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【结 构 式】

【药物名称】(-)-Epothilone A, Epothilone A

【化学名称】(4S,7R,8S,9S,13R,14S,16S)-13,14-Epoxy-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(methylthiazol-4-yl)vinyl]-1-oxacyclohexadecane-2,6-dione
　　　　　　(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[(E)-1-methyl-2-(2-methyl-4-thiazolyl)vinyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

【CA登记号】152044-53-6

【 分 子 式 】C26H39NO6S

【 分 子 量 】493.66783

【开发单位】GBF (Originator), Bristol-Myers Squibb (Licensee)

【药理作用】ONCOLYTIC DRUGS, Antimitotic Drugs, Epothilones, Microtubule-Stabilizing Agents

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7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23合成路线24合成路线25合成路线26合成路线27合成路线28合成路线29合成路线30合成路线31合成路线32合成路线33合成路线34合成路线35合成路线36合成路线37

合成路线1

C1-C6 fragment.- The reaction of 3-methyl-2-butenylmagnesium chloride (I) with propanal (II) gives racemic 4,4-dimethyl-5-hexen-3-ol (III), which was submitted to enzymatic resolution with ChiroCLEC-PC dry enzyme yielding the (R) enantiomer (IV). The esterification of (IV) with bromoacetyl bromide (V) and dimethylaniline yields the corresponding ester (VI), which is oxidized with O3 and trimethyl phosphite and cyclized with SmI2 in THF to afford chiral tetrahydropyran-2-one (VII). The reduction of (VII) with Red-Al, followed by cyclization with 2-methoxypropene (VIII) and PPTS yields the acetonide (IX), which is finally oxidized with N-methylmorpholine-N-oxide and PPTS in dichloromethane giving the target intermediate (X).

参考文献 中间体
【1】 Taylor, R.E.; et al.; A formal total synthesis of epothiolone A: Enantioselective preparation of the C1-C6 and C7-C12 fragments. J Org Chem 1998, 63, 25, 9580.
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) 27170 chloro(3-methyl-2-butenyl)magnesium C5H9ClMg 详情 详情
(II) 15966 propionaldehyde 123-38-6 C3H6O 详情 详情
(III) 27171 4,4-dimethyl-5-hexen-3-ol C8H16O 详情 详情
(IV) 27172 (3R)-4,4-dimethyl-5-hexen-3-ol C8H16O 详情 详情
(V) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(VI) 27173 (1R)-1-ethyl-2,2-dimethyl-3-butenyl 2-bromoacetate C10H17BrO2 详情 详情
(VII) 27174 (4S,6R)-6-ethyl-4,5,5-trimethyltetrahydro-2H-pyran-2-one C10H18O2 详情 详情
(VIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(IX) 27175 (3R)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanol C12H24O3 详情 详情
(X) 27176 2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanone C12H22O3 详情 详情

合成路线2

C7-C12 fragment.- The selective monoepoxidation of 1,7-octadiene (I) with m-chloroperbenzoic acid (MCPBA) gives the epoxide (II), which is oxidized with periodic acid to the aldehyde (III). Further oxidation of (III) by means of NaClO2 yields 6-heptenoic acid (IV), which is condensed with the lithium salt of the chiral oxazolidinone (V) by means of pivaloyl chloride affording the chiral imide (VI). The methylation of (VI) with methyl iodide and sodium hexamethyldisylazide (NaHMDS) in THF provides the methylated chiral imide (VII) as a single enantiomer. The hydrolysis of (VII) with H2O2 and LiOH gives the corresponding free acid (VIII), which is reduced with LiAlH4 to the primery alcohol (IX). Finally, (IX) is treated with Swern oxidant to afford the desired taret aldehyde (X).

参考文献 中间体
【1】 Taylor, R.E.; et al.; A formal total synthesis of epothiolone A: Enantioselective preparation of the C1-C6 and C7-C12 fragments. J Org Chem 1998, 63, 25, 9580.
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) 27177 1,7-octadiene 3710-30-3 C8H14 详情 详情
(II) 27178 2-(5-hexenyl)oxirane 19600-63-6 C8H14O 详情 详情
(III) 27179 6-heptenal C7H12O 详情 详情
(IV) 27180 6-heptenoic acid 1119-60-4 C7H12O2 详情 详情
(V) 10793 [(4S)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]lithium C10H10LiNO2 详情 详情
(VI) 27181 (4S)-4-benzyl-3-(6-heptenoyl)-1,3-oxazolidin-2-one C17H21NO3 详情 详情
(VII) 27182 (4S)-4-benzyl-3-[(2S)-2-methyl-6-heptenoyl]-1,3-oxazolidin-2-one C18H23NO3 详情 详情
(VIII) 27183 (2S)-2-methyl-6-heptenoic acid C8H14O2 详情 详情
(IX) 27184 (2S)-2-methyl-6-hepten-1-ol C8H16O 详情 详情
(X) 27185 (2S)-2-methyl-6-heptenal C8H14O 详情 详情

合成路线3

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
【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4

The synthesis of intermediate tridecenoic acid (VII) has been performed as follows: The condensation of previously reported 1,3-dioxane intermediate (I) (see intermediate (X) in scheme no. 22255601a) with 2(S)-methyl-6-heptenal (II) by means of LDA in THF gives the hydroxyundecenone (III), which is treated with pyridinium p-toluenesulfonate (PPTS) in methanol to cleave the 1,3-dioxane ring and yield the trihydroxy compound (IV). The silylation of (IV) with Tbdms-OTf and lutidine in dichloromethane affords the fully silylated compound (V), which is selectively monodesilylated with CSA to provide the primary alcohol (VI). Finally, this alcohol is oxidized by means of pyridinium dichromate (PDC) in DMF to furnish the desired tridecenoic acid intermediate (VII).

参考文献 中间体
【1】 Schinzer, D.; et al.; Total synthesis of (-)-epothilone A. Angew Chem. Int Ed Engl 1997, 36, 5, 523.
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) 27176 2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanone C12H22O3 详情 详情
(II) 27185 (2S)-2-methyl-6-heptenal C8H14O 详情 详情
(III) 44434 (4R,5S,6S)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-5-hydroxy-2,4,6-trimethyl-10-undecen-3-one C20H36O4 详情 详情
(IV) 44435 (3S,6R,7S,8S)-1,3,7-trihydroxy-4,4,6,8-tetramethyl-12-tridecen-5-one C17H32O4 详情 详情
(V) 44436 (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one C35H74O4Si3 详情 详情
(VI) 44437 (5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one C29H60O4Si2 详情 详情
(VII) 44438 (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid C29H58O5Si2 详情 详情

合成路线5

The silylation of 2-methyl-5-(tert-butyldimethylsilyloxy)-1-penten-3(s)-ol (VIII) with Tbdms-Cl and imidazole in DMF gives the disilylated compound (IX), which is treated with ozone and PPh3 in dichloromethane to yield the 2-pentanone (X). The condensation of (X) with phosphonate (XI) by means of BuLi in THF yields the fully silylated diol (XII), which is selectively monodesilylated with HF in acetonitrile to afford the primary alcohol (XIII). The oxidation of (XIII) with DMP in dichloromethane affords the aldehyde (XIV), which is methylenated with the phosphonium salt (XV) and NaNH2 in THF to provide the silylated hexadienol (XVI). The reaction of (XVI) with TBAF in THF gives the free secondary alcohol (XVII), which is esterified with the intermediate tridecenoic acid (VII) by means of DCC and DMAP in dichloromethane, yielding the ester (XVIII). Ring-closing metathesis of (XVIII), catalyzed by a Ru catalyst, affords the macrolactone (XIX), which is desilylated by means of HF in acetonitrile to furnish the dihydroxymacrolactone (XX). Finally, the double bond of (XX) is epoxidated with dimethyldioxirane (DMDO) in dichloromethane to provide the target epothilone A.

参考文献 中间体
【1】 Schinzer, D.; et al.; Total synthesis of (-)-epothilone A. Angew Chem. Int Ed Engl 1997, 36, 5, 523.
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) 44438 (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid C29H58O5Si2 详情 详情
(VIII) 44439 (3S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-penten-3-ol C12H26O2Si 详情 详情
(IX) 44440 (5S)-5-isopropenyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane; tert-butyl(dimethyl)silyl (1S)-1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-methyl-2-propenyl ether C18H40O2Si2 详情 详情
(X) 44441 (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-pentanone C17H38O3Si2 详情 详情
(XI) 44442 diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C9H16NO3PS 详情 详情
(XII) 44443 tert-butyl(dimethyl)silyl (1S,2E)-1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole C22H43NO2SSi2 详情 详情
(XIII) 40821 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol C16H29NO2SSi 详情 详情
(XIV) 40822 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal C16H27NO2SSi 详情 详情
(XV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XVI) 44444 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether C17H29NOSSi 详情 详情
(XVII) 43171 (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H15NOS 详情 详情
(XVIII) 44445 (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate C40H71NO5SSi2 详情 详情
(XIX) 44446 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C38H67NO5SSi2 详情 详情
(XX) 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6

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
【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 CAS号 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7

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
【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8

The oxoacid intermediate (VI) has been obtained as follows: The condensation of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) gives the chiral 5(S)-hydroxy-4,4-dimethyl-7-octen-3-one (III), which is protected with Tbdms-OTf, yielding the silyl ether (IV). The ozonolysis of (IV) in dichloromethane affords the aldehyde (V), which is finally oxidized with NaClO2 in tert-butanol/water to provide the target oxoacid intermediate (VI).

参考文献 中间体
【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 CAS号 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) 43162 (4-methoxybutylidene)(triphenyl)phosphorane; methyl 4-(triphenylphosphoranylidene)butyl ether C23H25OP 详情 详情

合成路线9

The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF, providing the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).

参考文献 中间体
【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 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
(VII) 44454 ethyl 2-methyl-1,3-thiazole-4-carboxylate 6436-59-5 C7H9NO2S 详情 详情
(VIII) 44455 2-methyl-1,3-thiazole-4-carbaldehyde C5H5NOS 详情 详情
(IX) 39940 2-(triphenylphosphoranylidene)propanal C21H19OP 详情 详情
(X) 44456 (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal C8H9NOS 详情 详情
(XI) 43171 (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H15NOS 详情 详情
(XII) 44444 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether C17H29NOSSi 详情 详情
(XIII) 40822 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal C16H27NO2SSi 详情 详情
(XIV) 40821 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol C16H29NO2SSi 详情 详情
(XV) 44458 tert-butyl(dimethyl)silyl (1S,2E)-1-(2-iodoethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole C16H28INOSSi 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

合成路线10

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
【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 CAS号 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11

Intermediate (XXVIII) separated at the carboxylic acid (XXX) step. The full silylation of (XXVIII) with Tbdms-OTf and lutidine in dichloromethane gives the tetrasilyloxy compound (XXIX), which is stepwise desilylated first with K2CO3 in methanol to yield the carboxylic acid (XXX), and then with TBAF in THF to afford the hydroxyacid (XXXI). The macrolactonization of (XXXI) was carried out with the Yamaguchi method using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF to yield the silylated macrolactone (XXXII), which is deprotected with TFA in dichloromethane to afford the dihydroxymacrolactone (XXXIII). Finally, the double bond of (XXXIII) is epoxidated with methyl(trifluoromethyl)dioxirane (A) in acetonitrile.

参考文献 中间体
【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 CAS号 分子式 供应商 用于合成
(A) 43177 3-methyl-3-(trifluoromethyl)-1,2-dioxirane C3H3F3O2 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
(XXIX) 44471 tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C50H97NO6SSi4 详情 详情
(XXX) 44472 (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C44H83NO6SSi3 详情 详情
(XXXI) 44473 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-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
(XXXII) 44446 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C38H67NO5SSi2 详情 详情
(XXXIII) 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

合成路线12

Synthesis of intermediate (XVI): The condensation of 3(S)-(phenyldimethylsilyl)-4(E)-hexenoic acid methyl ester (I) with 2-(tert-butyldimethylsilyloxy)acetaldehyde (II) by means of Tms-OBn, Tms-OTf and BF3/Et2O in dichloromethane gives the 3(E)-heptenoic ester (III), which is ozonolyzed with O3 and pyridine in methanol/dichloromethane to yield the aldehyde (IV). The condensation of (IV) with the silyl ketal (V) by means of TiCl4 in dichloromethane affords the partially protected trihydroxyester (VI), which is silylated with Tbdms-OTf and lutidine in dichloromethane to provide the fully protected ester (VII). Regioselective monodesilylation of (VII) by means of TBAF/HOAc in THF gives the primary alcohol (VIII), which is oxidized with oxalyl chloride to the corresponding aldehyde (IX). The condensation of (IX) with phosphorane (X) in refluxing benzene yields the octenedioic diester (XI), which is methylated with Me2CuLi and Tms-Cl in THF, affording the tetramethyl diester (XII). The two ester groups of (XII) were easily differentiated by a reduction with DIBAL in dichloromethane, providing the 8-hydroxyoctanal derivative (XIII), which was silylated with TBdms-Cl and imidazole in DMF to give the fully protected aldehyde (XIV). Finally, this compound was subjected to a Wittig olefination reaction with methyltriphenylphosphonium bromide (XV) and NaHMDS in THF to yield the desired intermediate (XVI).

参考文献 中间体
【1】 Panek, J.S.; Zhu, B.; Total synthesis of apothilone A. Org Lett 2000, 2, 17, 2575.
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) 44474 methyl (3S,4E)-3-[dimethyl(phenyl)silyl]-4-hexenoate C15H22O2Si 详情 详情
(II) 44475 2-[[tert-butyl(diphenyl)silyl]oxy]acetaldehyde C18H22O2Si 详情 详情
(III) 44476 methyl (E,5S,6R)-6-(benzyloxy)-7-[[tert-butyl(diphenyl)silyl]oxy]-5-methyl-3-heptenoate C32H40O4Si 详情 详情
(IV) 44477 (2R,3R)-3-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-2-methylbutanal C28H34O3Si 详情 详情
(V) 44478 1-Ethoxy-2-methyl-1-trimethylsiloxypropene;1-Ethoxy-2-methyl-1-(trimethylsilyloxy)propene;1-Ethoxy-2-methyl-1-(trimethylsilyl)oxy-1-propene;1-ethoxy-2-methyl-1-propenyl trimethylsilyl ether; [(1-ethoxy-2-methyl-1-propenyl)oxy](trimethyl)silane ;dimethylketene ethyl trimethylsilyl acetal 31469-16-6 C9H20O2Si 详情 详情
(VI) 44479 ethyl (3R,4S,5R)-5-(benzyloxy)-6-[[tert-butyl(diphenyl)silyl]oxy]-3-hydroxy-2,2,4-trimethylhexanoate C34H46O5Si 详情 详情
(VII) 44480 ethyl (3R,4R,5R)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-[[tert-butyl(diphenyl)silyl]oxy]-2,2,4-trimethylhexanoate C40H60O5Si2 详情 详情
(VIII) 44481 ethyl (3R,4R,5R)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-hydroxy-2,2,4-trimethylhexanoate C24H42O5Si 详情 详情
(IX) 44482 ethyl (3R,4R,5R)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4-trimethyl-6-oxohexanoate C24H40O5Si 详情 详情
(X) 14182 ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane 1099-45-2 C22H21O2P 详情 详情
(XI) 44483 diethyl (E,4S,5R,6R)-4-(benzyloxy)-6-[[tert-butyl(dimethyl)silyl]oxy]-5,7,7-trimethyl-2-octenedioate C28H46O6Si 详情 详情
(XII) 44484 diethyl (3R,4R,5S,6S)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4,6-tetramethyloctanedioate C29H50O6Si 详情 详情
(XIII) 44485 (3S,4S,5R,6R)-4-(benzyloxy)-6-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-3,5,7,7-tetramethyloctanal C25H44O4Si 详情 详情
(XIV) 44486 (3S,4S,5R,6R)-4-(benzyloxy)-6,8-bis[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyloctanal C31H58O4Si2 详情 详情
(XV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XVI) 44487 (5R)-5-[(1R,2S,3S)-2-(benzyloxy)-1,3-dimethyl-5-hexenyl]-2,2,3,3,6,6,9,9,10,10-decamethyl-4,8-dioxa-3,9-disilaundecane; benzyl (1S,2S)-1-((1R,2R)-2,4-bis[[tert-butyl(dimethyl)silyl]oxy]-1,3,3-trimethylbutyl)-2-methyl-4-pentenyl ether C32H60O3Si2 详情 详情

合成路线13

Synthesis of the thiazole intermediate (XXVI): The Grignard reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XVII) with vinylmagnesium bromide (XVIII) in THF gives the racemic secondary alcohol (XIX), which is submitted to enzymatic optical resolution with Pseudomonas AK lipase and vinyl acetate to yield the desired (S)-secondary alcohol (XX) along with the (R)-acetate, which is easily separated by chromatography. The silylation of (XX) with Tbdms-Cl and imidazole in DMF affords the silyl ether (XXI). The selective hydroboration of the terminal double bond of (XXI) with dicyclohexylborane followed by oxidation with H2O2 provided the primary alcohol (XXII), which is oxidized with DMP in dichloromethane to give the corresponding aldehyde (XXIII). The reaction of (XXIII) with the iodomethyl phosphonium salt (XXIV) by means of NaHMDS in THF yields the cis-iodovinyl compound (XXV), which is desilylated with aqueous HF in acetonitrile, affording the corresponding alcohol (XXVI). Finally, this alcohol is treated with acetic anhydride, TEA and DMAP to provide the desired thiazole intermediate (XXVII).

参考文献 中间体
【1】 Panek, J.S.; Zhu, B.; Total synthesis of apothilone A. Org Lett 2000, 2, 17, 2575.
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) 44456 (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal C8H9NOS 详情 详情
(XVIII) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(XIX) 44488 (1E)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,4-pentadien-3-ol C10H13NOS 详情 详情
(XX) 44489 (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,4-pentadien-3-ol C10H13NOS 详情 详情
(XXI) 44490 tert-butyl(dimethyl)silyl (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-vinyl-2-propenyl ether; 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,4-pentadienyl)-2-methyl-1,3-thiazole C16H27NOSSi 详情 详情
(XXII) 40821 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol C16H29NO2SSi 详情 详情
(XXIII) 40822 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal C16H27NO2SSi 详情 详情
(XXIV) 42718 (iodomethyl)(triphenyl)phosphonium iodide n/a C19H17I2P 详情 详情
(XXV) 44491 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether C17H28INOSSi 详情 详情
(XXVI) 44492 (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H14INOS 详情 详情
(XXVII) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情

合成路线14

Assembly of the target compound: The condensation of intermediates (XVI) and (XXVII) by means of 9-BBN, a Pd catalyst and Cs2CO3 in THF/DMF gives the adduct (XXVIII), which is selectively deprotected with HF/pyridine in THF, yielding the primary alcohol (XXIX). The oxidation of (XXIX) with DMP in dichloromethane affords the aldehyde (XXX), which is condensed with the silyl enol ether (XXXI) by means of TiCl4 in dichloromethane to provide the isopropyl carboxylate (XXXII). The desilylation of (XXXII) with TBAF in THF gives the dihydroxyester (XXXIII), which is selectively monosilylated with Tbdms-Cl and imidazole, yielding the hydroxyester (XXXIV). The oxidation of (XXXIV) with DMP in dichloromethane affords the ketoester (XXXV), which was submitted to a basic hydrolysis of its acetoxy and isopropyl ester groups with NaOH in refluxing methanol to furnish the hydroxyacid (XXXVI).

参考文献 中间体
【1】 Panek, J.S.; Zhu, B.; Total synthesis of apothilone A. Org Lett 2000, 2, 17, 2575.
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) 44487 (5R)-5-[(1R,2S,3S)-2-(benzyloxy)-1,3-dimethyl-5-hexenyl]-2,2,3,3,6,6,9,9,10,10-decamethyl-4,8-dioxa-3,9-disilaundecane; benzyl (1S,2S)-1-((1R,2R)-2,4-bis[[tert-butyl(dimethyl)silyl]oxy]-1,3,3-trimethylbutyl)-2-methyl-4-pentenyl ether C32H60O3Si2 详情 详情
(XXVII) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(XXVIII) 44494 (1S,3Z,8S,9S,10R,11R)-9-(benzyloxy)-11,13-bis[[tert-butyl(dimethyl)silyl]oxy]-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-tridecenyl acetate C45H77NO5SSi2 详情 详情
(XXIX) 44495 (1S,3Z,8S,9S,10R,11R)-9-(benzyloxy)-11-[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-tridecenyl acetate C39H63NO5SSi 详情 详情
(XXX) 44496 (1S,3Z,8S,9S,10R,11R)-9-(benzyloxy)-11-[[tert-butyl(dimethyl)silyl]oxy]-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-13-oxo-3-tridecenyl acetate C39H61NO5SSi 详情 详情
(XXXI) 44497 1-isopropoxyvinyl trimethylsilyl ether; [(1-isopropoxyvinyl)oxy](trimethyl)silane C8H18O2Si 详情 详情
(XXXII) 44498 isopropyl (3S,5R,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-7-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-12,16-heptadecadienoate C44H71NO7SSi 详情 详情
(XXXIII) 44499 isopropyl (3S,5R,6S,7S,8S,12Z,15S,16E)-15-(acetoxy)-7-(benzyloxy)-3,5-dihydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-12,16-heptadecadienoate C38H57NO7S 详情 详情
(XXXIV) 44500 isopropyl (3S,5R,6S,7S,8S,12Z,15S,16E)-15-(acetoxy)-7-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-12,16-heptadecadienoate C44H71NO7SSi 详情 详情
(XXXV) 44501 isopropyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-7-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C44H69NO7SSi 详情 详情
(XXXVI) 44502 (3S,6R,7S,8S,12Z,15S,16E)-7-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H61NO6SSi 详情 详情

合成路线15

The Yamaguchi macrolactonization of (XXXVI) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF gives the macrolactone (XXXVII), which is debenzylated with DDQ, yielding (XXXVIII) and desilylated with TFA to afford the dihydroxylactone (XXXIX). Finally, this compound is epoxidated by means of H2O2 and acetonitrile in methanol/water.

参考文献 中间体
【1】 Panek, J.S.; Zhu, B.; Total synthesis of apothilone A. Org Lett 2000, 2, 17, 2575.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXVI) 44502 (3S,6R,7S,8S,12Z,15S,16E)-7-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H61NO6SSi 详情 详情
(XXXVII) 44503 (4S,7R,8S,9S,16S)-8-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H59NO5SSi 详情 详情
(XXXVIII) 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
(XXXIX) 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16

Synthesis of undecenoic ester intermediate (XXI): The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, TsOH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and Me-Li in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and TsOH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).

参考文献 中间体
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
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) 12641 Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol 126-30-7 C5H12O2 详情 详情
(II) 44529 3-(benzyloxy)-2,2-dimethyl-1-propanol C12H18O2 详情 详情
(III) 44504 3-(benzyloxy)-2,2-dimethylpropanal C12H16O2 详情 详情
(IV) 33891 Methyl ethyl ketone; 2-Butanone 78-93-3 C4H8O 详情 详情
(V) 44505 (E)-7-(benzyloxy)-6,6-dimethyl-4-hepten-3-one C16H22O2 详情 详情
(VI) 44506 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone C16H22O3 详情 详情
(VII) 44507 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone O-methyloxime C17H25NO3 详情 详情
(VIII) 44508 (4R,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone O-methyloxime C18H29NO3 详情 详情
(IX) 44509 (4S,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone C17H26O3 详情 详情
(X) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XI) 44510 (4S,6S,7R)-9-(benzyloxy)-7-hydroxy-4,6,8,8-tetramethyl-1-nonen-5-one C20H30O3 详情 详情
(XII) 44511 (3R,4R,5S,6S)-1-(benzyloxy)-2,2,4,6-tetramethyl-8-nonene-3,5-diol C20H32O3 详情 详情
(XIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XIV) 44512 benzyl 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propyl ether; (4R,5S,6S)-4-[2-(benzyloxy)-1,1-dimethylethyl]-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxane C23H36O3 详情 详情
(XV) 44513 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]-1-propanol C16H30O3 详情 详情
(XVI) 44514 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propanal C16H28O3 详情 详情

合成路线17

The asymmetric catalytic aldol reaction of aldehyde (XVI) with acetophenone by means of a chiral lanthane catalyst yields a diastereomeric mixture of hydroxyketones from which the desired isomer (XVII) is isolated. The Baeyer-Villiger oxidation of (XVII) with trimethylsilyl peroxide and SnCl4 affords the phenyl ester (XVIII), which is deprotected with BCl3 in dichloromethane, giving the trihydroxyester (XIX). The selective protection of (XIX) with Tbdms-OTf and DIEA in dichloromethane yields the bis silylated compound (XX), which is finally oxidized with DMP in dichloromethane to furnish the target undecenoic ester intermediate (XXI).

参考文献 中间体
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
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) 44514 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propanal C16H28O3 详情 详情
(XVII) 44515 (3S)-3-hydroxy-4-methyl-1-phenyl-4-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]-1-pentanone C24H36O4 详情 详情
(XVIII) 44516 phenyl (3S)-3-hydroxy-4-methyl-4-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]pentanoate C24H36O5 详情 详情
(XIX) 44517 phenyl (3S,5R,6R,7S,8S)-3,5,7-trihydroxy-4,4,6,8-tetramethyl-10-undecenoate C21H32O5 详情 详情
(XX) 44518 phenyl (3S,5R,6S,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,4,6,8-tetramethyl-10-undecenoate C33H60O5Si2 详情 详情
(XXI) 44519 phenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate C33H58O5Si2 详情 详情

合成路线18

Synthesis of the thiazole intermediate (XXXIV): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII), which is esterified with methyl chloroformate (XXVIII), furnishing the carbonate (XXIX). The reduction of (XXIX) by means of Pd(OAc)2, Bu3P and ammonium formate gives the protected acetylenic compound (XXX). The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI), which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII). The desilylation of (XXXII) with HF and pyridine in THF gives the secondary alcohol (XXXIII), which is finally acetylated with Ac2O, TEA and DMAP in CH2Cl2 to yield the target thiazole intermediate (XXXIV).

参考文献 中间体
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 16299 Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium 54655-07-1 C5H9LiSi 详情 详情
(XXII) 44456 (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal C8H9NOS 详情 详情
(XXIII) 44520 (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile C9H10N2OS 详情 详情
(XXIV) 44521 ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate C11H15NO3S 详情 详情
(XXV) 44522 ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate C17H29NO3SSi 详情 详情
(XXVI) 44523 (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal C15H25NO2SSi 详情 详情
(XXVII) 44524 (4R,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1-(trimethylsilyl)-5-hexen-1-yn-3-ol C20H35NO2SSi2 详情 详情
(XXVIII) 16993 methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate 79-22-1 C2H3ClO2 详情 详情
(XXIX) 44525 (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-[2-(trimethylsilyl)ethynyl]-3-butenyl methyl carbonate C22H37NO4SSi2 详情 详情
(XXX) 44526 4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether C20H35NOSSi2 详情 详情
(XXXI) 44527 tert-butyl(dimethyl)silyl (1S,3Z)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butenyl ether; 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1,5-hexadienyl]-2-methyl-1,3-thiazole C20H37NOSSi2 详情 详情
(XXXII) 44491 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether C17H28INOSSi 详情 详情
(XXXIII) 44492 (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H14INOS 详情 详情
(XXXIV) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情

合成路线19

Assembly of the target compound: The condensation of intermediates (XXI) and (XXXIV) by means of 9-BBN, a PdCl2 catalyst and K3PO4 in hot DMF/water gives the adduct (XXXV), which is hydrolyzed with NaOH in methanol/water to yield the hydroxyacid (XXXVI). The macrolactonization of (XXXVI) by the Yamaguchi procedure using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF affords the macrolactone (XXXVII), which is desilylated with HF and pyridine in THF, furnishing the dihydroxylactone (XXXVIII). Finally, this compound is epoxidated by means of dimethyldioxirane (XXXIX) in dichloromethane.

参考文献 中间体
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXI) 44519 phenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate C33H58O5Si2 详情 详情
(XXXIV) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(XXXV) 44528 phenyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C46H75NO7SSi2 详情 详情
(XXXVI) 44473 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-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
(XXXVII) 44446 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C38H67NO5SSi2 详情 详情
(XXXVIII) 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
(XXXIX) 31501 3,3-dimethyl-1,2-dioxirane C3H6O2 详情 详情

合成路线20

Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) catalyzed by (S)(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to give the desired thiazole intermediate (IX).

参考文献 中间体
【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
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) 44455 2-methyl-1,3-thiazole-4-carbaldehyde C5H5NOS 详情 详情
(II) 39940 2-(triphenylphosphoranylidene)propanal C21H19OP 详情 详情
(III) 44456 (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal C8H9NOS 详情 详情
(IV) 40599 Allyltributyltin; Tributyl-2-propenylstannane 24850-33-7 C15H32Sn 详情 详情
(V) 43171 (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H15NOS 详情 详情
(VI) 44530 (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H17NO2S 详情 详情
(VII) 44531 (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate C12H15NO3S 详情 详情
(VIII) 44532 (iodomethylene)(triphenyl)phosphorane C19H16IP 详情 详情
(IX) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情

合成路线21

The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provide the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane, furnishing the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of KOtBu in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of TsOH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).

参考文献 中间体
【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
【2】 Bertinato, P.; Danishefsky, S.J.; Su, D.-S.; Kamenecka, T.; Meng, D.F.; Sorensen, E.J.; Savin, K.A.; Chou, T.-C.; Balog, A. (Sloan-Kettering Institute); Synthesis of epothilones, intermediates thereto, analogues and uses thereof. JP 2001507716; US 6242469; WO 9901124 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIIIa) 44545 tert-butyl(dimethyl)silyl (1S,2S,3E)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether; (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2E)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C40H58O3S2Si2 详情 详情
(XXIIIa) 44546 (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2Z)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S,3Z)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether C40H58O3S2Si2 详情 详情
(IX) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(X) 44533 (2S)-3-(benzyloxy)-2-methylpropanal C11H14O2 详情 详情
(XI) 44534 (Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl trimethylsilyl ether; ([(Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl]oxy)(trimethyl)silane C10H20O2Si 详情 详情
(XII) 44535 (2S,3R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-2,3-dihydro-4H-pyran-4-one C17H22O3 详情 详情
(XIII) 44536 (2S,3S,4R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-3,4-dihydro-2H-pyran-4-ol C17H24O3 详情 详情
(XIV) 44537 (1R,3S,4S,5R,6R)-3-[(1S)-2-(benzyloxy)-1-methylethyl]-4,6-dimethyl-2-oxabicyclo[4.1.0]heptan-5-ol C18H26O3 详情 详情
(XV) 44538 (3R,4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-3-(iodomethyl)-2-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol C19H29IO4 详情 详情
(XVI) 44539 (4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-ol C19H30O4 详情 详情
(XVII) 44540 benzyl (2S)-2-[(2S,3R,4R)-6-methoxy-3,5,5-trimethyl-4-[(triphenylsilyl)oxy]tetrahydro-2H-pyran-2-yl]propyl ether; ([(4R,5R,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-yl]oxy)(triphenyl)silane C37H44O4Si 详情 详情
(XVIII) 44541 (2S,3S,4R,5R)-1-(benzyloxy)-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-3-heptanol C39H48O3S2Si 详情 详情
(XIX) 44542 (3R,4R,5S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; benzyl (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptyl ether C45H62O3S2Si2 详情 详情
(XX) 44543 (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-1-heptanol C38H56O3S2Si2 详情 详情
(XXI) 44544 (2R,3R,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptanal C38H54O3S2Si2 详情 详情
(XXII) 39163 (methoxymethyl)(triphenyl)phosphonium chloride 4009-98-7 C20H20ClOP 详情 详情
(XXIV) 44547 (3S,4S,5R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-(1,3-dithian-2-yl)-3,5,7-trimethyl-6-[(triphenylsilyl)oxy]octanal C39H56O3S2Si2 详情 详情
(XXV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XXVI) 44548 (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether C40H58O2S2Si2 详情 详情
(XXVII) 44549 tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C39H58O4Si2 详情 详情
(XXVIII) 44550 (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate C52H75NO6SSi2 详情 详情

合成路线22

Hydrolysis of the dimethylacetal group of (XXVIII) with Ts-OH in dioxane/water yields the corresponding aldehyde (XXIX), which is submitted to an intramolecular aldolization by means of KHMDS in THF to afford a mixture of diastereomeric macrolactones (XXX) and (XXXI). The undesired isomer (XXX) was recovered, oxidized with DMP to the ketone (XXXII) and reduced again with NaBH4 to provide high yields of the desired isomer (XXXI). Selective desilylation of (XXXI) with HF/pyridine in THF gives the diol (XXXIII), which is selectively monosilylated with Tbdms-OTf and lutidine in dichloromethane, yielding the bis-silylated triol (XXXIV). The oxidation of the free OH group of (XXXIV) with DMP in dichloromethane affords the corresponding ketonic derivative (XXXV), which is deprotected with HF/pyridine in THF, providing the free dihydroxy compound (XXXVI). Finally, this compound is epoxidized by means of dimethyldioxirane (DMDO) in dichloromethane.

参考文献 中间体
【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
【2】 Bertinato, P.; Danishefsky, S.J.; Su, D.-S.; Kamenecka, T.; Meng, D.F.; Sorensen, E.J.; Savin, K.A.; Chou, T.-C.; Balog, A. (Sloan-Kettering Institute); Synthesis of epothilones, intermediates thereto, analogues and uses thereof. JP 2001507716; US 6242469; WO 9901124 .
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) 44550 (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate C52H75NO6SSi2 详情 详情
(XXIX) 44551 (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-13-oxo-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate C50H69NO5SSi2 详情 详情
(XXX) 44552 (4R,6R,7R,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-6-[(triphenylsilyl)oxy]oxa-13-cyclohexadecen-2-one C50H69NO5SSi2 详情 详情
(XXXI) 44553 (4S,6R,7R,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-6-[(triphenylsilyl)oxy]oxa-13-cyclohexadecen-2-one C50H69NO5SSi2 详情 详情
(XXXII) 44554 (6R,7R,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-6-[(triphenylsilyl)oxy]oxa-13-cyclohexadecene-2,4-dione C50H67NO5SSi2 详情 详情
(XXXIII) 44555 (4S,6R,7S,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-4,6-dihydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecen-2-one C32H55NO5SSi 详情 详情
(XXXIV) 44556 (4S,6R,7S,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-6-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecen-2-one C38H69NO5SSi2 详情 详情
(XXXV) 44446 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C38H67NO5SSi2 详情 详情
(XXXVI) 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23

Alternatively, the hydrolysis of the intermediate dimethylacetal (XXVII) with TsOH in dioxane/water gives the aldehyde (XXXVII), which is condensed with tert-butyl acetate (XXXVIII) by means of LDA in THF, yielding the hydroxyester (XXXIX). The desilylation of (XXXIX) with HF/pyridine in THF affords the trihydroxy compound (XL), which is selectively resilylated with Tbdms-OTf and lutidine, providing the bis-silylated compound (XLI). The oxidation of the free OH group of (XLI) with DMP in dichloromethane gives the ketonic compound (XLII), which is treated with Tbdms-OTf and lutidine in dichloromethane to furnish the silyl ester (XLIII). The condensation of (XLIII) with the thiazole intermediate (IX) as before gives the adduct (XLIV), which is hydrolyzed by means of K2CO3 in methanol/water, yielding the hydroxyacid (XLV). The intramolecular lactonization of (XLV) by means of 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in toluene affords the previously reported macrolactone (XXXV), which is desilylated with HF/pyridine to (XXXVI) and finally epoxidated with DMDO in dichloromethane.

参考文献 中间体
【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(XXVII) 44549 tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C39H58O4Si2 详情 详情
(XXXV) 44446 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C38H67NO5SSi2 详情 详情
(XXXVI) 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
(XXXVII) 44557 (3R,4R,5S,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4,6-tetramethyl-3-[(triphenylsilyl)oxy]-8-nonenal C37H52O3Si2 详情 详情
(XXXVIII) 15397 tert-butyl acetate 540-88-5 C6H12O2 详情 详情
(XXXIX) 44558 tert-butyl (3S,5R,6R,7S,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-4,4,6,8-tetramethyl-5-[(triphenylsilyl)oxy]-10-undecenoate C43H64O5Si2 详情 详情
(XL) 44559 tert-butyl (3S,5R,6R,7S,8S)-3,5,7-trihydroxy-4,4,6,8-tetramethyl-10-undecenoate C19H36O5 详情 详情
(XLI) 44560 tert-butyl (3S,5R,6S,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,4,6,8-tetramethyl-10-undecenoate C31H64O5Si2 详情 详情
(XLII) 44561 tert-butyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate C31H62O5Si2 详情 详情
(XLIII) 44562 tert-butyl(dimethyl)silyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate C33H68O5Si3 详情 详情
(XLIV) 44563 tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C46H85NO7SSi3 详情 详情
(XLV) 44473 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-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24

The reaction of (R)-glycidol (XLVI) with dihydropyran (DHP) and PPTS in dichloromethane gives the protected glycidol (XLVII), which is treated with the lithium acetylide (XLVIII) and BF3/Et2O in THF to yield the acetylenic alcohol (IL). The protection of the OH group of (IL) with Mem-Cl and DIEA in hot dichloroethane affords compound (L), which is treated with PPTS in methanol to provide the primary alcohol (LI). The oxidation of (LI) with oxalyl chloride in DMSO/dichloromethane gives the corresponding aldehyde (LII), which is treated with Me-MgBr in ethyl ether to yield the secondary alcohol (LIII). The oxidation of (LIII) with TPAP and NMO in dichloromethane affords the methyl ketone (LIV), which is condensed with the phosphine oxide (LV) by means of BuLi in THF, providing the adduct (LVI). The reaction of (LVI) with N-iodosuccinimide (NIS) and Cy2BH in ethyl ether gives the iodovinyl compound (LVII), which is treated with acetic anhydride, yielding the intermediate (IX).

参考文献 中间体
【1】 Bertinato, P.; Danishefsky, S.J.; Su, D.-S.; Kamenecka, T.; Meng, D.F.; Sorensen, E.J.; Savin, K.A.; Chou, T.-C.; Balog, A. (Sloan-Kettering Institute); Synthesis of epothilones, intermediates thereto, analogues and uses thereof. JP 2001507716; US 6242469; WO 9901124 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IL) 46994 (2S)-1-(tetrahydro-2H-pyran-2-yloxy)-5-(trimethylsilyl)-4-pentyn-2-ol C13H24O3Si 详情 详情
(IX) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(XLVI) 16260 (R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol 57044-25-4 C3H6O2 详情 详情
(XLVII) 46993 (2S)oxiranylmethyl tetrahydro-2H-pyran-2-yl ether; 2-[(2S)oxiranylmethoxy]tetrahydro-2H-pyran C8H14O3 详情 详情
(XLVIII) 16299 Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium 54655-07-1 C5H9LiSi 详情 详情
(L) 46995 (2S)-2-(methoxymethoxy)-5-(trimethylsilyl)-4-pentynyl tetrahydro-2H-pyran-2-yl ether; [(4S)-4-(methoxymethoxy)-5-(tetrahydro-2H-pyran-2-yloxy)-1-pentynyl](trimethyl)silane C15H28O4Si 详情 详情
(LI) 46996 (2S)-2-(methoxymethoxy)-5-(trimethylsilyl)-4-pentyn-1-ol C10H20O3Si 详情 详情
(LII) 46997 (2S)-2-(methoxymethoxy)-5-(trimethylsilyl)-4-pentynal C10H18O3Si 详情 详情
(LIII) 46998 (3S)-3-(methoxymethoxy)-6-(trimethylsilyl)-5-hexyn-2-ol C11H22O3Si 详情 详情
(LIV) 46999 (3S)-3-(methoxymethoxy)-6-(trimethylsilyl)-5-hexyn-2-one C11H20O3Si 详情 详情
(LV) 47000 (2-methyl-1,3-thiazol-4-yl)methyl(diphenyl)phosphine oxide; 4-[(diphenylphosphoryl)methyl]-2-methyl-1,3-thiazole C17H16NOPS 详情 详情
(LVI) 47001 4-[(E,3S)-3-(methoxymethoxy)-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; methoxymethyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether C16H25NO2SSi 详情 详情
(LVII) 47002 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl methoxymethyl ether; 4-[(1E,3S,5Z)-6-iodo-3-(methoxymethoxy)-2-methyl-1,5-hexadienyl]-2-methyl-1,3-thiazole C13H18INO2S 详情 详情

合成路线25

The intermediate carboxylic acid (XVIII) has been obtained as follows: The aldol condensation of 4-methoxy-alpha-methyl-cinnamaldehyde (I) with the enol ether of 3-pentanone (II) gives the racemic aldol (rac)-(III), which is submitted to an enantioselective retroaldol reaction catalyzed by antibody 38C2, yielding the chiral aldol (3R,4R)-(IV). The reduction of the double bond of (IV) with H2 over Rh/Al2O3 in THF affords the saturated hydroxyketone (V), which is treated with Tbdms-Cl and imidazole to provide the silyl ether (VI). The methylation of (VI) with methyl iodide and LDA in THF gives the isopropyl ketone (VII), which is condensed with aldehyde (VIII) by means of LDA in THF to yield the aldol (IX). The reaction of (IX) with Tbdms-Cl and imidazole affords the tris-silyl ether (X), which is oxidized at the aromatic ring by means of RuCl3 and NaIO4 to provide the aldehyde (XI).

参考文献 中间体
【1】 Sinha, S.C.; Barbas, C.F. III; Lerner, R.A.; The antibody catalysis route to the total synthesis of epothilones. Proc Natl Acad Sci USA 1998, 95, 25, 14603.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(rac)-(III) 45542 (rac)-(4R*,5R*,6E)-5-hydroxy-7-(4-methoxyphenyl)-4,6-dimethyl-6-hepten-3-one 2592-19-0 C16H22O3 详情 详情
(3R, 4R)-(IV) 55588 (4R,5R,6E)-5-hydroxy-7-(4-methoxyphenyl)-4,6-dimethyl-6-hepten-3-one C16H22O3 详情 详情
(I) 45540 (E)-3-(4-methoxyphenyl)-2-methyl-2-propenoic acid C11H12O3 详情 详情
(II) 45541 (E)-1-ethyl-1-propenyl dibutylborinate C13H27BO 详情 详情
(V) 45543 (4R,5S,6S)-5-hydroxy-7-(4-methoxyphenyl)-4,6-dimethyl-3-heptanone 71-44-3 C16H24O3 详情 详情
(VI) 45544 (4R,5S,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-(4-methoxyphenyl)-4,6-dimethyl-3-heptanone C22H38O3Si 详情 详情
(VII) 45545 (4R,5S,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-(4-methoxyphenyl)-2,4,6-trimethyl-3-heptanone C23H40O3Si 详情 详情
(VIII) 45546 3-[[tert-butyl(dimethyl)silyl]oxy]propanal 570-24-1 C9H20O2Si 详情 详情
(IX) 45547 (5S,6R,9S)-9-hydroxy-5-[(1S)-2-(4-methoxyphenyl)-1-methylethyl]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disilapentadecan-7-one 18063-02-0 C32H60O5Si2 详情 详情
(X) 45548 (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-[(1S)-2-(4-methoxyphenyl)-1-methylethyl]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disilapentadecan-7-one C38H74O5Si3 详情 详情
(XI) 45549 (3S,4S,5R,8S)-4,8,10-tris[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyl-6-oxodecanal C32H68O5Si3 详情 详情

合成路线26

The condensation of (XI) with phosphonate (XII) by means of NaH in THF furnishes the unsaturated ester (XIII). The reduction of the double bond of (XIII) with H2 over Rh/Al2O3, followed by reduction of the ester group with DIBAL and oxidation of the resulting alcohol with DMP, gives rise to the aldehyde (XIV). The Wittig condensation of (XIV) with phosphonium salt (XV) by means of BuLi in THF yields the terminal olefin (XVI), which is selectively desilylated with Ts-OH to afford the primary alcohol (XVII). Finally, this compound is oxidized to the target carboxylic acid intermediate (XVIII) with DMP and NaClO2 in dichloromethane/THF.

参考文献 中间体
【1】 Sinha, S.C.; Barbas, C.F. III; Lerner, R.A.; The antibody catalysis route to the total synthesis of epothilones. Proc Natl Acad Sci USA 1998, 95, 25, 14603.
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) 45549 (3S,4S,5R,8S)-4,8,10-tris[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyl-6-oxodecanal C32H68O5Si3 详情 详情
(XII) 35909 ethyl 3-(diethoxyphosphoryl)propanoate 3699-67-0 C9H19O5P 详情 详情
(XIII) 45550 ethyl (E,5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxo-2-dodecenoate 2463-77-6 C36H74O6Si3 详情 详情
(XIV) 45551 (5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxododecanal 94-59-7 C34H72O5Si3 详情 详情
(XV) 13484 Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide 2065-66-9 C19H18IP 详情 详情
(XVI) 44436 (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one C35H74O4Si3 详情 详情
(XVII) 44437 (5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one C29H60O4Si2 详情 详情
(XVIII) 44438 (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid C29H58O5Si2 详情 详情

合成路线27

The aldol condensation of 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XIX) with acetone (XX) catalyzed by antibody 38C2 gives the chiral aldol (XXI), which is protected with Tbdms-Cl and imidazole, yielding the silyl ether (XXII). The reaction of (XXII) with Tbdms-OTf, followed by oxidation with MCPBA and reduction with NaBH4, affords the vicinal diol (XXIII), which is cleaved with Pb(OAc)4 to provide the aldehyde (XXIV). The Wittig condensation of (XXIV) with phosphonium salt (XV) gives olefinic silyl ether (XXV), which is desilylated with TBAF in THF to yield the homoallylic alcohol (XXVI). The esterification of alcohol (XXVI) with the previously described carboxylic acid (XVIII) by means of EDC in dichloromethane affords the ester (XXVII), which is submitted to a ring-closing metathesis by means of Grubb's catalyst to provide the macrolactone (XXVIII). The desilylation of (XXVIII) with HF and pyridine furnishes the precursor (XXIX), which is finally epoxidated with trifluoroacetone and oxone to give the target epothilone A.

参考文献 中间体
【1】 Sinha, S.C.; Barbas, C.F. III; Lerner, R.A.; The antibody catalysis route to the total synthesis of epothilones. Proc Natl Acad Sci USA 1998, 95, 25, 14603.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 13484 Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide 2065-66-9 C19H18IP 详情 详情
(XVIII) 44438 (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid C29H58O5Si2 详情 详情
(XIX) 44456 (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal C8H9NOS 详情 详情
(XX) 23199 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether 67-64-1 C3H6O 详情 详情
(XXI) 45552 (4S,5E)-4-hydroxy-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexen-2-one C11H15NO2S 详情 详情
(XXII) 45553 (4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexen-2-one 2815-95-4 C17H29NO2SSi 详情 详情
(XXIII) 45554 (4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexene-1,2-diol C17H31NO3SSi 详情 详情
(XXIV) 40822 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal C16H27NO2SSi 详情 详情
(XXV) 44444 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether C17H29NOSSi 详情 详情
(XXVI) 43171 (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H15NOS 详情 详情
(XXVII) 44445 (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate C40H71NO5SSi2 详情 详情
(XXVIII) 44446 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C38H67NO5SSi2 详情 详情
(XXIX) 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28

The ozonolysis of the terminal double bond of (I) gives the aldehyde (II), which is condensed with the acetylenic alcohol (II) by means of Zn(OTf)2 in the presence of (+)-N-methylephedrine to yield the chiral acetylenic diol (IV). The reaction of (IV) with benzoyl chloride and TEA affords the monobenzoate (V), which is treated with K2CO3 and LiAlH4 to provide the chiral allyl alcohol derivative (VI). The cyclization of (VI) with the phosphonate (VII) by means of Et-MgBr in isopropanol/dichloromethane gives the isooxazoline (VIII), which is treated with Tbdms-OTf to yield the corresponding silyl ether (IX). The condensation of (IX) with 2-methylthiazole-4-carbaldehyde (X) by means of DBU and LiCl affords the isooxazoline derivative (XI), which is treated with SmI2, Et3B and NaBH4 to cleave the isoxazoline ring and yield the diol (XII). The reaction of (XII) with SOCl2, TEA and TBAF affords the chiral epoxide (XIII), which is silylated with Tes-Cl and TEA to provide the silyl ether (XIV). The selective hydrolysis of the primary silyl ether of (XIV) with HOAc in THF/water gives the primary alcohol (XV), which is oxidized with TPAP and NMO in dichloromethane to yield the corresponding aldehyde (XVI).

参考文献 中间体
【1】 Bode, J.W.; Carreira, E.M.; Stereoselective syntheses of epothilones A and B via directed nitrile oxide cycloaddition. J Am Chem Soc 2001, 123, 18, 3611.
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) 49304 triisopropyl[[(2S)-2-methyl-6-heptenyl]oxy]silane; (2S)-2-methyl-6-heptenyl triisopropylsilyl ether C17H36OSi 详情 详情
(II) 49305 (5S)-5-methyl-6-[(triisopropylsilyl)oxy]hexanal C16H34O2Si 详情 详情
(III) 17922 2-methyl-3-butyn-2-ol; 3-Methyl butynol 115-19-5 C5H8O 详情 详情
(IV) 49306 (5R,9S)-2,9-dimethyl-10-[(triisopropylsilyl)oxy]-3-decyne-2,5-diol C21H42O3Si 详情 详情
(V) 49307 (1R)-4-hydroxy-4-methyl-1-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]-2-pentynyl benzoate C28H46O4Si 详情 详情
(VI) 49308 (3R,7S)-7-methyl-8-[(triisopropylsilyl)oxy]-1-octen-3-ol C18H38O2Si 详情 详情
(VII) 49286 diethyl 2-(hydroxyimino)-1-methylethylphosphonate C7H16NO4P 详情 详情
(VIII) 49309 diethyl 1-((5R)-5-[(1R,5S)-1-hydroxy-5-methyl-6-[(triisopropylsilyl)oxy]hexyl]-4,5-dihydro-3-isoxazolyl)ethylphosphonate C25H52NO6PSi 详情 详情
(IX) 44455 2-methyl-1,3-thiazole-4-carbaldehyde C5H5NOS 详情 详情
(X) 49310 diethyl 1-((5R)-5-[(1R,5S)-1-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-[(triisopropylsilyl)oxy]hexyl]-4,5-dihydro-3-isoxazolyl)ethylphosphonate C31H66NO6PSi2 详情 详情
(XI) 49311 (5R)-5-[(1R,5S)-1-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-[(triisopropylsilyl)oxy]hexyl]-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydroisoxazole; tert-butyl(dimethyl)silyl (1R,5S)-5-methyl-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-6-[(triisopropylsilyl)oxy]hexyl ether C32H60N2O3SSi2 详情 详情
(XII) 49312 (E,3S,5R,6R,10S)-6-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-1-(2-methyl-1,3-thiazol-4-yl)-11-[(triisopropylsilyl)oxy]-1-undecene-3,5-diol C32H63NO4SSi2 详情 详情
(XIII) 49313 (2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-((2S,3R)-3-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]oxiranyl)-3-buten-2-ol C26H47NO3SSi 详情 详情
(XIV) 49314 (2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentyl triisopropylsilyl ether; 2-methyl-4-[(E,3S)-2-methyl-4-((2S,3R)-3-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]oxiranyl)-3-[(triethylsilyl)oxy]-1-butenyl]-1,3-thiazole C32H61NO3SSi2 详情 详情
(XV) 49315 (2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-pentanol C23H41NO3SSi 详情 详情
(XVI) 49316 (2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal C23H39NO3SSi 详情 详情

合成路线29

The condensation of (XVI) with ketone (XVII) by means of LDA affords the open-chain precursor (XVIII), which is protected at the OH group with Troc-Cl and pyridine to afford compound (XIX). The oxidation of (XIX) at the terminal vinyl group by means of OsO4, NMO and Pb(OAc)4 provides the carboxylic acid (XVIII), which by selective cleavage of its Tes- protecting group with HF and pyridine furnishes the hydroxyacid (XIX). The macrolactonization of (XIX) by means of 2,4,6-trichlorobenzoyl chloride gives the protected macrolactone (XX). The reaction of (XX) with Zn and NH4Cl in methanol cleaves the Troc-protecting group, yielding the silylated precursor (XXI), which is finally treated with HF and pyridine to afford the target epothilone A

参考文献 中间体
【1】 Bode, J.W.; Carreira, E.M.; Stereoselective syntheses of epothilones A and B via directed nitrile oxide cycloaddition. J Am Chem Soc 2001, 123, 18, 3611.
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) 49316 (2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal C23H39NO3SSi 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) 49317 (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one C39H71NO5SSi2 详情 详情
(XIX) 49318 (1S,2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4,4-trimethyl-1-[(1S)-1-methyl-4-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)butyl]-3-oxo-7-octenyl 2,2,2-trichloroethyl carbonate C42H72Cl3NO7SSi2 详情 详情
(XX) 49319 (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-11-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]undecanoic acid C41H70Cl3NO9SSi2 详情 详情
(XXI) 49320 (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-11-[(2R,3S)-3-[(2S,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]oxiranyl]-4,4,6,8-tetramethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]undecanoic acid C35H56Cl3NO9SSi 详情 详情
(XXII) 49321 (1S,3S,7S,10R,11S,12S,16R)-7-[[tert-butyl(dimethyl)silyl]oxy]-8,8,10,12-tetramethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-11-yl 2,2,2-trichloroethyl carbonate C35H54Cl3NO8SSi 详情 详情
(XXIII) 49322 (1S,3S,7S,10R,11S,12S,16R)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-8,8,10,12-tetramethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione C32H53NO6SSi 详情 详情

合成路线30

The intermediate carboxylic acid (VI) has been obtained as follows: The condensation of the chiral oxazolidinone (I) with the aldehyde (II) gives the chiral ketone (III) as the major product. The cleavage of the chiral auxiliary with LiOOH in THF yields the carboxylic acid (IV), which is deprotected with HCl in THF to afford the oxoacid (V). Finally, the OH group of (V) is silylated with Tbdms-Cl to furnish the target intermediate carboxylic acid (VI).

参考文献 中间体
【1】 Panicker, B.; et al.; An unusual reversal of stereoselectivity in a boron mediated aldol reaction: Enantioselective synthesis of the C1-C6 segment of the epothilones. Tetrahedron 2000, 56, 40, 7859.
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) 52572 4-(1-methylethyl)-3-[2-(methylsulfanyl)acetyl]-1,3-oxazolidin-2-one C9H15NO3S 详情 详情
(II) 52593 2-(2-ethyl-1,3-dioxolan-2-yl)-2-methylpropanal C9H16O3 详情 详情
(III) 52594 3-[4-(2-ethyl-1,3-dioxolan-2-yl)-3-hydroxy-4-methylpentanoyl]-4-(1-methylethyl)-1,3-oxazolidin-2-one C17H29NO6 详情 详情
(IV) 52595 4-(2-ethyl-1,3-dioxolan-2-yl)-3-hydroxy-4-methylpentanoic acid C11H20O5 详情 详情
(V) 52596 3-hydroxy-4,4-dimethyl-5-oxoheptanoic acid C9H16O4 详情 详情
(VI) 43166 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid C15H30O4Si 详情 详情

合成路线31

The silylation of the epoxide (VII) with Tbdms-Cl gives the silyl ether (VIII), which is condensed with alkynyl aluminum (X) (obtained by reaction of 5-(tert-butyldimethylsilyloxy)-1-pentyne (IX) with dimethylaluminum and BuLi) in toluene, followed by treatment with HOAc to yield the unsaturated diol (XI). The controlled hydrogenation of the triple bond of (XI) with H2 over Lindlar catalyst affords the (Z)-olefin (XII), which is treated with Ts-Cl to provide the monotosylate (XIII). The silylation of the remaining OH group of (XIII) with Tms-OTf gives the fully protected triol (XIV), which is treated with NaI in refluxing acetone to yield the iodide (XV). The condensation of (XV) with the chiral amide (XVI) by means of BuLi in THF/HMPA affords the adduct (XVII), which by elimination of the chiral auxiliary by reduction with DIBAL in dichloromethane, followed by controlled oxidation with SO3/pyridine, provides the aldehyde (XVIII). The aldol condensation of aldehyde (XVIII) with the intermediate oxoacid (VI) by means of LDA in THF gives the heptadecanoic acid (XIX), which is fully silylated with Tbdms-OTf and lutidine, yielding the silylated silyl ester (XX). Selective elimination of the Tms and ester-Tbdms- groups with aqueous HOAc affords the hydroxyacid (XXI).

参考文献 中间体
【1】 Hindupur, R.M.; et al.; Total synthesis of epothilone A. Tetrahedron Lett 2001, 42, 42, 7341.
中间体序号 中间体编号 品名 CAS号 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
(VII) 52597 1-(2-oxiranyl)-1-ethanol C4H8O2 详情 详情
(VIII) 52598 (1,1-dimethylethyl)(dimethyl)((1-(2-oxiranyl)ethyl)oxy)silane; (1,1-dimethylethyl)(dimethyl)silyl 1-(2-oxiranyl)ethyl ether C10H22O2Si 详情 详情
(IX) 52599 4-pentynyl trimethylsilyl ether; trimethyl(4-pentynyloxy)silane C8H16OSi 详情 详情
(X) 52600 dimethyl{5-[(trimethylsilyl)oxy]-1-pentynyl}aluminium C10H21AlOSi 详情 详情
(XI) 52601 8-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-nonyne-1,7-diol C15H30O3Si 详情 详情
(XII) 52602 8-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-nonene-1,7-diol C15H32O3Si 详情 详情
(XIII) 52603 8-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-4-nonenyl 4-methylbenzenesulfonate C22H38O5SSi 详情 详情
(XIV) 52604 8-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-[(trimethylsilyl)oxy]-4-nonenyl 4-methylbenzenesulfonate C25H46O5SSi2 详情 详情
(XV) 52605 4-(6-iodo-2-hexenyl)-2,2,5,7,7,8,8-heptamethyl-3,6-dioxa-2,7-disilanonane; (1,1-dimethylethyl)(dimethyl)silyl 8-iodo-1-methyl-2-[(trimethylsilyl)oxy]-4-octenyl ether C18H39IO2Si2 详情 详情
(XVI) 52606 　 C13H21NO3S 详情 详情
(XVII) 52607 　 C31H59NO5SSi2 详情 详情
(XVIII) 52608 10-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-9-[(trimethylsilyl)oxy]-6-undecenal C21H44O3Si2 详情 详情
(XIX) 52609 3,16-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-15-[(trimethylsilyl)oxy]-12-heptadecenoic acid C36H74O7Si3 详情 详情
(XX) 52610 (1,1-dimethylethyl)(dimethyl)silyl 3,7,16-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4,4,6,8-tetramethyl-5-oxo-15-[(trimethylsilyl)oxy]-12-heptadecenoate C48H102O7Si5 详情 详情
(XXI) 52612 3,7,16-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-heptadecenoic acid C39H80O7Si3 详情 详情

合成路线32

The macrolactonization of (XXII) under Yamaguchi conditions (2,4,6-trichlorobenzoyl chloride), followed by selective desilylation with H2SiF6, gives the macrolactone (XXII). The oxidation of the secondary OH group of (XXII) with (COCl)2 and TEA in DMSO/dichloromethane yields the ketone (XXIII), which is submitted to a Wadsworth-Emmons condensation with the phosphonate (XXIV) by means of BuLi in THF to afford the protected precursor (XXV). Elimination of the silyl protecting groups of (XXV) with TFA in dichloromethane affords the free precursor (XXVI), which is finally epoxidated with methyl(trifluoromethyl)dioxirane (MTFDO) in acetonitrile to afford the target epothilone A.

参考文献 中间体
【1】 Hindupur, R.M.; et al.; Total synthesis of epothilone A. Tetrahedron Lett 2001, 42, 42, 7341.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXI) 52612 3,7,16-tris{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-heptadecenoic acid C39H80O7Si3 详情 详情
(XXII) 52611 4,8-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-16-(1-hydroxyethyl)-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione C33H64O6Si2 详情 详情
(XXIII) 52613 16-acetyl-4,8-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione C33H62O6Si2 详情 详情
(XXIV) 52614 dimethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C7H12NO3PS 详情 详情
(XXV) 44446 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C38H67NO5SSi2 详情 详情
(XXVI) 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33

The omega iodoalkyl thiazole intermediate (XII) is obtained as follows: The cyclization of 2-hydroxypropionaldehyde dimethyl acetal (I) with acetaldehyde (II) by means of warm Dowex (H+) and catalyzed by 2-deoxyribose-5-phosphate aldolase (DERA) gives the chiral tetrahydrofuran derivative (III), which is acylated with Ac-Cl and pyridine to yield the acetoxy compound (IV). The reaction of (IV) with BF3/Et2O, propane-1,3-dithiol (V) and TiCl4 affords the protected dithiane (VI), which is oxidized with oxalyl chloride in DMSO to provide the ketone (VII). The Wittig condensation of (VII) with phosphine oxide (VIII) by means of BuLi in THF provides the protected alkyl thiazole (IX), which is treated with HgClO4 to cleave the dithiane ring and yield carbaldehyde (X). Finally, this aldehyde is coupled with iodomethylenephosphorane (XI) by means of NaHMDS in THF/HMPA to afford the target omega iodoalkyl thiazole intermediate (XII).

参考文献 中间体
【1】 Wong, C.-H.; Liu, J.; Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones. Angew Chem. Int Ed 2002, 41, 8, 1404.
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) 54261 1,1-dimethoxy-2-propanol 42919-42-6 C5H12O3 详情 详情
(II) 11974 Acetaldehyde 75-07-0 C2H4O 详情 详情
(III) 54262 (4S,5R)-5-methyltetrahydro-2,4-furandiol C5H10O3 详情 详情
(IV) 54263 (2R,3S)-5-hydroxy-2-methyltetrahydro-3-furanyl acetate n/a C7H12O4 详情 详情
(V) 29729 1,3-propanedithiol; 3-sulfanylpropylhydrosulfide 109-80-8 C3H8S2 详情 详情
(VI) 54264 (1S,2R)-1-(1,3-dithian-2-ylmethyl)-2-hydroxypropyl acetate n/a C10H18O3S2 详情 详情
(VII) 54265 (1S)-1-(1,3-dithian-2-ylmethyl)-2-oxopropyl acetate C10H16O3S2 详情 详情
(VIII) 47000 (2-methyl-1,3-thiazol-4-yl)methyl(diphenyl)phosphine oxide; 4-[(diphenylphosphoryl)methyl]-2-methyl-1,3-thiazole C17H16NOPS 详情 详情
(IX) 54266 (1S,2E)-1-(1,3-dithian-2-ylmethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl acetate C15H21NO2S3 详情 详情
(X) 44531 (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate C12H15NO3S 详情 详情
(XI) 44532 (iodomethylene)(triphenyl)phosphorane C19H16IP 详情 详情
(XII) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情

合成路线34

The oxidation of the lactol (XIII) with Br2 and BaCO3 gives the lactone (XIV), which is stereoselectively alkylated with allyl bromide (XV) by means of LDA in HMPA to yield lactone (XVI). The opening of the lactone ring of (XVI) with MeONa affords the dihydroxyester (XVII), which is protected by reaction with anisaldehyde dimethylacetal (XVIII) and CSA to provide the benzylidene derivative (XIX). The reduction of the ester group of (XIX) with LiAlH4 gives the corresponding carbinol (XX), which is acylated with Ms-Cl and TEA to yield the mesylate (XXI). The reduction of the mesyloxy group of (XXI) with LiAlH4 affords the dimethyl compound (XXII), which is submitted to a regioselective cleavage of the Pmp protecting group by means of DIBAL in toluene to provide the primary alcohol (XXIII). The oxidation of (XXIII) with DMP gives the corresponding aldehyde (XXIV), which is condensed with tert-butyl isobutyrylacetate (XXV) by means of NaH and BuLi to yield the unsaturated ketoester (XXVI). Stereoselective reduction of the beta-oxo group of (XXVI) by means of Me4NBH(OAc)3 affords the desired diol (XXVII), which is regioselectively silylated at the beta-hydroxy group by means of Tbdms-OTf to provide the monosilyl ether (XXVIII). The oxidation of the remaining hydroxy group of (XXVIII) by means of DMP gives the unsaturated ketoester (XXIX).

参考文献 中间体
【1】 Wong, C.-H.; Liu, J.; Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones. Angew Chem. Int Ed 2002, 41, 8, 1404.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 54267 (4S,5S)-5-methyltetrahydro-2H-pyran-2,4-diol C6H12O3 详情 详情
(XIV) 54268 (4S,5S)-4-hydroxy-5-methyltetrahydro-2H-pyran-2-one C6H10O3 详情 详情
(XV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XVI) 54269 (3S,4R,5S)-3-allyl-4-hydroxy-5-methyltetrahydro-2H-pyran-2-one C9H14O3 详情 详情
(XVII) 54270 methyl (2S)-2-[(1R,2S)-1,3-dihydroxy-2-methylpropyl]-4-pentenoate C10H18O4 详情 详情
(XVIII) 26485 1-(dimethoxymethyl)-4-methoxybenzene 2186-92-7 C10H14O3 详情 详情
(XIX) 54271 methyl (2S)-2-[(4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-pentenoate n/a C18H24O5 详情 详情
(XX) 54272 (2R)-2-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-penten-1-ol n/a C17H24O4 详情 详情
(XXI) 54273 (2R)-2-[(4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-pentenyl methanesulfonate n/a C18H26O6S 详情 详情
(XXII) 54274 (4S,5S)-2-(4-methoxyphenyl)-5-methyl-4-[(1S)-1-methyl-3-butenyl]-1,3-dioxane; methyl 4-{(4S,5S)-5-methyl-4-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-2-yl}phenyl ether n/a C17H24O3 详情 详情
(XXIII) 54275 (2S,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-6-hepten-1-ol n/a C17H26O3 详情 详情
(XXIV) 54276 (2R,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-6-heptenal n/a C17H24O3 详情 详情
(XXV) 54277 tert-butyl 4-methyl-3-oxopentanoate 94250-54-1 C10H18O3 详情 详情
(XXVI) 54278 tert-butyl (5S,6S,7S,8S)-5-hydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-3-oxo-10-undecenoate n/a C27H42O6 详情 详情
(XXVII) 54279 tert-butyl (3S,5S,6S,7S,8S)-3,5-dihydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-10-undecenoate n/a C27H44O6 详情 详情
(XXVIII) 54280 tert-butyl (3S,5S,6S,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-10-undecenoate n/a C33H58O6Si 详情 详情
(XXIX) 54281 tert-butyl (3S,6R,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate n/a C33H56O6Si 详情 详情

合成路线35

The Suzuki coupling of the unsaturated ketoester (XXIX) with the omega iodoalkyl thiazole intermediate (XII) by means of PdCl2(dppf)2, AsPh3, Cs2CO3 and 9-BBN gives the heptadienoic ester (XXX), which is treated with MeONa, Tms-OTf and NaOH to yield the hydroxyacid (XXXI). The macrocyclization of (XXXI) under Yamaguchi conditions affords the macrolactone (XXXII), which is treated with DDQ (cleavage of the Pmb group) to provide the still silylated compound (XXXIII). The treatment of (XXXIII) with HF and pyridine (cleavage of the Tbdms group) gives the free macrolactone (XXXIV), which is finally epoxidated by means of DMDO to furnish the target epothilone A.

参考文献 中间体
【1】 Wong, C.-H.; Liu, J.; Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones. Angew Chem. Int Ed 2002, 41, 8, 1404.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(XXIX) 54281 tert-butyl (3S,6R,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate n/a C33H56O6Si 详情 详情
(XXX) 54282 tert-butyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate n/a C46H73NO8SSi 详情 详情
(XXXI) 54283 (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-15-hydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid n/a C40H63NO7SSi 详情 详情
(XXXII) 54284 (4S,7R,8S,9S,16S)-4-{[tert-butyl(dimethyl)silyl]oxy}-8-[(4-methoxybenzyl)oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione n/a C40H61NO6SSi 详情 详情
(XXXIII) 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
(XXXIV) 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36

The protection of 2(S)-methyl-6-hepten-1-ol (I) with Tes-Cl gives the silyl ether (II), which is oxidized by known methods to yield the aldehyde (III). The condensation of (III) with the acetylenic alcohol (IV) by means of Zn(OTf)2 and TEA to afford the acetylenic diol (V), which is selectively monobenzoylated with benzoyl chloride and TEA, providing the benzoate (VI). Extrusion of acetone from (VI) by means of K2CO3 in refluxing toluene gives the chiral octyne derivative (VII), which is reduced and debenzoylated with LiAlH4 in ethyl ether to yield the unsaturated alcohol (VIII). The condensation of (VIII) with the phosphonate (IX) by means of Et-MgBr affords the isoxazoline (X), which is treated with Tbdms-OTf and DIEA to provide the silyl ether (XI). The condensation of the phosphonate (XI) with 2-methylthiazole-4-carbaldehyde (XII) gives the adduct (XIII), which is treated with SmI2 to open the isoxazoline ring and yield the beta-hydroxy ketone (XIV). The reduction of (XIV) by means of BEt3 and NaBH4 affords the beta-diol (XV), which is treated with SOCl2 and TEA to provide the cyclic sulfite (XVI). The treatment of (XVI) with TBAF in refluxing THF/water gives the chiral epoxide (XVII), which is silylated with Tes-Cl and TEA to yield the bis silyl ether (XVIII). The selective deprotection of the primary silyl ether of (XVIII) by means of Ac-OH in THF/water affords the primary alcohol (XIX).

参考文献 中间体
【1】 Bode, J.W.; Carreira, E.M.; Stereoselective syntheses of epothilones A and B via nitrile oxide cycloadditions and related studies. J Org Chem 2001, 66, 19, 6410.
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) 27184 (2S)-2-methyl-6-hepten-1-ol C8H16O 详情 详情
(II) 49304 triisopropyl[[(2S)-2-methyl-6-heptenyl]oxy]silane; (2S)-2-methyl-6-heptenyl triisopropylsilyl ether C17H36OSi 详情 详情
(III) 49305 (5S)-5-methyl-6-[(triisopropylsilyl)oxy]hexanal C16H34O2Si 详情 详情
(IV) 17922 2-methyl-3-butyn-2-ol; 3-Methyl butynol 115-19-5 C5H8O 详情 详情
(V) 49306 (5R,9S)-2,9-dimethyl-10-[(triisopropylsilyl)oxy]-3-decyne-2,5-diol C21H42O3Si 详情 详情
(VI) 49307 (1R)-4-hydroxy-4-methyl-1-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]-2-pentynyl benzoate C28H46O4Si 详情 详情
(VII) 60464 (1R)-1-{(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl}-2-propynyl benzoate C25H40O3Si 详情 详情
(VIII) 49308 (3R,7S)-7-methyl-8-[(triisopropylsilyl)oxy]-1-octen-3-ol C18H38O2Si 详情 详情
(IX) 60465 　 C4H8ClNO4PT 详情 详情
(X) 60466 　 C22H45NO6PSiT 详情 详情
(XI) 60467 　 C28H59NO6PSi2T 详情 详情
(XII) 44455 2-methyl-1,3-thiazole-4-carbaldehyde C5H5NOS 详情 详情
(XIII) 49311 (5R)-5-[(1R,5S)-1-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-[(triisopropylsilyl)oxy]hexyl]-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydroisoxazole; tert-butyl(dimethyl)silyl (1R,5S)-5-methyl-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-6-[(triisopropylsilyl)oxy]hexyl ether C32H60N2O3SSi2 详情 详情
(XIV) 60468 (E,5R,6R,10S)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-2,10-dimethyl-1-(2-methyl-1,3-thiazol-4-yl)-11-[(triisopropylsilyl)oxy]-1-undecen-3-one C32H61NO4SSi2 详情 详情
(XV) 49312 (E,3S,5R,6R,10S)-6-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-1-(2-methyl-1,3-thiazol-4-yl)-11-[(triisopropylsilyl)oxy]-1-undecene-3,5-diol C32H63NO4SSi2 详情 详情
(XVI) 60469 (4R,6S)-4-{(1R,5S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-6-[(triisopropylsilyl)oxy]hexyl}-6-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1,3,2lambda~4~-dioxathian-2-one C32H61NO5S2Si2 详情 详情
(XVII) 60470 (2S,3E)-1-{(2S,3R)-3-[(4S)-5-hydroxy-4-methylpentyl]oxiranyl}-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-buten-2-ol C17H27NO3S 详情 详情
(XVIII) 60471 (2S)-2-methyl-5-((2R,3S)-3-{(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl}oxiranyl)pentyl triethylsilyl ether; 2-methyl-4-{(E,3S)-2-methyl-4-((2S,3R)-3-{(4S)-4-methyl-5-[(triethylsilyl)oxy]pentyl}oxiranyl)-3-[(triethylsilyl)oxy]-1-butenyl}-1,3-thiazole C29H55NO3SSi2 详情 详情
(XIX) 49315 (2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-pentanol C23H41NO3SSi 详情 详情

合成路线37

The oxidation of (XIX) by means of TPAP and NMO gives the aldehyde (XX), which is condensed with the chiral ketone (XXI) by means of LDA in THF to yield the aldol (XXII). The protection of the OH group of (XXII) with Troc-Cl and pyridine affords the Troc-ester (XXIII). The oxidation of the terminal vinyl group of (XXIII) with OsO4, NMO and Pb(OAc)4 provides the aldehyde (XXIV), which is selectively monodesilylated by treatment with HF and pyridine at 0 C to give the alcohol (XXV). The oxidation of the aldehyde group of (XXV) with NaClO2 yields the hydroxyacid (XXVI), which is submitted to macrolactonization by means of 2,4,6-trichlrobenzoyl chloride, TEA and DMAP to afford the protected macrolactone (XXVII). The cleavage of the Troc- protecting group of (XXVII) by means of Zn and NH4Cl in methanol provides the silylated precursor (XXVIII), which is finally treated with HF and pyridine at 40 C to furnish the target Epothilone A.

参考文献 中间体
【1】 Bode, J.W.; Carreira, E.M.; Stereoselective syntheses of epothilones A and B via nitrile oxide cycloadditions and related studies. J Org Chem 2001, 66, 19, 6410.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIX) 49315 (2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-pentanol C23H41NO3SSi 详情 详情
(XX) 49316 (2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal C23H39NO3SSi 详情 详情
(XXI) 44451 (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one C16H32O2Si 详情 详情
(XXII) 49317 (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one C39H71NO5SSi2 详情 详情
(XXIII) 60472 trityl (3S,4R,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}-4,6,6-trimethyl-3-[(1S)-1-methyl-4-((2R,3S)-3-{(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl}oxiranyl)butyl]-5-oxo-9-decenoate C60H87NO6SSi2 详情 详情
(XXIV) 60473 trityl (3S,4R,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}-4,6,6-trimethyl-3-[(1S)-1-methyl-4-((2R,3S)-3-{(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl}oxiranyl)butyl]-5,9-dioxononanoate C59H85NO7SSi2 详情 详情
(XXV) 60474 trityl (3S,4R,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}-3-((1S)-4-{(2R,3S)-3-[(2S,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]oxiranyl}-1-methylbutyl)-4,6,6-trimethyl-5,9-dioxononanoate C53H71NO7SSi 详情 详情
(XXVI) 60475 (3S,6R,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-11-{(2R,3S)-3-[(2S,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]oxiranyl}-4,4,6,8-tetramethyl-5-oxo-7-[2-oxo-2-(trityloxy)ethyl]undecanoic acid C53H71NO8SSi 详情 详情
(XXVII) 60476 trityl 2-{(1S,3S,7S,10R,11S,12S,16R)-7-{[tert-butyl(dimethyl)silyl]oxy}-8,8,10,12-tetramethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-11-yl}acetate C53H69NO7SSi 详情 详情
(XXVIII) 49322 (1S,3S,7S,10R,11S,12S,16R)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-8,8,10,12-tetramethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione C32H53NO6SSi 详情 详情
Extended Information