(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexanal -Drug Synthesis Database

【结构式】

【分子编号】43163

【品名】(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexanal

【CA登记号】

【分子式】C₁₃H₂₈O₂Si

【分子量】244.44962

【元素组成】C 63.88% H 11.55% O 13.09% Si 11.49%

与该中间体有关的原料药合成路线共 6 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5 合成路线6

合成路线1

该中间体在本合成路线中的序号：(V)

Butane-1,4-diol (II) is anchored to chloromethyl-RESIN (I) by means of tetrabutylammonium iodide and NaH in DMF, and without isolation is treated with PPh3 I2 and imidazole to yield the phosphonium salt (III), which is treated with NaHMDS in THF/DMSO, affording the phosphorane (IV). The condensation of (IV) with the chiral aldehyde (V) in THF provides the anchored olefin (VI), which is desilylated with HF in pyridine/THF. The resulting alcohol is submitted to a Swern oxidation to give the anchored aldehyde (VII). The condensation of (VII) with the ketoacid (VIII) by means of LDA and ZnCl2 in THF yields the adduct (IX) as a diastereomeric mixture. The esterification of carboxylic acid (IX) with the alcohol (X) by means of DCC and DMAP affords the corresponding ester (XI), which is submitted to a macrocyclic ring-closing metathesis catalyzed by a ruthenium catalyst providing, after chromatographic separation of isomers, the macrocyclic lactone (XII). The desilylation of (XII) by means of TFA in dichloromethane gives the precursor (XIII), which is finally epoxidated with methyl(trifluoromethyl)dioxirane (XI) to yield the target epothilone A.

参考文献中间体

合成目标

【1】 Park, K.-H.; Kurth, M.J.; Cyclo-elimination release strategies applied to solid-phase organic synthesis in drug discovery. Drugs Fut 2000, 25, 12, 1265.
【2】 Nicolaou, K.C.; et al.; Synthesis of epothilones A and B in solid and solution phase. Nature 1997, 387, 6630, 268.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IXa)	43167	(3S,6S,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid		C₂₇H₅₂O₆Si	详情	详情
(IXb)	43168	(3S,6R,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid		C₂₇H₅₂O₆Si	详情	详情
(IXc)	43169	(3S,6R,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid		C₂₇H₅₂O₆Si	详情	详情
(IXd)	43170	(3S,6S,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid		C₂₇H₅₂O₆Si	详情	详情
(XIa)	43172	(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6S,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate		C₃₈H₆₅NO₆SSi	详情	详情
(XIb)	43173	(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6S,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate		C₃₈H₆₅NO₆SSi	详情	详情
(XIc)	43174	(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate		C₃₈H₆₅NO₆SSi	详情	详情
(XId)	43175	(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate		C₃₈H₆₅NO₆SSi	详情	详情
(II)	43160	1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol	110-63-4	C₄H₁₀O₂	详情	详情
(III)	43161	(4-methoxybutyl)(triphenyl)phosphonium iodide		C₂₃H₂₆IOP	详情	详情
(IV)	43162	(4-methoxybutylidene)(triphenyl)phosphorane; methyl 4-(triphenylphosphoranylidene)butyl ether		C₂₃H₂₅OP	详情	详情
(V)	43163	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexanal		C₁₃H₂₈O₂Si	详情	详情
(VI)	43164	tert-butyl(dimethyl)silyl (2S,6Z)-10-methoxy-2-methyl-6-decenyl ether; tert-butyl[[(2S,6Z)-10-methoxy-2-methyl-6-decenyl]oxy]dimethylsilane		C₁₈H₃₈O₂Si	详情	详情
(VII)	43165	(2S,6Z)-10-methoxy-2-methyl-6-decenal		C₁₂H₂₂O₂	详情	详情
(VIII)	43166	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid		C₁₅H₃₀O₄Si	详情	详情
(X)	43171	(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol		C₁₁H₁₅NOS	详情	详情
(XII)	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
(XIII)	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
(XIV)	43177	3-methyl-3-(trifluoromethyl)-1,2-dioxirane		C₃H₃F₃O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXIV)

Assembly of the final product: The condensation of SAMP hydrazone (XVII) with 4-(benzyloxy)butyl iodide (XVIII) by means of LDA in THF gives the chiral 2-methylhexanal hydrazone (XIX), which is ozonolyzed in dichloromethane, yielding the free aldehyde (XX). The reduction of (XX) with NaBH4 in methanol affords the corresponding alcohol (XXI), which is protected with Tbdms-Cl and TEA in dichloromethane, providing the silyl ether (XXII). The hydrogenolysis of (XXII) with H2 over Pd/C in THF furnishes the alcohol (XXIII), which is oxidized to the aldehyde (XXIV) with oxalyl chloride, DMSO and TEA in dichloromethane. The condensation of aldehyde (XXIV) with the intermediate phosphonium salt (XVI) by means of NaHMDS in THF gives the silylated diol (XXV), which is selectively monodesilylated with CSA in dichloromethane/methanol to yield the primary alcohol (XXVI). The oxidation of (XXVI) with SO3/pyridine, DMSO and TEA in dichloromethane affords the corresponding aldehyde (XXVII), which is condensed with the oxoacid intermediate (VI) by means of LDA in THF to provide the linear heptadecadienoic acid (XXVIII) as a diastereomeric mixture.

参考文献中间体

合成目标

【1】 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
(VI)	43166	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid	C₁₅H₃₀O₄Si	详情	详情
(XVI)	44459	[(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide	C₃₄H₄₃INOPSSi	详情	详情
(XVII)	44460	N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine	C₈H₁₆N₂O	详情	详情
(XVIII)	44461	benzyl 4-iodobutyl ether; 1-[(4-iodobutoxy)methyl]benzene	C₁₁H₁₅IO	详情	详情
(XIX)	44462	N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine; (2R)-N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-2-methoxy-1-pyrrolidinamine	C₁₉H₃₀N₂O₂	详情	详情
(XX)	44463	(2S)-6-(benzyloxy)-2-methylhexanal	C₁₄H₂₀O₂	详情	详情
(XXI)	44464	(2S)-6-(benzyloxy)-2-methyl-1-hexanol	C₁₄H₂₂O₂	详情	详情
(XXII)	44465	benzyl (5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexyl ether; [[(2S)-6-(benzyloxy)-2-methylhexyl]oxy](tert-butyl)dimethylsilane	C₂₀H₃₆O₂Si	详情	详情
(XXIII)	44466	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-1-hexanol	C₁₃H₃₀O₂Si	详情	详情
(XXIV)	43163	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexanal	C₁₃H₂₈O₂Si	详情	详情
(XXV)	44467	4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienyl ether	C₂₉H₅₅NO₂SSi₂	详情	详情
(XXVI)	44468	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol	C₂₃H₄₁NO₂SSi	详情	详情
(XXVII)	44469	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal	C₂₃H₃₉NO₂SSi	详情	详情
(XXVIII)	44470	(3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid	C₃₈H₆₉NO₆SSi₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXIV)

Assembly of the final product: The condensation of SAMP hydrazone (XVII) with 4-(benzyloxy)butyl iodide (XVIII) by means of LDA in THF gives the chiral 2-methylhexanal hydrazone (XIX), which is ozonolyzed in dichloromethane, yielding the free aldehyde (XX). The reduction of (XX) with NaBH4 in methanol affords the corresponding alcohol (XXI), which is protected with Tbdms-Cl and TEA in dichloromethane, providing the silyl ether (XXII). The hydrogenolysis of (XXII) with H2 over Pd/C in THF furnishes the alcohol (XXIII), which is oxidized to the aldehyde (XXIV) with oxalyl chloride, DMSO and TEA in dichloromethane. The methylation of aldehyde (XXIV) with Me-MgBr in THF gives the secondary alcohol (XXV), which is oxidized with tetrapropylammonium perruthenate (TPAP) in dichloromethane, yielding the methyl ketone (XXVI). The condensation of ketone (XXVI) with the intermediate phosphonium salt (XVI) by means of NaHMDS in THF gives the silylated diol (XXVII), which is selectively monodesilylated with CSA in dichloromethane/methanol to yield the primary alcohol (XXVIII). The oxidation of (XXVIII) with SO3/pyridine, DMSO and TEA in dichloromethane affords the corresponding aldehyde (XXIX), which is condensed with the oxoacid intermediate (VI) by means of LDA in THF to provide the linear heptadecadienoic acid (XXX) as a diastereomeric mixture that is separated at the carboxylic acid (XXXII) step.

参考文献中间体

合成目标

【1】 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
(VI)	43166	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid	C₁₅H₃₀O₄Si	详情	详情
(XVI)	44459	[(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide	C₃₄H₄₃INOPSSi	详情	详情
(XVII)	44460	N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine	C₈H₁₆N₂O	详情	详情
(XVIII)	44461	benzyl 4-iodobutyl ether; 1-[(4-iodobutoxy)methyl]benzene	C₁₁H₁₅IO	详情	详情
(XIX)	44462	N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine; (2R)-N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-2-methoxy-1-pyrrolidinamine	C₁₉H₃₀N₂O₂	详情	详情
(XX)	44463	(2S)-6-(benzyloxy)-2-methylhexanal	C₁₄H₂₀O₂	详情	详情
(XXI)	44464	(2S)-6-(benzyloxy)-2-methyl-1-hexanol	C₁₄H₂₂O₂	详情	详情
(XXII)	44465	benzyl (5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexyl ether; [[(2S)-6-(benzyloxy)-2-methylhexyl]oxy](tert-butyl)dimethylsilane	C₂₀H₃₆O₂Si	详情	详情
(XXIII)	44466	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-1-hexanol	C₁₃H₃₀O₂Si	详情	详情
(XXIV)	43163	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexanal	C₁₃H₂₈O₂Si	详情	详情
(XXV)	46120	(6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2-heptanol	C₁₄H₃₂O₂Si	详情	详情
(XXVI)	46121	(6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2-heptanone	C₁₄H₃₀O₂Si	详情	详情
(XXVII)	40827	tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole	C₃₀H₅₇NO₂SSi₂	详情	详情
(XXVIII)	40828	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol	C₂₄H₄₃NO₂SSi	详情	详情
(XXIX)	40829	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal	C₂₄H₄₁NO₂SSi	详情	详情
(XXX)	46118	(3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-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

合成路线4

该中间体在本合成路线中的序号：(XXIV)

参考文献中间体

合成目标

【1】 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
(VI)	43166	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid	C₁₅H₃₀O₄Si	详情	详情
(XVI)	44459	[(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide	C₃₄H₄₃INOPSSi	详情	详情
(XVII)	44460	N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine	C₈H₁₆N₂O	详情	详情
(XVIII)	44461	benzyl 4-iodobutyl ether; 1-[(4-iodobutoxy)methyl]benzene	C₁₁H₁₅IO	详情	详情
(XIX)	44462	N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine; (2R)-N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-2-methoxy-1-pyrrolidinamine	C₁₉H₃₀N₂O₂	详情	详情
(XX)	44463	(2S)-6-(benzyloxy)-2-methylhexanal	C₁₄H₂₀O₂	详情	详情
(XXI)	44464	(2S)-6-(benzyloxy)-2-methyl-1-hexanol	C₁₄H₂₂O₂	详情	详情
(XXII)	44465	benzyl (5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexyl ether; [[(2S)-6-(benzyloxy)-2-methylhexyl]oxy](tert-butyl)dimethylsilane	C₂₀H₃₆O₂Si	详情	详情
(XXIII)	44466	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-1-hexanol	C₁₃H₃₀O₂Si	详情	详情
(XXIV)	43163	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexanal	C₁₃H₂₈O₂Si	详情	详情
(XXV)	46120	(6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2-heptanol	C₁₄H₃₂O₂Si	详情	详情
(XXVI)	46121	(6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2-heptanone	C₁₄H₃₀O₂Si	详情	详情
(XXVII)	40827	tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole	C₃₀H₅₇NO₂SSi₂	详情	详情
(XXVIII)	40828	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol	C₂₄H₄₃NO₂SSi	详情	详情
(XXIX)	40829	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal	C₂₄H₄₁NO₂SSi	详情	详情
(XXX)	46118	(3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-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

合成路线5

该中间体在本合成路线中的序号：(XXIV)

参考文献中间体

合成目标

【1】 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
(VI)	43166	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid	C₁₅H₃₀O₄Si	详情	详情
(XVI)	44459	[(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide	C₃₄H₄₃INOPSSi	详情	详情
(XVII)	44460	N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine	C₈H₁₆N₂O	详情	详情
(XVIII)	44461	benzyl 4-iodobutyl ether; 1-[(4-iodobutoxy)methyl]benzene	C₁₁H₁₅IO	详情	详情
(XIX)	44462	N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine; (2R)-N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-2-methoxy-1-pyrrolidinamine	C₁₉H₃₀N₂O₂	详情	详情
(XX)	44463	(2S)-6-(benzyloxy)-2-methylhexanal	C₁₄H₂₀O₂	详情	详情
(XXI)	44464	(2S)-6-(benzyloxy)-2-methyl-1-hexanol	C₁₄H₂₂O₂	详情	详情
(XXII)	44465	benzyl (5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexyl ether; [[(2S)-6-(benzyloxy)-2-methylhexyl]oxy](tert-butyl)dimethylsilane	C₂₀H₃₆O₂Si	详情	详情
(XXIII)	44466	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-1-hexanol	C₁₃H₃₀O₂Si	详情	详情
(XXIV)	43163	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexanal	C₁₃H₂₈O₂Si	详情	详情
(XXV)	44467	4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienyl ether	C₂₉H₅₅NO₂SSi₂	详情	详情
(XXVI)	44468	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol	C₂₃H₄₁NO₂SSi	详情	详情
(XXVII)	44469	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal	C₂₃H₃₉NO₂SSi	详情	详情
(XXVIII)	44470	(3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid	C₃₈H₆₉NO₆SSi₂	详情	详情

合成路线6

该中间体在本合成路线中的序号：(V)

Butane-1,4-diol (II) is anchored to chloromethyl-RESIN (I) by means of tetrabutylammonium iodide and NaH in DMF, and without isolation is treated with PPh3 I2 and imidazole to yield the phosphonium salt (III), which is treated with NaHMDS in THF/DMSO, affording the phosphorane (IV). The condensation of (IV) with the chiral aldehyde (V) in THF provides the anchored olefin (VI), which is desilylated with HF in pyridine/THF. The resulting alcohol is submitted to a Swern oxidation to give the anchored aldehyde (VII). The condensation of (VII) with the ketoacid (VIII) by means of LDA and ZnCl2 in THF yields the adduct (IX) as a diastereomeric mixture. The esterification of carboxylic acid (IX) with the alcohol (X) by means of DCC and DMAP affords the corresponding ester (XI), which is submitted to a macrocyclic ring-closing metathesis catalyzed by a ruthenium catalyst providing, after chromatographic separation of isomers, the macrocyclic lactone (XII). Compound (XII) is finally desilylated by means of TFA in dichloromethane to give the target epothilone C.

参考文献中间体

合成目标

【1】 Park, K.-H.; Kurth, M.J.; Cyclo-elimination release strategies applied to solid-phase organic synthesis in drug discovery. Drugs Fut 2000, 25, 12, 1265.
【2】 Nicolaou, K.C.; et al.; Synthesis of epothilones A and B in solid and solution phase. Nature 1997, 387, 6630, 268.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IXa)	43167	(3S,6S,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid		C₂₇H₅₂O₆Si	详情	详情
(IXb)	43168	(3S,6R,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid		C₂₇H₅₂O₆Si	详情	详情
(IXc)	43169	(3S,6R,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid		C₂₇H₅₂O₆Si	详情	详情
(IXd)	43170	(3S,6S,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoic acid		C₂₇H₅₂O₆Si	详情	详情
(XIa)	43172	(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6S,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate		C₃₈H₆₅NO₆SSi	详情	详情
(XIb)	43173	(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6S,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate		C₃₈H₆₅NO₆SSi	详情	详情
(XIc)	43174	(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7R,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate		C₃₈H₆₅NO₆SSi	详情	详情
(XId)	43175	(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S,12Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-16-methoxy-4,4,6,8-tetramethyl-5-oxo-12-hexadecenoate		C₃₈H₆₅NO₆SSi	详情	详情
(II)	43160	1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol	110-63-4	C₄H₁₀O₂	详情	详情
(III)	43161	(4-methoxybutyl)(triphenyl)phosphonium iodide		C₂₃H₂₆IOP	详情	详情
(IV)	43162	(4-methoxybutylidene)(triphenyl)phosphorane; methyl 4-(triphenylphosphoranylidene)butyl ether		C₂₃H₂₅OP	详情	详情
(V)	43163	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexanal		C₁₃H₂₈O₂Si	详情	详情
(VI)	43164	tert-butyl(dimethyl)silyl (2S,6Z)-10-methoxy-2-methyl-6-decenyl ether; tert-butyl[[(2S,6Z)-10-methoxy-2-methyl-6-decenyl]oxy]dimethylsilane		C₁₈H₃₈O₂Si	详情	详情
(VII)	43165	(2S,6Z)-10-methoxy-2-methyl-6-decenal		C₁₂H₂₂O₂	详情	详情
(VIII)	43166	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid		C₁₅H₃₀O₄Si	详情	详情
(X)	43171	(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol		C₁₁H₁₅NOS	详情	详情
(XII)	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