2-methyl-1,3-thiazole-4-carboxylate	6436-59-5	C₇H₉NO₂S	详情	详情
(X)	44455	2-methyl-1,3-thiazole-4-carbaldehyde		C₅H₅NOS	详情	详情
(XI)	39940	2-(triphenylphosphoranylidene)propanal		C₂₁H₁₉OP	详情	详情
(XII)	44456	(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal		C₈H₉NOS	详情	详情
(XIII)	43171	(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol		C₁₁H₁₅NOS	详情	详情
(XIV)	44457	(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate		C₃₄H₅₇NO₅SSi	详情	详情
(XV)	43176	(4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione		C₃₂H₅₃NO₅SSi	详情	详情

Extended Information