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【结 构 式】

【药物名称】Patupilone, (-)-Epothilone B, Epothilone B, EPO-906

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

【CA登记号】152044-54-7

【 分 子 式 】C27H41NO6S

【 分 子 量 】507.69492

【开发单位】GBF (Originator), Novartis (Not Determined), Bristol-Myers Squibb (Licensee)

【药理作用】Oncolytic Drugs, Solid Tumors Therapy, Antimitotic Drugs, Epothilones, Microtubule-Stabilizing Agents

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合成路线1

The silylation of 3(S)-hydroxytetrahydrofuran-2-one (I) with TBDMS-Cl and imidazole gives the silyl ether (II), which is methylated with MeLi in THF yields the 3(S)-(TBDMSO)-5-hydroxy-2-pentanone (IV), through the hemiketal intermediate (III). Simultaneously, the cyclization of 1,3-dichloropropanone (V) with thioacetamide (VI) in refluxing ethanol affords 4-(chloromethyl)-2-methylthiazole (VII), which is treated with tributylphosphine to provide the phosphonium salt (VIII). The condensation of (VIII) with the ketone (IV) gives the unsaturated alcohol (IX), which is oxidized to the corresponding aldehyde (X) by means of oxalyl chloride in DMSO. The condensation of (X) with 2-phosphonopropionic acid triethyl ester (XI) by means of KHMDS gives the dienoic acid ethyl ester (XII), which is reduced with DIBAL in THF yielding the corresponding primary alcohol (XIII). The condensation of (XIII) with the chiral sulfone intermediate (XIV) by means of KHMDS and PPh3 affords the corresponding adduct (XV), which is desulfurized with Na/Hg in THF/methanol giving the silylated diol (XVI). The selective monodesilylation of (XVI) with CSA in methanol/dichloromethane yields the primary alcohol (XVII), which is oxidized with Dess Martin periodinane (DMP) to the aldehyde (XVIII). The condensation of (XVIII) with the intermediate chiral ketone (XIX) by means of LDA in THF affords the hydroxy ketone (XX).

参考文献 中间体
【1】 Mulzer, J.; Ohler, E.; Mantoulidis, A. (Schering AG); Method for producing epothilone B and derivs., and intermediate products for this method. WO 0023452 .
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) 40815 (3S)-3-hydroxydihydro-2(3H)-furanone 19444-84-9 C4H6O3 详情 详情
(II) 40816 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]dihydro-2(3H)-furanone C10H20O3Si 详情 详情
(III) 40817 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyltetrahydro-2-furanol C11H24O3Si 详情 详情
(IV) 40818 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-2-pentanone C11H24O3Si 详情 详情
(V) 63907 1,3-dichloroacetone C3H4Cl2O 详情 详情
(VI) 19170 ethanethioamide 62-55-5 C2H5NS 详情 详情
(VII) 40819 4-(chloromethyl)-2-methyl-1,3-thiazole C5H6ClNS 详情 详情
(VIII) 40820 tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride C17H33ClNPS 详情 详情
(IX) 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
(X) 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
(XI) 18816 ethyl 2-(diethoxyphosphoryl)propanoate 3699-66-9 C9H19O5P 详情 详情
(XII) 40823 ethyl (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate C21H35NO3SSi 详情 详情
(XIII) 40824 (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol C19H33NO2SSi 详情 详情
(XIV) 40825 tert-butyl(dimethyl)[[(2S)-2-methyl-4-(phenylsulfonyl)butyl]oxy]silane; (3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl phenyl sulfone C17H30O3SSi 详情 详情
(XV) 40826 (1R,3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-1-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl phenyl sulfone; 4-[(1E,3S,5Z,8R,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-8-(phenylsulfonyl)-1,5-undecadienyl]-2-methyl-1,3-thiazole C36H61NO4S2Si2 详情 详情
(XVI) 40827 tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole C30H57NO2SSi2 详情 详情
(XVII) 40828 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol C24H43NO2SSi 详情 详情
(XVIII) 40829 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal C24H41NO2SSi 详情 详情
(XIX) 40830 (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone C21H46O3Si2 详情 详情
(XX) 40831 (7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one C45H87NO5SSi3 详情 详情

合成路线2

The silylation of the OH group of (XX) with TBDMS-triflate gives the fully silylated ketone (XXI), which is selectively monodesilylated with CSA in methanol/dichloromethane affording the primary alcohol (XXII). Oxidation of (XXII) first with Dess Martin periodinane (DMP) and then with NaClO2 provides the corresponding carboxylic acid (XXIII), which is again selectively desilylated with TBAF in THF to give the 15-hydroxy-5-oxoheptadecadienoic acid (XXIV). The cyclization of (XXIV) by means of DEC and DMAP in chloroform yields fully silylated Epothilon D (XXV), which is desilylated with HF/pyridine in THF to afford Epothilon D (XXVI). Finally, this compound is epoxidized with MCPBA in chloroform to afford the target Epothilon B.

参考文献 中间体
【1】 Mulzer, J.; Ohler, E.; Mantoulidis, A. (Schering AG); Method for producing epothilone B and derivs., and intermediate products for this method. WO 0023452 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XX) 40831 (7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one C45H87NO5SSi3 详情 详情
(XXI) 40832 (7S,10R,11S,12S,16Z,19S)-7,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one C51H101NO5SSi4 详情 详情
(XXII) 40833 (5S,8R,9S,10S,14Z,17S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,14,19,19,20,20-tridecamethyl-17-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one C45H87NO5SSi3 详情 详情
(XXIII) 40834 (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C45H85NO6SSi3 详情 详情
(XXIV) 40835 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(XXV) 40836 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H69NO5SSi2 详情 详情
(XXVI) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情

合成路线3

The chiral sulfone intermediate (XIV) has been obtained as follows: The silylation of 3-hydroxy-2(R)-methylpropionic acid methyl ester (XXVII) as usual gives the silylated ester (XXVIII), which is reduced to the chiral propanol (XXIX). The reaction of (XXIX) with TsCl and pyridine yields the tosylate (XXX), which is condensed with methyl phenyl sulfone (XXXI) by means of n-BuLi in THF to afford the chiral sulfone (XXXII). Desilylation of (XXXII) with TBAF in THF provides the 4-hydroxy-3-methylbutylsulfone (XXXIII), which is finally resilylated with TBDMS-Cl and imidazole to furnish the target intermediate (XIV).

参考文献 中间体
【1】 Mulzer, J.; Ohler, E.; Mantoulidis, A. (Schering AG); Method for producing epothilone B and derivs., and intermediate products for this method. WO 0023452 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 40825 tert-butyl(dimethyl)[[(2S)-2-methyl-4-(phenylsulfonyl)butyl]oxy]silane; (3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl phenyl sulfone C17H30O3SSi 详情 详情
(XXVII) 14965 methyl 3-hydroxy-2-methylpropanoate; METHYL (S)-(+)-3-HYDROXY-2-METHYLPROPIONATE 80657-57-4 C5H10O3 详情 详情
(XXVIII) 40838 methyl (2R)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-methylpropanoate C21H28O3Si 详情 详情
(XXIX) 40839 (2S)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-methyl-1-propanol C20H28O2Si 详情 详情
(XXX) 40840 (2R)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-methylpropyl 4-methylbenzenesulfonate C27H34O4SSi 详情 详情
(XXXI) 23622 methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane 3112-85-4 C7H8O2S 详情 详情
(XXXII) 40841 (3S)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methylbutyl phenyl sulfone; tert-butyl[[(2S)-2-methyl-4-(phenylsulfonyl)butyl]oxy]diphenylsilane C27H34O3SSi 详情 详情
(XXXIII) 40842 (2S)-2-methyl-4-(phenylsulfonyl)-1-butanol C11H16O3S 详情 详情

合成路线4

The intermediate chiral ketone (XIX) has been obtained as follows: The silylation of 3(S)-hydroxy-2,2-dimethyl-5-(TBDMSO)pentanoic acid methyl ester (XXXIV) with TBDMS-triflate gives the fully silylated ester (XXXV), which is reduced with DIBAL in THF to yield the alcohol (XXXVI). The oxidation of (XXXVI) with Dess Martin periodinane (DMP) affords the aldehyde (XXXVII), which by reaction with ethylmagnesium bromide in ethyl ether provides the expected secondary alcohol (XXXVIII). Finally, this compound is oxidized with Dess Martin periodinane (DMP) to furnish the target chiral ketone (XIX).

参考文献 中间体
【1】 Mulzer, J.; Ohler, E.; Mantoulidis, A. (Schering AG); Method for producing epothilone B and derivs., and intermediate products for this method. WO 0023452 .
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) 40830 (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone C21H46O3Si2 详情 详情
(XXXIV) 40843 methyl (3S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-2,2-dimethylpentanoate C14H30O4Si 详情 详情
(XXXV) 40844 methyl (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanoate C20H44O4Si2 详情 详情
(XXXVI) 40845 (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-1-pentanol C19H44O3Si2 详情 详情
(XXXVII) 40846 (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanal C19H42O3Si2 详情 详情
(XXXVIII) 40847 (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanol C21H48O3Si2 详情 详情

合成路线5

The synthesis of the intermediate chiral aldehyde (XVIII) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid methyl ester (I) with DIBAL in dichloromethane gives the aldehyde (II), which by condensation with phosphorane (III) in refluxing benzene yields the unsaturated aldehyde (IV). The condensation of (IV) with the chiral borane (V) in ethyl ether affords the chiral unsaturated alcohol (VI), which is treated with Tbdms-Cl and imidazole to provide the sill ether (VII). The oxidation of the terminal double bond of (VIII) with OsO4 and Pb(OAc)4 in THF/tBuOH/water gives the aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the carboxylic acid (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is reduced by reaction with CCl4 and PPh3, followed by a reductive dechlorination with LiBHEt3, to furnish the dimethylated olefin (XII). Hydroxylation of the terminal double bond of (XII) with 9-BBN in THF gives the primary alcohol (XIII), which is treated with I2 and PPh3 in ethyl ether/CH3CN to yield the iodo derivative (XIV). The condensation of (XIV) with the chiral 1-(propylideneamino)pyrrolidine (XV) by means of LDA in THF affords intermediate (XVI), which is converted into the nitrile (XVII) by reaction with monoperoxyphthalic acid magnesium salt (MMPP) in MeOH. Finally this compound is reduced with DIBAL in toluene to afford the target aldehyde intermediate (XVIII).

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) 44454 ethyl 2-methyl-1,3-thiazole-4-carboxylate 6436-59-5 C7H9NO2S 详情 详情
(II) 44455 2-methyl-1,3-thiazole-4-carbaldehyde C5H5NOS 详情 详情
(III) 39940 2-(triphenylphosphoranylidene)propanal C21H19OP 详情 详情
(IV) 44456 (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal C8H9NOS 详情 详情
(V) 44449 allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane C23H39B 详情 详情
(VI) 43171 (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H15NOS 详情 详情
(VII) 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
(VIII) 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
(IX) 46110 methyl 2-(triphenylphosphoranylidene)-4-pentenoate C24H23O2P 详情 详情
(X) 46113 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5,8-nonatrienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,6-heptadienyl ether C21H35NOSSi 详情 详情
(XI) 46114 (4Z,7S,8E)-7-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-9-(2-methyl-1,3-thiazol-4-yl)-4,8-nonadien-1-ol C21H37NO2SSi 详情 详情
(XII) 46115 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-9-iodo-2,6-dimethyl-1,5-nonadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-7-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-heptenyl ether C21H36INOSSi 详情 详情
(XIII) 46116 (2R)-N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-2-methoxy-1-pyrrolidinamine; N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine C29H51N3O2SSi 详情 详情
(XIV) 46117 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienenitrile C24H40N2OSSi 详情 详情
(XV) 44460 N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine C8H16N2O 详情 详情
(XVI) 46118 (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(XVII) 46119 tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C51H99NO6SSi4 详情 详情
(XVIII) 40829 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal C24H41NO2SSi 详情 详情

合成路线6

The condensation of 2,2-dimethyl-3-oxopentanal (XIX) with the chiral borane (V) in ethyl ether gives the chiral hydroxyketone (XX), which is treated with Tbdms-OTf and lutidine in dichloromethane to yield the silyl ether (XXI). Ozonolysis of the terminal double bond of (XXI) affords the aldehyde (XXII), which is oxidized to the carboxylic acid (XXIII) with NaClO2. The condensation of (XXIII) with the reported intermediate aldehyde (XVIII) by means of LDA in THF provides the hydroxyacid (XXIV), which is silylated with Tbdms-OTf and lutidine in dichloromethane to furnish the fully silylated compound (XXV). The hydrolysis of the silyl ester of (XXV) with K2CO3 in methanol gives the carboxylic acid (XXVI), which is selectively desilylated with TBAF in THF to yield the hydroxyacid (XXVII).The macrolactonization of (XXVII) by treatment with 2,4,6-trichlorobenzoyl chloride and TEA in THF, followed by a treatment with DMAP in toluene, affords the silylated macrolactone (XXVIII).

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
(V) 44449 allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane C23H39B 详情 详情
(XVIII) 40829 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal C24H41NO2SSi 详情 详情
(XIX) 44448 2,2-dimethyl-3-oxopentanal C7H12O2 详情 详情
(XX) 44450 (5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one C10H18O2 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) 44452 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal C15H30O3Si 详情 详情
(XXIII) 43166 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid C15H30O4Si 详情 详情
(XXIV) 46118 (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(XXV) 46119 tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C51H99NO6SSi4 详情 详情
(XXVI) 40834 (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C45H85NO6SSi3 详情 详情
(XXVII) 40835 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(XXVIII) 40836 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H69NO5SSi2 详情 详情

合成路线7

Compound (XXVIII) is deprotected with TFA in CH2Cl2 to provide the dihydroxymacrolactone (XXIX). Finally, this compound is epoxidated with methyl(trifluoromethyl)dioxirane (XXX) or MCPBA to furnish the target epothilone B.

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
(XXVIII) 40836 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H69NO5SSi2 详情 详情
(XXIX) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情
(XXX) 43177 3-methyl-3-(trifluoromethyl)-1,2-dioxirane C3H3F3O2 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) 43166 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid C15H30O4Si 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 methylation of aldehyde (XXIV) with Me-MgBr in THF gives the secondary alcohol (XXV), which is oxidized with tetrapropylammonium perruthenate (TPAP) in dichloromethane, yielding the methyl ketone (XXVI). The condensation of ketone (XXVI) with the intermediate phosphonium salt (XVI) by means of NaHMDS in THF gives the silylated diol (XXVII), which is selectively monodesilylated with CSA in dichloromethane/methanol to yield the primary alcohol (XXVIII). The oxidation of (XXVIII) with SO3/pyridine, DMSO and TEA in dichloromethane affords the corresponding aldehyde (XXIX), which is condensed with the oxoacid intermediate (VI) by means of LDA in THF to provide the linear heptadecadienoic acid (XXX) as a diastereomeric mixture that is separated at the carboxylic acid (XXXII) step.

参考文献 中间体
【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) 46120 (6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2-heptanol C14H32O2Si 详情 详情
(XXVI) 46121 (6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2-heptanone C14H30O2Si 详情 详情
(XXVII) 40827 tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole C30H57NO2SSi2 详情 详情
(XXVIII) 40828 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol C24H43NO2SSi 详情 详情
(XXIX) 40829 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal C24H41NO2SSi 详情 详情
(XXX) 46118 (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情

合成路线11

The fully silylation of (XXX) with Tbdms-OTf and lutidine in dichloromethane gives the tetrasilyloxy compound (XXXI). The stepwise desilylation first with K2CO3 in methanol to yield the carboxylic acid (XXXII), and then with TBAF in THF, affords the hydroxyacid (XXXIII). The macrolactonization of (XXXIII) was carried out with the Yamaguchi method using 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in THF to yield the silylated macrolactone (XXXIV), which is deprotected with TFA in dichloromethane to afford the dihydroxymacrolactone (XXXV). Finally, the double bond of (XXXV) is epoxidated with methyl(trifluoromethyl)dioxirane (XXXVI) in acetonitrile to provide the target epothilone B.

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
(XXX) 46118 (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(XXXI) 46119 tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C51H99NO6SSi4 详情 详情
(XXXII) 40834 (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C45H85NO6SSi3 详情 详情
(XXXIII) 40835 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(XXXIV) 40836 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H69NO5SSi2 详情 详情
(XXXV) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情
(XXXVI) 43177 3-methyl-3-(trifluoromethyl)-1,2-dioxirane C3H3F3O2 详情 详情

合成路线12

The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, Ts-OH 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 MeLi 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 Ts-OH, 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13

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14

Synthesis of the thiazole intermediate (XXXIII): 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 phosphonium salt (XXVII), LHMDS, Hg(OAc)2 and tetrabutylammonium iodine (TBAI) in THF provides the olefin (XXX), which is iodinated with I2 and NaHMDS in THF to give the iodinated olefin (XXXI). The desilylation of (XXXI) with HF and pyridine in THF yields the secondary alcohol (XXXII), which is acylated with Ac2O, TEA and DMAP in dichloromethane to afford the target thiazole intermediate (XXXIII).

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
(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) 39163 (methoxymethyl)(triphenyl)phosphonium chloride 4009-98-7 C20H20ClOP 详情 详情
(XXVIII) 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
(XXIX) 46122 ethyl(triphenyl)phosphonium iodide C20H20IP 详情 详情
(XXX) 46123 tert-butyl(dimethyl)silyl (1S,3E)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole C18H31NOSSi 详情 详情
(XXXI) 26246 tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole C18H30INOSSi 详情 详情
(XXXII) 46124 (1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-heptadien-3-ol C12H16INOS 详情 详情
(XXXIII) 46125 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl acetate C14H18INO2S 详情 详情

合成路线15

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

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
(XXXIII) 46125 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl acetate C14H18INO2S 详情 详情
(XXXIV) 46126 phenyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate C47H77NO7SSi2 详情 详情
(XXXV) 40835 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(XXXVI) 40836 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H69NO5SSi2 详情 详情
(XXXVII) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情
(XXXVIII) 31501 3,3-dimethyl-1,2-dioxirane C3H6O2 详情 详情

合成路线16

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) and 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 gives 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.
【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
(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) 42754 (1-iodoethylidene)(triphenyl)phosphorane C20H18IP 详情 详情
(IX) 46125 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl acetate C14H18INO2S 详情 详情

合成路线17

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 to furnish the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of tBu-OK in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of Ts-OH 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.
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
(XXIIIb) 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) 46125 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl acetate C14H18INO2S 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) 46127 (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-4,8,10,12,12-pentamethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate C53H77NO6SSi2 详情 详情

合成路线18

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 to afford the target epothilone B.

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) 46127 (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-4,8,10,12,12-pentamethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate C53H77NO6SSi2 详情 详情
(XXIX) 46128 (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8,10,12,12-pentamethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-13-oxo-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate C51H71NO5SSi2 详情 详情
(XXX) 46129 (4R,6R,7R,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-6-[(triphenylsilyl)oxy]oxa-13-cyclohexadecen-2-one C51H71NO5SSi2 详情 详情
(XXXI) 46130 (4S,6R,7R,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-6-[(triphenylsilyl)oxy]oxa-13-cyclohexadecen-2-one C51H71NO5SSi2 详情 详情
(XXXII) 46131 (6R,7R,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-6-[(triphenylsilyl)oxy]oxa-13-cyclohexadecene-2,4-dione C51H69NO5SSi2 详情 详情
(XXXIII) 46132 (4S,6R,7S,8S,9S,16S)-8-[[tert-butyl(dimethyl)silyl]oxy]-4,6-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecen-2-one C33H57NO5SSi 详情 详情
(XXXIV) 46133 (4S,6R,7S,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-6-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecen-2-one C39H71NO5SSi2 详情 详情
(XXXV) 40836 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H69NO5SSi2 详情 详情
(XXXVI) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情

合成路线19

The condensation of the phosphonium salt (I) with the ketone (II) by means of NaHMDS in THF gives the diene (III), which is selectively monodeprotected with CSA in methanol/dichloromethane to yield the primary alcohol (IV). The oxidation of (IV) with SO3/pyridine affords the corresponding aldehyde (V), which is condensed with the ketoacid (VI) by means of LDA in THF to provide the heptadienoic acid (VII). The protection of the OH group of (VII) y means of Tbdms-OTf and lutidine in dichloromethane gives the fully silylated compound (VIII), which is selectively monodeprotected with TBAF in THF to yield the hydroxyacid (IX). The macrolactonization of (IX) by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF affords the macrolactone (X), which is deprotected with TFA in dichloromethane to provide the precursor (XI). Finally, this compound is epoxidized by means of methyl(trifluoromethyl)dioxirane in acetonitrile to furnish the target epothilone B.

参考文献 中间体
【1】 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
(I) 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
(II) 46121 (6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2-heptanone C14H30O2Si 详情 详情
(III) 40827 tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole C30H57NO2SSi2 详情 详情
(IV) 40828 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol C24H43NO2SSi 详情 详情
(V) 40829 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal C24H41NO2SSi 详情 详情
(VI) 43166 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid C15H30O4Si 详情 详情
(VII) 46118 (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(VIII) 40834 (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C45H85NO6SSi3 详情 详情
(IX) 40835 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(X) 40836 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H69NO5SSi2 详情 详情
(XI) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情
(XII) 31501 3,3-dimethyl-1,2-dioxirane C3H6O2 详情 详情

合成路线20

The reaction of (S)-malic acid (I) with dimethoxypropane (II) and Ts-OH gives the carboxymethyldioxolanone (III), which is reduced with BH3/DMS and Ts-OH in toluene, yielding the chiral 2-hydroxybutyrolactone (IV). The silylation of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V), which is methylated to the lactol (Via) by means of methyl lithium in THF. The condensation of the partially silylated dihydroxypentanone (VIb) (tautomer of (VIa)) with thiazolylphosphonium salt (VII) by means of LiHMDS in THF provides the unsaturated primary alcohol (VIII), which by Swern oxidation is converted into the corresponding aldehyde (IX). The condensation of (IX) with phosphonate (X) by means of KHMDS in THF furnishes the heptadienoic ester (XI), which is reduced with DIBAL in THF to give the primary alcohol (XII). The reaction of (XII) with I2 and PPh3 in acetonitrile/Et2O gives the allylic iodide (XIII), which is condensed with sulfone (XIV) by means of KHMDS and Na/Hg in MeOH/THF, yielding the protected diol (XVII). The sulfone (XIV) has been obtained by condensation of the chiral propanol (XV) with methylphenylsulfone (XVI) by means of Ts-Cl and BuLi. The selective deprotection of the primary silyl ether of (XVIII) with CSA in methanol/dichloromethane affords the primary alcohol (XVIII), which is finally oxidized with DMP in dichloromethane to afford the target intermediate carbaldehyde (XIX).

参考文献 中间体
【1】 Mulzer, J.; et al.; Total synthesis of epothilones B and D. J Org Chem 2000, 65, 22, 7456.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIa) 40817 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyltetrahydro-2-furanol C11H24O3Si 详情 详情
(VIb) 40818 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-2-pentanone C11H24O3Si 详情 详情
(I) 11058 (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid 97-67-6 C4H6O5 详情 详情
(II) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(III) 39221 2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid 73991-95-4 C7H10O5 详情 详情
(IV) 40815 (3S)-3-hydroxydihydro-2(3H)-furanone 19444-84-9 C4H6O3 详情 详情
(V) 40816 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]dihydro-2(3H)-furanone C10H20O3Si 详情 详情
(VII) 40820 tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride C17H33ClNPS 详情 详情
(VIII) 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
(IX) 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
(X) 42703 methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]propanoate C8H11F6O5P 详情 详情
(XI) 46134 propyl (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate C22H37NO3SSi 详情 详情
(XII) 40824 (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol C19H33NO2SSi 详情 详情
(XIII) 46136 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-iodo-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-5-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether C19H32INOSSi 详情 详情
(XIV) 40825 tert-butyl(dimethyl)[[(2S)-2-methyl-4-(phenylsulfonyl)butyl]oxy]silane; (3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl phenyl sulfone C17H30O3SSi 详情 详情
(XV) 46135 (2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-propanol C10H24O2Si 详情 详情
(XVI) 23622 methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane 3112-85-4 C7H8O2S 详情 详情
(XVII) 40827 tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole C30H57NO2SSi2 详情 详情
(XVIII) 40828 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol C24H43NO2SSi 详情 详情
(XIX) 40829 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal C24H41NO2SSi 详情 详情

合成路线21

The enantioselective condensation of 3-(tert-butyldimethylsilyloxy)propanal (XX) with ketene acetal (XXI) catalyzed by N-tosyl-D-valine and BH3/THF gives the beta-hydroxyester (XXII), which is silylated with Tbdms-OTf, yielding the bis-silyl ether (XXIII). The reduction of (XXIII) with DIBAL in toluene affords the carbinol (XXIV), which is oxidized to the corresponding aldehyde (XXV) with DMP in dichloromethane. The Grignard condensation of (XXV) with Et-MgBr in ethyl ether gives the secondary alcohol (XXVI), which is oxidized with DMP as before to yield the ketone (XXVII). Alternatively, the silylated ester (XXIII) can be treated with Tms-CH2-Li in pentane/methanol to give the methyl ketone (XXVIII), which is methylated again with MeI and LDA in THF to afford the ketone (XXVII). The condensation of ketone (XXVII) with the intermediate carbaldehyde (XIX) by means of BuLi in THF gives the adduct (XXIX), which is silylated with Tbdms-OTf, yielding the fully silylated compound (XXX). The selective monodesilylation of (XXX) with CSA in MeOH/dichloromethane affords the primary alcohol (XXXI), which is oxidized with DMP and NaClO2 to provide the carboxylic acid (XXXII).

参考文献 中间体
【1】 Mulzer, J.; et al.; Total synthesis of epothilones B and D. J Org Chem 2000, 65, 22, 7456.
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) 40829 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal C24H41NO2SSi 详情 详情
(XX) 45546 3-[[tert-butyl(dimethyl)silyl]oxy]propanal 570-24-1 C9H20O2Si 详情 详情
(XXI) 42016 1-Methoxy-2-methyl-1-(trimethylsiloxy)propene;1-Methoxy-2,2-dimethyl-1-(trimethylsiloxy)ethene;1-Methoxy-1-(trimethylsilyloxy)-2-methylpropene;[(1-methoxy-2-methyl-1-propenyl)oxy](trimethyl)silane; 1-methoxy-2-methyl-1-propenyl trimethylsilyl ether ;dimethylketene methyl trimethylsilyl acetal 31469-15-5 C8H18O2Si 详情 详情
(XXII) 40843 methyl (3S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-2,2-dimethylpentanoate C14H30O4Si 详情 详情
(XXIII) 40844 methyl (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanoate C20H44O4Si2 详情 详情
(XXIV) 40845 (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-1-pentanol C19H44O3Si2 详情 详情
(XXV) 40846 (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanal C19H42O3Si2 详情 详情
(XXVI) 40847 (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanol C21H48O3Si2 详情 详情
(XXVII) 40830 (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone C21H46O3Si2 详情 详情
(XXVIII) 46137 (4S)-4,6-bis[[tert-butyl(dimethyl)silyl]oxy]-3,3-dimethyl-2-hexanone C20H44O3Si2 详情 详情
(XXIX) 40831 (7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one C45H87NO5SSi3 详情 详情
(XXX) 40832 (7S,10R,11S,12S,16Z,19S)-7,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one C51H101NO5SSi4 详情 详情
(XXXI) 40833 (5S,8R,9S,10S,14Z,17S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,14,19,19,20,20-tridecamethyl-17-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one C45H87NO5SSi3 详情 详情
(XXXII) 40834 (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C45H85NO6SSi3 详情 详情

合成路线22

The selective monodesilylation of (XXXII) with TBAF in THF gives the hydroxyacid (XXXIII), which is submitted to a macrolactonization by means of EDC and DMAP in chloroform to yield the macrolactone (XXXIV). The desilylation of (XXXIV) with HF in pyridine/THF affords the dihydroxy macrolactone (XXXV), which is finally epoxidized by means of MCPBA in chloroform to furnish the target epothilone B.

参考文献 中间体
【1】 Mulzer, J.; et al.; Total synthesis of epothilones B and D. J Org Chem 2000, 65, 22, 7456.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXII) 40834 (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C45H85NO6SSi3 详情 详情
(XXXIII) 40835 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(XXXIV) 40836 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H69NO5SSi2 详情 详情
(XXXV) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情

合成路线23

The protection of the allyl alcohol (I) with dihydropyran and PPTS in dichloromethane gives the tetrahydropyranyl ether (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi and CuCN in THF to yield the adduct (IV). The hydroxylation of (IV) with Davis' oxaziridine, NaHMDS and CSA affords the alcohol (V), which is silylated with Tbdms-OTf and lutidine to provide the silyl ether (VII). The hydrolysis of the oxazolidinone group of (VII) with Et-SH and Et-SK in THF gives the thioester (VIII), which is methylated with Me2CuLi in ethyl ether, yielding the methyl ketone (IX). The condensation of (IX) with phosphonate (X) by means of BuLi in THF affords the diene (XI), which is treated with MgBr2 in ethyl ether in order to eliminate the THP protecting group and obtain the primary alcohol (XII). The sulfonation of (XII) with Ms2O and TEA in dichloromethane gives the mesylate (XIII), which is treated with LiBr in acetone to yield the allyl bromide (XIV). Finally, (XIV) is condensed with methyltriphenylphosphonium bromide (XV) by means of BuLi in THF affording the desired intermediate phosphonium salt (XVI).

参考文献 中间体
【1】 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407.
【2】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 46138 (Z)-3-iodo-2-methyl-2-propen-1-ol C4H7IO 详情 详情
(II) 46139 (Z)-3-iodo-2-methyl-2-propenyl tetrahydro-2H-pyran-2-yl ether; 2-[[(Z)-3-iodo-2-methyl-2-propenyl]oxy]tetrahydro-2H-pyran C9H15IO2 详情 详情
(III) 40307 (4S)-3-acryloyl-4-benzyl-1,3-oxazolidin-2-one C13H13NO3 详情 详情
(IV) 46140 (4S)-4-benzyl-3-[(Z)-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenoyl]-1,3-oxazolidin-2-one C22H29NO5 详情 详情
(V) 31834 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine;2-(Phenylsulfonyl)-3-phenyloxaziridine;2-Benzenesulfonyl-3-phenyloxaziridine;3-Phenyl-2-phenylsulfonyloxaziridine;3-Phenyl-N-phenylsulfonyloxaziridine;N-(Phenylsulfonyl)phenyloxaziridine;N-Benzenesulfonyl-3-phenyloxaziridine 63160-13-4 C13H11NO3S 详情 详情
(VI) 46141 (4S)-4-benzyl-3-[(2S,4Z)-2-hydroxy-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenoyl]-1,3-oxazolidin-2-one C22H29NO6 详情 详情
(VII) 46142 (4S)-4-benzyl-3-[(2S,4Z)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenoyl]-1,3-oxazolidin-2-one C28H43NO6Si 详情 详情
(VIII) 46143 S-ethyl (2S,4Z)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenethioate C20H38O4SSi 详情 详情
(IX) 46144 (3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-(tetrahydro-2H-pyran-2-yloxy)-5-hepten-2-one C19H36O4Si 详情 详情
(X) 44442 diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C9H16NO3PS 详情 详情
(XI) 46145 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)-1,5-heptadienyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5-(tetrahydro-2H-pyran-2-yloxy)-3-pentenyl ether C24H41NO3SSi 详情 详情
(XII) 40824 (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol C19H33NO2SSi 详情 详情
(XIII) 46146 tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-5-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1,5-heptadienyl)-2-methyl-1,3-thiazole C22H39NO2S2Si 详情 详情
(XIV) 46147 4-((1E,3S,5Z)-7-bromo-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; (1S,3Z)-5-bromo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl tert-butyl(dimethyl)silyl ether C19H32BrNOSSi 详情 详情
(XV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XVI) 46148 [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide C38H49BrNOPSSi 详情 详情

合成路线24

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

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

合成路线25

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

参考文献 中间体
【1】 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407.
【2】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXVIII) 46158 (3S,6R,7S,8S,9Z,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-9,12,16-heptadecatrienoic acid C39H69NO6SSi2 详情 详情
(XXIX) 46159 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-10,13-cyclohexadecadiene-2,6-dione C39H67NO5SSi2 详情 详情
(XXX) 46160 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-10,13-cyclohexadecadiene-2,6-dione C27H39NO5S 详情 详情
(XXXI) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情
(XXXII) 31501 3,3-dimethyl-1,2-dioxirane C3H6O2 详情 详情

合成路线26

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

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

合成路线27

Synthesis of intermediate triphenylphosphonium salt (VII): The condensation of the chiral oxazolidinone (I) with cinnamyl bromide (II) by means of NaHMDS in THF gives the adduct (III), which is treated with LiBH4 in Et2O/water to yield the alcohol (IV). The protection of (IV) with Tbdms-Cl and imidazole in DMF affords the silyl ether (V), which is treated with ozone and reduced with NaBH4 to provide the alcohol (VI). The reaction of (VI) with I2 and PPh3 gives the desired triphenylphosphonium iodide (VII).

参考文献 中间体
【1】 Mulzer, J.; et al.; A novel highly stereoselective total synthesis of epothilone B and of its (12R,13R) acetonide. Tetrahedron Lett 2000, 41, 40, 7635.
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) 46163 (4R,5S)-4-methyl-5-phenyl-3-propionyl-1,3-oxazolidin-2-one C13H15NO3 详情 详情
(II) 21131 1-[(E)-3-bromo-1-propenyl]benzene 4392-24-9 C9H9Br 详情 详情
(III) 46164 (4R,5S)-4-methyl-3-[(2S,4E)-2-methyl-5-phenyl-4-pentenoyl]-5-phenyl-1,3-oxazolidin-2-one C22H23NO3 详情 详情
(IV) 46165 (2S,4E)-2-methyl-5-phenyl-4-penten-1-ol C12H16O 详情 详情
(V) 46166 tert-butyl(dimethyl)silyl (2S,4E)-2-methyl-5-phenyl-4-pentenyl ether; tert-butyl(dimethyl)[[(2S,4E)-2-methyl-5-phenyl-4-pentenyl]oxy]silane C18H30OSi 详情 详情
(VI) 46167 (3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-1-butanol C11H26O2Si 详情 详情
(VII) 46168 ((3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl)(triphenyl)phosphonium iodide C29H40IOPSi 详情 详情

合成路线28

Synthesis of intermediate aldehyde (XV): The oxidation of 4-(benzyloxy)butanol (VIII) with oxalyl chloride gives the aldehyde (IX), which is condensed with 2-(triphenylphosphoranylidene)propionic acid ethyl ester (X) in hot THF to yield the unsaturated ester (XI). The enantioselective dihydroxylation of (XI) by means of AD-mix beta and methanesulfonamide in butanol/water affords the chiral dihydroxyester (XII), which is protected with 2,2-dimethoxypropane and CSA to provide the acetonide (XIII). The reduction of the ester group of (XIII) with DIBAL in THF gives the alcohol (XIV), which is finally oxidized with DMP to yield the desired intermediate aldehyde (XV).

参考文献 中间体
【1】 Mulzer, J.; et al.; A novel highly stereoselective total synthesis of epothilone B and of its (12R,13R) acetonide. Tetrahedron Lett 2000, 41, 40, 7635.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 46169 4-(benzyloxy)-1-butanol C11H16O2 详情 详情
(IX) 46170 4-(benzyloxy)butanal C11H14O2 详情 详情
(X) 37071 ethyl 2-(triphenylphosphoranylidene)propanoate 5717-37-3 C23H23O2P 详情 详情
(XI) 46171 ethyl (E)-6-(benzyloxy)-2-methyl-2-hexenoate C16H22O3 详情 详情
(XII) 46172 ethyl (2S,3R)-6-(benzyloxy)-2,3-dihydroxy-2-methylhexanoate C16H24O5 详情 详情
(XIII) 46173 ethyl (4S,5R)-5-[3-(benzyloxy)propyl]-2,2,4-trimethyl-1,3-dioxolane-4-carboxylate C19H28O5 详情 详情
(XIV) 46174 [(4R,5R)-5-[3-(benzyloxy)propyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl]methanol C17H26O4 详情 详情
(XV) 46175 (4S,5R)-5-[3-(benzyloxy)propyl]-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde C17H24O4 详情 详情

合成路线29

Synthesis of intermediate ketone (XVIII): The reaction of 2,2-dimethyl-3-oxopentanal (XVI) with (+)-allyldi(isopinocampheyl)borane in ethyl ether gives the chiral beta-hydroxyketone (XVII), which is silylated with Tbdms-OTf and lutidine in dichloromethane to afford the desired intermediate ketone (XVIII).

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
(XVI) 44448 2,2-dimethyl-3-oxopentanal C7H12O2 详情 详情
(XVII) 44450 (5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one C10H18O2 详情 详情
(XVIII) 44451 (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one C16H32O2Si 详情 详情

合成路线30

Assembly of the target compound: The condensation of the phosphonium salt (VII) with the aldehyde (XV) by means of NaHMDS in THF gives the adduct (XIX), which is debenzylated and hydrogenated with H2 over Pd/Al2O3 in ethanol and oxidized with NaIO4 and RuCl3 to yield the carboxylic acid (XX). The activation of (XX) with pivaloyl chloride affords the anhydride (XXI), which is condensed with the lithium oxazolidinone (XXII) to provide the cyclic amide (XXIII). The enantioselective hydroxylation of (XXIII) by means of the Davis oxaziridine and NaHMDS gives the alpha-hydroxyamide (XXIV), which is treated with N,O-dimethylhydroxylamine (XXV) to yield the methoxyamide (XXVI). The protection of the OH group of (XXVI) with Tbdms-OTf and lutidine affords the silyl ether (XXVII), which is treated with MeLi in THF, affording the methyl ketone (XXVIII). The condensation of (XXVIII) with tributyl(2-methylthiazol-4-ylmethyl)phosphonium chloride (XXIX) by means of KHMDS in THF provides the adduct (XXX).

参考文献 中间体
【1】 Mulzer, J.; et al.; A novel highly stereoselective total synthesis of epothilone B and of its (12R,13R) acetonide. Tetrahedron Lett 2000, 41, 40, 7635.
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) 46168 ((3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl)(triphenyl)phosphonium iodide C29H40IOPSi 详情 详情
(XV) 46175 (4S,5R)-5-[3-(benzyloxy)propyl]-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde C17H24O4 详情 详情
(XIX) 46176 benzyl 3-[(4R,5R)-5-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-1-pentenyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]propyl ether; [((2S,4E)-5-[(4R,5R)-5-[3-(benzyloxy)propyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl]-2-methyl-4-pentenyl)oxy](tert-butyl)dimethylsilane C28H48O4Si 详情 详情
(XX) 46177 3-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]propionic acid C21H42O5Si 详情 详情
(XXI) 46178 2-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]propionic 1,1-dimethylpropionic anhydride C26H50O6Si 详情 详情
(XXII) 46185 [(4S,5R)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]lithium C10H10LiNO2 详情 详情
(XXIII) 46179 (4S,5R)-3-[3-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one C31H51NO6Si 详情 详情
(XXIV) 46180 (4S,5R)-3-[(2S)-3-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-hydroxypropanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one C31H51NO7Si 详情 详情
(XXV) 13361 (Methoxyamino)methane; N,O-Dimethylhydroxylamine 1117-97-1 C2H7NO 详情 详情
(XXVI) 46181 (2S)-3-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-hydroxy-N-methoxy-N-methylpropanamide C23H47NO6Si 详情 详情
(XXVII) 46182 (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]-N-methoxy-N-methylpropanamide C29H61NO6Si2 详情 详情
(XXVIII) 46183 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-butanone C28H58O5Si2 详情 详情
(XXIX) 40820 tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride C17H33ClNPS 详情 详情
(XXX) 46184 tert-butyl(dimethyl)silyl (2S)-5-[(4R,5R)-5-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl]-2-methylpentyl ether; 4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-methyl-1-butenyl]-2-methyl-1,3-thiazole C33H63NO4SSi2 详情 详情

合成路线31

The selective deprotection of (XXX) with CSA in dichloromethane gives the primary alcohol (XXXI), which is oxidized with DMP in dichloromethane to yield the aldehyde (XXXII). The condensation of (XXXII) with methyltriphenylphosphonium iodide (XXXIII) by means of BuLi in hexane/THF, followed by treatment with HCl in ethanol, affords the diunsaturated vicinal diol (XXXIV), which is selectively silylated to provide the vicinal diol (XXXV). The monosulfonation of (XXXV) with Ms-Cl and TEA furnishes the mesylate (XXXVI), which is cyclized to the epoxide (XXXVII) by means of K2CO3 in methanol. The oxidation of the terminal double bond of (XXXVII) with OsO4 and NaIO4 gives the aldehyde (XXXVIII), which is condensed with the intermediate ketone (XVIII) by means of LDA in THF to provide the adduct (XXXIX).

参考文献 中间体
【1】 Mulzer, J.; et al.; A novel highly stereoselective total synthesis of epothilone B and of its (12R,13R) acetonide. Tetrahedron Lett 2000, 41, 40, 7635.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXIIII) 13484 Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide 2065-66-9 C19H18IP 详情 详情
(XVIII) 44451 (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one C16H32O2Si 详情 详情
(XXX) 46184 tert-butyl(dimethyl)silyl (2S)-5-[(4R,5R)-5-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl]-2-methylpentyl ether; 4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-methyl-1-butenyl]-2-methyl-1,3-thiazole C33H63NO4SSi2 详情 详情
(XXXI) 46186 (2S)-5-[(4R,5R)-5-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl]-2-methyl-1-pentanol C27H49NO4SSi 详情 详情
(XXXII) 46187 (2S)-5-[(4R,5R)-5-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl]-2-methylpentanal C27H47NO4SSi 详情 详情
(XXXIV) 46188 (1E,3S,5R,6R,10S)-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-1,11-dodecadiene-3,5,6-triol C19H31NO3S 详情 详情
(XXXV) 46189 (1E,3S,5R,6R,10S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-1,11-dodecadiene-5,6-diol C25H45NO3SSi 详情 详情
(XXXVI) 46190 (1R,2R,6S)-1-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-hydroxy-2,6-dimethyl-7-octenyl methanesulfonate C26H47NO5S2Si 详情 详情
(XXXVII) 46191 tert-butyl(dimethyl)silyl (1S,2E)-2-methyl-1-([(2S,3R)-3-methyl-3-[(4S)-4-methyl-5-hexenyl]oxiranyl]methyl)-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-4-[(2S,3R)-3-methyl-3-[(4S)-4-methyl-5-hexenyl]oxiranyl]-1-butenyl)-2-methyl-1,3-thiazole C25H43NO2SSi 详情 详情
(XXXVIII) 46192 (2S)-5-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-2-methylpentanal C24H41NO3SSi 详情 详情
(XXXIX) 46193 (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-12-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-8-hydroxy-5,5,7,9-tetramethyl-1-dodecen-6-one C40H73NO5SSi2 详情 详情

合成路线32

The treatment of (XXXIX) with Tbdms-OTf as before gives the silyl ether (XL), which is oxidized at its terminal double bond with OsO4 and NaIO4 to give the aldehyde (XLI).The oxidation of (XLI) with NaClO2 yields the carboxylic acid (XLII), which is selectively deprotected with TBAF in THF affording the hydroxyacid (XLIII). The macrolactonization of (XLIII) by means of 2,3,6-trichlorobenzoyl chloride and TEA in toluene provides the protected macrolactone (XLIV), which is finally desilylated by means of TFA in dichloromethane to yield the target epothilone B.

参考文献 中间体
【1】 Mulzer, J.; et al.; A novel highly stereoselective total synthesis of epothilone B and of its (12R,13R) acetonide. Tetrahedron Lett 2000, 41, 40, 7635.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXIX) 46193 (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-12-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-8-hydroxy-5,5,7,9-tetramethyl-1-dodecen-6-one C40H73NO5SSi2 详情 详情
(XL) 46194 (5S,8R,9S)-5-allyl-9-((1S)-4-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-1-methylbutyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-4,10-dioxa-3,11-disilatridecan-7-one C46H87NO5SSi3 详情 详情
(XLI) 46195 (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-11-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-4,4,6,8-tetramethyl-5-oxoundecanal C45H85NO6SSi3 详情 详情
(XLII) 46196 (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-11-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-4,4,6,8-tetramethyl-5-oxoundecanoic acid C45H85NO7SSi3 详情 详情
(XLIII) 46197 (3S,6R,7S,8S)-3,7-bis[[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]-2-methyloxiranyl]-4,4,6,8-tetramethyl-5-oxoundecanoic acid C39H71NO7SSi2 详情 详情
(XLIV) 46198 (1S,3S,7S,10R,11S,12S,16R)-7,11-bis[[tert-butyl(dimethyl)silyl]oxy]-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione C39H69NO6SSi2 详情 详情

合成路线33

The reduction of the protected (S)-ethyl lactate (I) with DIBAL in dichloromethane gives the aldehyde (II), which by a Grignard condensation with allylmagnesium bromide (III) in ethyl ether yields the homoallylic alcohol (IV). The reaction of (IV) with Tbdms-Cl and imidazole in DMF affords the silyl ether (V), which is ozonolyzed with O3 in dichloromethane/methanol to provide the aldehyde (VI), which, by a new Grignard condensation with isopropenylmagnesium bromide (VII) in THF, gives the allyl alcohol derivative (VIII). Compound (VIII) is treated with triethyl orthoacetate (refluxing xylene) in a Johnson Claisen rearrangement to yield the (E)-unsaturated ester (IX), which is debenzylated by treatment with DDQ to afford the secondary alcohol (X). The oxidation of (X) with oxalyl chloride provides the ketoester (XI), which is oxidized with AD-mix beta in tert-butanol/water to furnish the diol (XII) as an inseparable mixture of isomers. This mixture, by a Wittig condensation with the phosphonium salt (XIII) and KHMDS in THF, gives a mixture of the hydroxylactones (XIV) and (XV) that are separated by chromatography. Compound (XIV) is mesylated with MsCl and TEA and treated with K2CO3 in methanol to give the desired epoxyester (XVI). The diastereomer (XV) with wrong configuration is recovered by a double inversion: Compound (XV) is mesylated and the resulting derivative is then epoxidated with K2CO3 in methanol to yield the epoxide (XVII), which is treated with K2CO3 in methanol/water to afford the hydroxylactone (XIV) with the adequate configuration.

参考文献 中间体
【1】 Martin, H.J.; et al.; How stable are epoxides? A novel synthesis of epothilone B. Angew Chem. Int Ed Engl 2000, 39, 3, 581.
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) 49259 ethyl (2S)-2-[(4-methoxybenzyl)oxy]propanoate C13H18O4 详情 详情
(II) 49260 (2S)-2-[(4-methoxybenzyl)oxy]propanal C11H14O3 详情 详情
(III) 10386 Allyl(bromo)magnesium 1730-25-2 C3H5BrMg 详情 详情
(IV) 49261 (2S,3S)-2-[(4-methoxybenzyl)oxy]-5-hexen-3-ol C14H20O3 详情 详情
(V) 49262 tert-butyl[((1S)-1-[(1S)-1-[(4-methoxybenzyl)oxy]ethyl]-3-butenyl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (1S)-1-[(1S)-1-[(4-methoxybenzyl)oxy]ethyl]-3-butenyl ether C20H34O3Si 详情 详情
(VI) 49263 (3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]pentanal C19H32O4Si 详情 详情
(VII) 43649 bromo(isopropenyl)magnesium；isopropenyl magnesium bromide；1-Methylvinylmagnesiumbromide;1-Propen-2-ylmagnesium bromide;a-Methylvinylmagnesium bromide 13291-18-4 C3H5BrMg 详情 详情
(VIII) 49264 (5S,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(4-methoxybenzyl)oxy]-2-methyl-1-hepten-3-ol C22H38O4Si 详情 详情
(IX) 49265 ethyl (E,7S,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-8-[(4-methoxybenzyl)oxy]-4-methyl-4-nonenoate C26H44O5Si 详情 详情
(X) 49266 ethyl (E,7S,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-4-methyl-4-nonenoate C18H36O4Si 详情 详情
(XI) 49267 ethyl (E,7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-8-oxo-4-nonenoate C18H34O4Si 详情 详情
(XII) 49268 ethyl (7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-4,5-dihydroxy-4-methyl-8-oxononanoate C18H36O6Si 详情 详情
(XIII) 40820 tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride C17H33ClNPS 详情 详情
(XIV) 49269 (5R)-5-[(1R,3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl]-5-methyldihydro-2(3H)-furanone C21H35NO4SSi 详情 详情
(XV) 49270 (5S)-5-[(1S,3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl]-5-methyldihydro-2(3H)-furanone C21H35NO4SSi 详情 详情
(XVI) 49271 methyl 3-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]propanoate C22H37NO4SSi 详情 详情
(XVII) 49272 methyl 3-[(2S,3R)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]propanoate C22H37NO4SSi 详情 详情

合成路线34

The reduction of the methyl ester of (XVI) with DIBAL in dichloromethane gives the aldehyde (XVIII), which is condensed with the chiral phosphonate (XIX) by means of BuLi in ethyl ether to yield the enoylsultam (XX). The methylation of (XX) with L-selectride and methyl iodide affords the methylated sultam (XXI), which is desilylated with TBAF and reprotected with Tes-Cl and TEA to provide triethylsilyl ether (XXII) with a more favorable silyl leaving group needed in the remaining synthetic steps. Elimination of the sultam group of (XXII) by means of DIBAL in dichloromethane gives the aldehyde (XXIII), which is condensed with the ketone (XXIV) by means of LDA to yield the aldol (XXV). The protection of the OH group of (XXV) with Troc-Cl ad pyridine affords compound (XXVI), which is oxidized at the terminal vinyl group by means of OsO4 and NaIO4 to provide the aldehyde (XXVII). The selective desilylation of (XXVII) by means of HF and pyridine furnishes the hydroxy aldehyde (XXVIII).

参考文献 中间体
【1】 Martin, H.J.; et al.; How stable are epoxides? A novel synthesis of epothilone B. Angew Chem. Int Ed Engl 2000, 39, 3, 581.
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) 49271 methyl 3-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]propanoate C22H37NO4SSi 详情 详情
(XVIII) 49273 3-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]propanal C21H35NO3SSi 详情 详情
(XIX) 49274 diethyl 2-(10,10-dimethyl-2,2-dioxo-2lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl)-2-oxoethylphosphonate C16H28NO6PS 详情 详情
(XX) 49275 4-((E)-5-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-2-pentenoyl)-10,10-dimethyl-2lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-2,2-dione C33H52N2O5S2Si 详情 详情
(XXI) 49276 4-((2S)-5-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-2-methylpentanoyl)-10,10-dimethyl-2lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-2,2-dione C34H56N2O5S2Si 详情 详情
(XXII) 49277 10,10-dimethyl-4-[(2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanoyl]-2lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-2,2-dione C34H56N2O5S2Si 详情 详情
(XXIII) 49278 (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal C24H41NO3SSi 详情 详情
(XXIV) 44451 (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one C16H32O2Si 详情 详情
(XXV) 49279 (4S,7R,8R,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one C40H73NO5SSi2 详情 详情
(XXVI) 49280 (1R,2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4,4-trimethyl-1-[(1S)-1-methyl-4-((2R,3S)-2-methyl-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 C43H74Cl3NO7SSi2 详情 详情
(XXVII) 49281 (1R,2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4,4-trimethyl-1-[(1S)-1-methyl-4-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)butyl]-3,7-dioxoheptyl 2,2,2-trichloroethyl carbonate C42H72Cl3NO8SSi2 详情 详情
(XXVIII) 49282 (1R,2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-1-((1S)-4-[(2R,3S)-3-[(2S,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-1-methylbutyl)-2,4,4-trimethyl-3,7-dioxoheptyl 2,2,2-trichloroethyl carbonate C36H58Cl3NO8SSi 详情 详情

合成路线35

The oxidation of the aldehyde group of (XXVIII) with NaClO2 gives the hydroxyacid (XXIX), which is submitted to a Yamaguchi cyclization by means of 2,4,6-trichlorobenzoyl chloride to yield the macrolactone (XXX). Elimination of the Troc protecting group of (XXX) with Zn and NH4Cl affords the silylated precursor (XXXI), which is finally treated with HF and pyridine to provide the target epothilone B.

参考文献 中间体
【1】 Martin, H.J.; et al.; How stable are epoxides? A novel synthesis of epothilone B. Angew Chem. Int Ed Engl 2000, 39, 3, 581.
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) 49282 (1R,2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-1-((1S)-4-[(2R,3S)-3-[(2S,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-1-methylbutyl)-2,4,4-trimethyl-3,7-dioxoheptyl 2,2,2-trichloroethyl carbonate C36H58Cl3NO8SSi 详情 详情
(XXIX) 49283 　 C37H61Cl3NO9SSi 详情 详情
(XXX) 49284 (1S,3S,7S,10R,11R,12S,16R)-7-[[tert-butyl(dimethyl)silyl]oxy]-8,8,10,12,16-pentamethyl-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 C36H56Cl3NO8SSi 详情 详情
(XXXI) 49285 (1S,3S,7S,10R,11R,12S,16R)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione C33H55NO6SSi 详情 详情

合成路线36

The cyclization of phosphonate (I) with the chiral alcohol (II) by means of tert-butyl hypochlorite and Et-MgBr gives the isoxazoline (III), which is condensed with 2-methylthiazole-4-carbaldehyde (IV) by means of DBU and LiCl in acetonitrile to yield the secondary alcohol (V). The oxidation of (V) with TPAP and NMO in dichloromethane affords the corresponding ketone (VI), which is treated with the Grignard reagent (VII) in THF to provide the expected secondary alcohol (VIII). The silylation of (VIII) with Tes-OTf in dichloromethane gives the silyl ether (IX), which is treated with SmI2, Et3B and NaBH4 to cleave the isoxazoline ring and yield the diol (X). The reaction of (X) with SOCl2, TEA and TBAF affords the chiral epoxide (XI), which is silylated with Tes-Cl and TEA to provide the silyl ether (XII). The selective hydrolysis of the primary silyl ether of (XII) with HOAc in THF/water gives the primary alcohol (XIII), which is oxidized with TPAP and NMO in dichloromethane to yield the corresponding aldehyde (XIV). The condensation of (XIV) with ketone (XV) by means of LDA affords the open-chain precursor (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) 49286 diethyl 2-(hydroxyimino)-1-methylethylphosphonate C7H16NO4P 详情 详情
(II) 49287 (2R)-3-buten-2-ol 33447-72-2 C4H8O 详情 详情
(III) 49288 diethyl 1-[(5R)-5-[(1R)-1-hydroxyethyl]-4,5-dihydro-3-isoxazolyl]ethylphosphonate C11H22NO5P 详情 详情
(IV) 44455 2-methyl-1,3-thiazole-4-carbaldehyde C5H5NOS 详情 详情
(V) 49289 (1R)-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-1-ethanol C12H16N2O2S 详情 详情
(VI) 49290 1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-1-ethanone C12H14N2O2S 详情 详情
(VII) 49291 bromo[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]magnesium C15H33BrMgOSi 详情 详情
(VIII) 49292 (2R,6S)-6-methyl-2-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-7-[(triisopropylsilyl)oxy]-2-heptanol C27H48N2O3SSi 详情 详情
(IX) 49293 (5R)-5-[(1R,5S)-1,5-dimethyl-1-[(triethylsilyl)oxy]-6-[(triisopropylsilyl)oxy]hexyl]-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydroisoxazole; (1R,5S)-1,5-dimethyl-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-6-[(triisopropylsilyl)oxy]hexyl triethylsilyl ether C33H62N2O3SSi2 详情 详情
(X) 49294 (E,3S,5R,6R,10S)-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-6-[(triethylsilyl)oxy]-11-[(triisopropylsilyl)oxy]-1-undecene-3,5-diol C33H65NO4SSi2 详情 详情
(XI) 49295 (2S,3E)-3-methyl-1-((2S,3R)-3-methyl-3-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]oxiranyl)-4-(2-methyl-1,3-thiazol-4-yl)-3-buten-2-ol C27H49NO3SSi 详情 详情
(XII) 49296 (2S)-2-methyl-5-((2R,3S)-2-methyl-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-methyl-3-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]oxiranyl)-3-[(triethylsilyl)oxy]-1-butenyl]-1,3-thiazole C33H63NO3SSi2 详情 详情
(XIII) 49297 (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-pentanol C24H43NO3SSi 详情 详情
(XIV) 49278 (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal C24H41NO3SSi 详情 详情
(XV) 44451 (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one C16H32O2Si 详情 详情
(XVI) 49298 (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one C40H73NO5SSi2 详情 详情

合成路线37

The protection of the OH group of (XVI) with Troc-Cl and pyridine affords compound (XVII), which is oxidized at the terminal vinyl group by means of OsO4, NMO and Pb(OAc)4 to provide the carboxylic acid (XVIII). The selective cleavage of the Tes- protecting group with HF and pyridine furnishes the hydroxyacid (XIX), which is submitted to a macrolactonization by means of 2,4,6-trichlorobenzoyl chloride to give 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 B.

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) 49298 (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one C40H73NO5SSi2 详情 详情
(XVII) 49299 (1S,2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4,4-trimethyl-1-[(1S)-1-methyl-4-((2R,3S)-2-methyl-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 C43H74Cl3NO7SSi2 详情 详情
(XVIII) 49300 (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-11-((2R,3S)-2-methyl-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 C42H72Cl3NO9SSi2 详情 详情
(XIX) 49301 (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]-2-methyloxiranyl]-4,4,6,8-tetramethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]undecanoic acid C36H58Cl3NO9SSi 详情 详情
(XX) 49302 (1S,3S,7S,10R,11S,12S,16R)-7-[[tert-butyl(dimethyl)silyl]oxy]-8,8,10,12,16-pentamethyl-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 C36H56Cl3NO8SSi 详情 详情
(XXI) 49303 (1S,3S,7S,10R,11S,12S,16R)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione C33H55NO6SSi 详情 详情

合成路线38

The synthesis of the chiral 3-heptanone intermediate has been obtained as follows: The protection of the OH group of the chiral lactone (I) with Tbdms-Cl and imidazole gives the silyl ether (II), which is reduced with DIBAL to yield the lactol (III).The reaction of (III) with the Tebbe reagent affords the pentenol derivative (IV), which is oxidized with Dess-Martin periodinane (DMP), affording the aldehyde (V). The Grignard synthesis of (V) with ethylmagnesium bromide (VI) provides the 3-heptanol derivative (VII), which is hydroxylated at the terminal double bond by means of BH3/THF and H2O2, giving the diol (VIII). The selective protection of the primary OH group of (VIII) with Dmt-Cl, DIEA and DMAP yields the trityl ether (IX), which is finally oxidized with DMP to afford the desired chiral heptanone (X)

参考文献 中间体
【1】 Martin, N.; Thomas, E.J.; Total syntheses of epothilones B and D: Applications of allylstannanes in organic synthesis. Tetrahedron Lett 2001, 42, 47, 8373.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51427 D-Pantolactone; R(-)-2-Hydroxy-3,3-dimethyl-gamma-butyrolactone 599-04-2 C6H10O3 详情 详情
(II) 51428 (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyldihydro-2(3H)-furanone C12H24O3Si 详情 详情
(III) 51429 (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyltetrahydro-2-furanol C12H26O3Si 详情 详情
(IV) 51430 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-4-penten-1-ol C13H28O2Si 详情 详情
(V) 51431 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-4-pentenal C13H26O2Si 详情 详情
(VI) 24239 bromo(ethyl)magnesium；ethylmagnesium bromide 925-90-6 C2H5BrMg 详情 详情
(VII) 51432 (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-6-hepten-3-ol C15H32O2Si 详情 详情
(VIII) 51433 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-1,5-heptanediol C15H34O3Si 详情 详情
(IX) 51434 (5S)-7-[bis(4-methoxyphenyl)(phenyl)methoxy]-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanol C36H52O5Si 详情 详情
(X) 51435 (5S)-7-[bis(4-methoxyphenyl)(phenyl)methoxy]-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone C36H50O5Si 详情 详情

合成路线39

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

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

合成路线40

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

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

合成路线41

The ketonic intermediate (VI) has been obtained as follows: The condensation of the 3-(tert-butyldimethylsilyloxy)propionaldehyde (I) with the silylated enol ether (II), catalyzed by the chiral boron reagent (III), gives the phenyl hydroxyester (IV), which is protected with Tbdms-Cl to provide the silyl ether (V). Finally, the Grignard reaction of (V) with Et-MgBr affords the target ketonic intermediate (VI).

参考文献 中间体
【1】 Chen, Y.; Taylor, R.E.; Total synthesis of epothilones B and D. Org Lett 2001, 3, 14, 2221.
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) 45546 3-[[tert-butyl(dimethyl)silyl]oxy]propanal 570-24-1 C9H20O2Si 详情 详情
(II) 52563 trimethyl{[2-methyl-1-(phenyloxy)-1-propenyl]oxy}silane; 2-methyl-1-(phenyloxy)-1-propenyl trimethylsilyl ether C13H20O2Si 详情 详情
(III) 52564 4-(1-methylethyl)-3-[(4-nitrophenyl)sulfonyl]-1,3,2-oxazaborolidin-5-one C11H13BN2O6S 详情 详情
(IV) 52565 phenyl 5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-hydroxy-2,2-dimethylpentanoate C19H32O4Si 详情 详情
(V) 52566 phenyl 3,5-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,2-dimethylpentanoate C25H46O4Si2 详情 详情
(VI) 40830 (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone C21H46O3Si2 详情 详情

合成路线42

The chiral iodovinyl derivative (IX) has been obtained as follows: The chiral alkyne (VII) is treated with trimethylsilyl chloride and NaI to give the iodovinyl compound (VIII), which is finally enantioselectively methylated with NaHMDS and methyl iodide to afford the target iodovinyl compound (IX).

参考文献 中间体
【1】 Chen, Y.; Taylor, R.E.; Total synthesis of epothilones B and D. Org Lett 2001, 3, 14, 2221.
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) 52567 3-(6-heptynoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one C17H19NO3 详情 详情
(VIII) 52568 3-(6-iodo-6-heptenoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one C17H20INO3 详情 详情
(IX) 52569 3-(6-iodo-2-methyl-6-heptenoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one C18H22INO3 详情 详情

合成路线43

The allylation of 2-(2-methylthiazol-4-ylmethylene)propionaldehyde (X) with allyl(diisopinocampheyl)borane gives the chiral secondary alcohol (XI), which is protected with Tbdms-Cl, yielding the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and NaIO4 affords the chiral aldehyde (XIII), which is condensed with the intermediate iodovinyl compound (IX) by means of Ni/Cr to provide the allyl alcohol derivative (XIV). The reaction of (XIV) with SOCl2 gives the rearranged chloromethyl compound (XV), which is treated with LiEt3BH to cleave the oxazolidine chiral auxiliary and dechlorinate the chloromethyl group, yielding the primary alcohol (XVI). The controlled oxidation of the OH group of (XVI) with PCC affords the aldehyde (XVII), which is submitted to an aldol condensation with the intermediate ketone (VI) by means of LDA to provide the aldol (XVIII). The protection of the OH group of (XVIII) with Tbdms-Cl gives the fully silylated compound (XIX), which is regioselectively monodesilylated with camphorsulfonic acid (CSA) to yield the primary alcohol (XX).

参考文献 中间体
【1】 Chen, Y.; Taylor, R.E.; Total synthesis of epothilones B and D. Org Lett 2001, 3, 14, 2221.
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) 40830 (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone C21H46O3Si2 详情 详情
(IX) 52569 3-(6-iodo-2-methyl-6-heptenoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one C18H22INO3 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) 52571 3-[9-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-2,10-dimethyl-6-methylidene-11-(2-methyl-1,3-thiazol-4-yl)-10-undecenoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one C34H50N2O5SSi 详情 详情
(XV) 52570 3-[6-(chloromethyl)-9-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one C34H49ClN2O4SSi 详情 详情
(XVI) 40828 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol C24H43NO2SSi 详情 详情
(XVII) 40829 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal C24H41NO2SSi 详情 详情
(XVIII) 40831 (7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one C45H87NO5SSi3 详情 详情
(XIX) 40832 (7S,10R,11S,12S,16Z,19S)-7,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one C51H101NO5SSi4 详情 详情
(XX) 40833 (5S,8R,9S,10S,14Z,17S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,14,19,19,20,20-tridecamethyl-17-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one C45H87NO5SSi3 详情 详情

合成路线44

The oxidation of alcohol (XX) with PCC and NaClO2 gives the carboxylic acid (XXI), which is regioselectively monodesilylated with TBAF, yielding the hydroxyacid (XXII). The macrolactonization of (XXII) under Yamaguchi conditions (2,4,6-trichlorobenzoyl chloride) affords the macrolactone (XXIII), which is desilylated with HF and pyridine to provide the precursor (XXIV). Finally, this compound is epoxidated with MCPBA to afford the target epothilone B.

参考文献 中间体
【1】 Chen, Y.; Taylor, R.E.; Total synthesis of epothilones B and D. Org Lett 2001, 3, 14, 2221.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XX) 40833 (5S,8R,9S,10S,14Z,17S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,14,19,19,20,20-tridecamethyl-17-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one C45H87NO5SSi3 详情 详情
(XXI) 40834 (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C45H85NO6SSi3 详情 详情
(XXII) 40835 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(XXIII) 40836 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H69NO5SSi2 详情 详情
(XXIV) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情

合成路线45

The intermediate carboxylic acid (V) has been obtained as follows: The reaction of the chiral auxiliary oxazolidinone (I) with the oxoaldehyde (II) by means of Bu2B-OTf, DIEA and Raney Ni in dichloromethane gives the oxazolidide (III), which is treated with Tbdms-OTf, yielding the silyl ether (IV), which is easily purified. Elimination of the auxiliary with LiOH and H2O2 in THF/water affords the target carboxylic acid (V).

参考文献 中间体
【1】 Valluri, M.; et al.; Total synthesis of epothilone B. Org Lett 2001, 3, 23, 3607.
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) 52571 3-[9-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-2,10-dimethyl-6-methylidene-11-(2-methyl-1,3-thiazol-4-yl)-10-undecenoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one C34H50N2O5SSi 详情 详情
(II) 44448 2,2-dimethyl-3-oxopentanal C7H12O2 详情 详情
(III) 52572 4-(1-methylethyl)-3-[2-(methylsulfanyl)acetyl]-1,3-oxazolidin-2-one C9H15NO3S 详情 详情
(IV) 52573 3-hydroxy-4,4-dimethyl-1-[4-(1-methylethyl)-2-oxo-1,3-oxazolidin-3-yl]-1,5-heptanedione C15H25NO5 详情 详情
(V) 43166 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid C15H30O4Si 详情 详情

合成路线46

The reaction of bromide (V) with Mg and then with CuBr and propyne gives a cuprate complex that is treated with 1-hexyne, yielding the nonisolated copper complex (VII). The reaction of the protected chiral epoxide (IX) (obtained by reaction of the epoxide (VIII) with Pmb-Br, NaH and TBAI in THF) with copper complex (VII) affords the (Z)-alkene (X), which is treated with Sem-Cl and DIEA to protect its OH group, providing (XI). Selective elimination of the Pmb protecting group of (XI) with DDQ furnishes the secondary alcohol (XII), which is oxidized under Swern protocol to the ketone (XIII) with (COCl)2 and TEA in dichloromethane. The Wadsworth-Emmons olefination of (XIII) with the known phosphonate (XIV) by means of BuLi in THF gives pure triene (XV), which is submitted to a diastereoselective hydroboration with bis(diisopinocampheyl)borane and oxidative workup to yield the primary alcohol (XVI). The Swern oxidation of (XVI) with (COCl)2 affords the aldehyde (XVII), which is submitted to an aldol condensation with the intermediate oxoacid (V) by means of LDA in THF to provide the aldol product (XVIII) as a (6R,7S)(6S,7R) diastereomeric mixture.

参考文献 中间体
【1】 Valluri, M.; et al.; Total synthesis of epothilone B. Org Lett 2001, 3, 23, 3607.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIIIa) 52584 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-12,16-heptadecadienoic acid C39H71NO7S2Si 详情 详情
(XVIIIb) 52585 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-12,16-heptadecadienoic acid C39H71NO7S2Si 详情 详情
(V) 43166 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid C15H30O4Si 详情 详情
(VI) 52575 5-bromo-2-methyl-1-pentene C6H11Br 详情 详情
(VII) 52576 (2,6-dimethyl-1,6-heptadienyl)(1-hexynyl)copper C15H24Cu 详情 详情
(VIII) 52577 1-(2-oxiranyl)-1-ethanol n/a C4H8O2 详情 详情
(IX) 52578 methyl 4-({[1-(2-oxiranyl)ethyl]oxy}methyl)phenyl ether; 2-[1-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]oxirane C2H5NS 详情 详情
(X) 52579 6,10-dimethyl-2-({[4-(methyloxy)phenyl]methyl}oxy)-5,10-undecadien-3-ol C21H32O3 详情 详情
(XI) 52580 4-(3,7-dimethyl-2,7-octadienyl)-3,10,10-trimethyl-1-[4-(methyloxy)phenyl]-2,5,7-trioxa-10lambda~4~-thiaundecane; 4,8-dimethyl-1-[1-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]-3,8-nonadienyl {[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl ether C27H46O4S 详情 详情
(XII) 52581 6,10-dimethyl-3-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-5,10-undecadien-2-ol C19H38O3S 详情 详情
(XIII) 52582 6,10-dimethyl-3-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-5,10-undecadien-2-one C19H36O3S 详情 详情
(XIV) 44442 diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C9H16NO3PS 详情 详情
(XV) 52583 4,8-dimethyl-1-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl {[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl ether; 2-methyl-4-{2,6,10-trimethyl-3-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-1,5,10-undecatrienyl}-1,3-thiazole C24H41NO2S2 详情 详情
(XVI) 51454 (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6,10-undecadien-1-ol C24H43NO3S2 详情 详情
(XVII) 51455 (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[[2-(trimethyl-lambda(4)-sulfanyl)ethoxy]methoxy]-6,10-undecadienal C24H41NO3S2 详情 详情

合成路线47

The treatment of (XVIII) with Troc-Cl and pyridine gives fully protected (XIX) as the same diastereomeric mixture, which is selectively deprotected at the Sem group with TFA in dichloromethane to yield the corresponding mixture of hydroxyacids (XX). The macrolactonization of (XX) by the Yamaguchi method (2,4,6-trichlrobenzoyl chloride, TEA and DMAP in toluene) gives the diastereomeric mixture of lactones (XXI), which are readily separated by flash column chromatography. The desired diastereomer (XXII) is desilylated with HF and pyridine, yielding the hydroxylactone (XXIII), which is treated with Zn and NH4Cl in refluxing aqueous methanol to eliminate the Troc protecting group and provide the unprotected precursor (XXIV). Finally, this compound is epoxidated with methyl(trifluoromethyl)dioxirane (MTFDO) to afford the target epothilone B.

参考文献 中间体
【1】 Valluri, M.; et al.; Total synthesis of epothilone B. Org Lett 2001, 3, 23, 3607.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIIIa) 52584 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-12,16-heptadecadienoic acid C39H71NO7S2Si 详情 详情
(XVIIIb) 52585 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-12,16-heptadecadienoic acid C39H71NO7S2Si 详情 详情
(XIXa) 52586 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-({[(2,2,2-trichloroethyl)oxy]carbonyl}oxy)-15-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-12,16-heptadecadienoic acid C42H72Cl3NO9S2Si 详情 详情
(XIXb) 52587 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-({[(2,2,2-trichloroethyl)oxy]carbonyl}oxy)-15-[({[2-(trimethyl-lambda~4~-sulfanyl)ethyl]oxy}methyl)oxy]-12,16-heptadecadienoic acid C42H72Cl3NO9S2Si 详情 详情
(XXa) 52588 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-({[(2,2,2-trichloroethyl)oxy]carbonyl}oxy)-12,16-heptadecadienoic acid C36H58Cl3NO8SSi 详情 详情
(XXb) 52589 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-({[(2,2,2-trichloroethyl)oxy]carbonyl}oxy)-12,16-heptadecadienoic acid C36H58Cl3NO8SSi 详情 详情
(XXIa),(XXII) 52590 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-2,6-dioxooxa-13-cyclohexadecen-8-yl 2,2,2-trichloroethyl carbonate C36H56Cl3NO7SSi 详情 详情
(XXIb) 52591 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-2,6-dioxooxa-13-cyclohexadecen-8-yl 2,2,2-trichloroethyl carbonate C36H56Cl3NO7SSi 详情 详情
(XXIII) 52592 4-hydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-2,6-dioxooxa-13-cyclohexadecen-8-yl 2,2,2-trichloroethyl carbonate C30H42Cl3NO7S 详情 详情
(XXIV) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情

合成路线48

The reaction of 4-methyl-4-penten-1-ol (I) with PBr3 gives the corresponding alkyl bromide (II), which is condensed with epoxide (III) and propyne (IV) by means of Mg, CuI and pentynyl lithium to yield, after silylation with Tbdms-Cl, the protected diol (V). The selective deprotection of (V) with DDQ gives the secondary alcohol (VI), which is oxidized by the Swern reagent to afford the ketone (VII). Alternatively, ketone (VII) can also be obtained by direct oxidation of the protected diol (V) with the Jones reagent. The Horner Emmons condensation of ketone (VII) with phosphonate (VIII) provides the unsaturated alkyl thiazole (IX), which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X). The oxidation of (X) with the complex SO3/Pyr yields the carbaldehyde (XI). Alternatively, (XI) can also be obtained by direct oxidation of the terminal double bond of (IX) with (Ipc)2BH and pyridinium chlorochromate (PCC). The condensation of aldehyde (XI) with ketoacid (XII) by means of LDA in THF affords the heptadecadienoic acid (XIII), which is silylated with Tbdms-OTf to provide the protected linear precursor (XIV). The cyclization of (XIV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XV), which is desilylated by means of TBAF in THF to yield the unprotected precursor (XVI). Finally, this compound is epoxidated by means of dimethyldioxirane (DMDO) in acetone to afford the target epothilone B.

参考文献 中间体
【1】 Avery, M.A. (University of Mississippi); Synthesis of epothilones and related analogs. WO 0230356 .
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) 54285 4-methyl-4-penten-1-ol 22508-64-1 C6H12O 详情 详情
(II) 52575 5-bromo-2-methyl-1-pentene C6H11Br 详情 详情
(III) 52578 methyl 4-({[1-(2-oxiranyl)ethyl]oxy}methyl)phenyl ether; 2-[1-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]oxirane C2H5NS 详情 详情
(IV) 51602 1-Propyne C3H4 详情 详情
(V) 54286 tert-butyl(dimethyl)silyl (1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl ether; tert-butyl[((1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl)oxy]dimethylsilane n/a C27H46O3Si 详情 详情
(VI) 54287 (2R,3S,5Z)-3-{[tert-butyl(dimethyl)silyl]oxy}-6,10-dimethyl-5,10-undecadien-2-ol n/a C19H38O2Si 详情 详情
(VII) 54288 (3S,5Z)-3-{[tert-butyl(dimethyl)silyl]oxy}-6,10-dimethyl-5,10-undecadien-2-one n/a C19H36O2Si 详情 详情
(VIII) 44442 diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C9H16NO3PS 详情 详情
(IX) 54289 tert-butyl(dimethyl)silyl (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl ether; 4-((1E,3S,5Z)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,6,10-trimethyl-1,5,10-undecatrienyl)-2-methyl-1,3-thiazole n/a C24H41NOSSi 详情 详情
(X) 40828 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol C24H43NO2SSi 详情 详情
(XI) 40829 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal C24H41NO2SSi 详情 详情
(XII) 43166 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid C15H30O4Si 详情 详情
(XIII) 46118 (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(XIV) 40834 (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C45H85NO6SSi3 详情 详情
(XV) 40836 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H69NO5SSi2 详情 详情
(XVI) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情

合成路线49

The condensation of 3-buten-2-one (I) with the phosphonate (II) by means of LDA gives the alkylated thiazole (III), which is enantioselectively epoxidated to the chiral oxirane (V) by means of oxone and the chiral ketone (IV). Alternatively, the oxidation of the chiral epoxybutanol (VI) with CrO3 or SO3 /pyridine yields the epoxybutanone (VII), which is condensed with phosphorane (II) by means of LDA to afford the already reported chiral oxirane (V). The condensation of (V) with alkyl bromide (VIII) and propyne (IX) by means of Mg, CuBr and pentynyl lithium provides the undecatrienyl thiazole (X), which is treated with Tms-OTf in order to protect its OH group, yielding the silyl ether (XI). The oxidation of the terminal double bond of (XI) by means of (Ipc)2BH and CrO3 affords the carbaldehyde (XII), which is condensed with ketoacid (XIII) by means of LDA in THF to provide the undecadienoic acid (XIV). The cyclization of (XIV) by means of benzenesulfonyl chloride and pyridine gives the macrocyclic intermediate (XV), which is finally epoxidated by means of DMDO in acetone to furnish the target epothilone B.

参考文献 中间体
【1】 Avery, M.A. (University of Mississippi); Synthesis of epothilones and related analogs. WO 0230356 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
54294 1-pentynyllithium n/a C5H7Li 详情 详情
(I) 30324 3-buten-2-one; methyl vinyl ketone 78-94-4 C4H6O 详情 详情
(II) 44442 diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C9H16NO3PS 详情 详情
(III) 54290 2-methyl-4-[(1E)-2-methyl-1,3-butadienyl]-1,3-thiazole n/a C9H11NS 详情 详情
(IV) 54291 　 n/a C13H20O5 详情 详情
(V) 54293 2-methyl-4-{(E)-2-[(2R)oxiranyl]-1-propenyl}-1,3-thiazole n/a C9H11NOS 详情 详情
(VI) 52597 1-(2-oxiranyl)-1-ethanol C4H8O2 详情 详情
(VII) 54292 1-[(2R)oxiranyl]-1-ethanone n/a C4H6O2 详情 详情
(VIII) 52575 5-bromo-2-methyl-1-pentene C6H11Br 详情 详情
(IX) 51602 1-Propyne C3H4 详情 详情
(X) 54295 (1E,3S,5Z)-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5,10-undecatrien-3-ol n/a C18H27NOS 详情 详情
(XI) 54296 2-methyl-4-{(1E,3S,5Z)-2,6,10-trimethyl-3-[(trimethylsilyl)oxy]-1,5,10-undecatrienyl}-1,3-thiazole; (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl trimethylsilyl ether n/a C21H35NOSSi 详情 详情
(XII) 54297 (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[(trimethylsilyl)oxy]-6,10-undecadienal n/a C21H35NO2SSi 详情 详情
(XIII) 52596 3-hydroxy-4,4-dimethyl-5-oxoheptanoic acid C9H16O4 详情 详情
(XIV) 54298 (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-trihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid n/a C27H43NO6S 详情 详情
(XV) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情

合成路线50

The condensation of alkyl bromide (I) with epoxide (II) and propyne (III) by means of Mg, CuI and pentynyl lithium gives the secondary alcohol (IV), which is silylated with Sem-Cl to yield the protected diol (V). The selective deprotection of (V) with DDQ gives the secondary alcohol (VI), which is oxidized by means of SO3 /pyridine to afford the ketone (VII). The condensation of ketone (VII) with phosphonate (VIII) by means of BuLi in THF provides the unsaturated alkyl thiazole (IX), which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X). The oxidation of (X) with oxalyl chloride yields the carbaldehyde (XI), which is condensed with ketoacid (XII) by means of LDA in THF to afford the heptadecadienoic acid (XIII). The protection of the free OH group of (XIII) with Troc-Cl and DMAP in dichloromethane provides the protected linear precursor (XIV), which is selectively monodeprotected with TFA in dichloromethane to furnish the linear hydroxyacid (XV). The macrocyclization of (XV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XVI), which is deprotected first with HF and pyridine (desilylation), and then with Zn and HOAc (elimination of the Troc protecting group), to yield the unprotected precursor (XVII). Finally, this compound is epoxidated by means of dimethyldioxirane (DMDO) in acetone to afford the target epothilone B.

参考文献 中间体
【1】 Avery, M.A. (University of Mississippi); Synthesis of epothilones and related analogs. WO 0230356 .
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) 52575 5-bromo-2-methyl-1-pentene C6H11Br 详情 详情
(II) 52578 methyl 4-({[1-(2-oxiranyl)ethyl]oxy}methyl)phenyl ether; 2-[1-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]oxirane C2H5NS 详情 详情
(III) 51602 1-Propyne C3H4 详情 详情
(IV) 54286 tert-butyl(dimethyl)silyl (1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl ether; tert-butyl[((1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl)oxy]dimethylsilane n/a C27H46O3Si 详情 详情
(V) 54299 (3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-1-(4-methoxyphenyl)-3,10,10-trimethyl-2,5,7-trioxa-10-silaundecane; 4-{(3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-3,10,10-trimethyl-2,5,7-trioxa-10-silaundec-1-yl}phenyl methyl ether n/a C27H46O4Si 详情 详情
(VI) 54300 (2R,3S,5Z)-6,10-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5,10-undecadien-2-ol n/a C19H38O3Si 详情 详情
(VII) 54301 (3S,5Z)-6,10-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5,10-undecadien-2-one n/a C19H36O3Si 详情 详情
(VIII) 44442 diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C9H16NO3PS 详情 详情
(IX) 54302 2-methyl-4-((1E,3S,5Z)-2,6,10-trimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-1,5,10-undecatrienyl)-1,3-thiazole; (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl [2-(trimethylsilyl)ethoxy]methyl ether n/a C24H41NO2SSi 详情 详情
(X) 54303 (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methoxy}-6,10-undecadien-1-ol n/a C24H43NO3SSi 详情 详情
(XI) 54304 (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methoxy}-6,10-undecadienal n/a C24H41NO3SSi 详情 详情
(XII) 43166 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid C15H30O4Si 详情 详情
(XIII) 54305 (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid n/a C39H71NO7SSi2 详情 详情
(XIV) 54306 (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid n/a C42H72Cl3NO9SSi2 详情 详情
(XV) 54307 (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-12,16-heptadecadienoic acid n/a C36H58Cl3NO8SSi 详情 详情
(XVI) 52590 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-2,6-dioxooxa-13-cyclohexadecen-8-yl 2,2,2-trichloroethyl carbonate C36H56Cl3NO7SSi 详情 详情
(XVII) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情

合成路线51

The intermediate phosphonium bromide (XVII) is obtained as follows: The reaction of the glucoside (I) with Me2CuLi in THF gives the methyl derivative (II), which is converted into the unsaturated pyranoside (III). The reductive deoxygenation of (III) with Pd(OAc)2 and NaBH4 affords the acetate (IV), which is treated with NaOMe in methanol to afford the carbinol (V). The oxidation of (V) with oxalyl chloride in DMSO provides the carbaldehyde (VI), which is treated with Me-Mg-Br in THF to give the secondary alcohol (VII). The oxidation of (VII) with oxalyl chloride in DMSO yields the ketone (VIII), which is condensed with the phosphonate (IX) (obtained by reaction of 4-(chloromethyl)-2-methylthiazole (X) with triethyl phosphite (XI) at 165 C) by means of tBu-OK in THF to afford the vinyl-dihydropyran (XII). The opening of the dihydropyran ring of (XII) by means of HOAc in THF/water, followed by reduction of the intermediate aldehyde, provides the unsaturated diol (XIII). The regioselective bromination of (XIII) with CBr4 and PPh3 in acetonitrile gives the bromo derivative (XIV), which is silylated with Tbdms-OTf to yield the silyl ether derivative (XV). Finally, this compound is condensed with methylenetriphenylphosphorane (XVI) in THF to afford the target intermediate, the phosphonium bromide (XVII).

参考文献 中间体
【1】 Potier, P.; Ermolenko, M.S.; Synthesis of epothilones B and D from D-glucose. Tetrahedron Lett 2002, 43, 16, 2895.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 54335 (1aR,2S,3aR,6R,7aS,7bS)-2-methoxy-6-phenylhexahydrooxireno[2',3':4,5]pyrano[3,2-d][1,3]dioxine; (1aR,2S,3aR,6R,7aS,7bS)-6-phenylhexahydrooxireno[2',3':4,5]pyrano[3,2-d][1,3]dioxin-2-yl methyl ether n/a C14H16O5 详情 详情
(II) 54336 (2R,4aR,6S,7S,8S,8aS)-6-methoxy-7-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ol n/a C15H20O5 详情 详情
(III) 54337 [(2R,3S,6S)-3-(acetyloxy)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]methyl acetate n/a C12H18O6 详情 详情
(IV) 54338 [(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]methyl acetate n/a C10H16O4 详情 详情
(V) 54339 [(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]methanol n/a C8H14O3 详情 详情
(VI) 54340 (2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde n/a C8H12O3 详情 详情
(VII) 54341 (1R)-1-[(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]-1-ethanol n/a C9H16O3 详情 详情
(VIII) 54342 1-[(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]-1-ethanone n/a C9H14O3 详情 详情
(IX) 44442 diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C9H16NO3PS 详情 详情
(X) 40819 4-(chloromethyl)-2-methyl-1,3-thiazole C5H6ClNS 详情 详情
(XII) 54343 4-{(E)-2-[(2S,6S)-6-methoxy-5-methyl-3,6-dihydro-2H-pyran-2-yl]-1-propenyl}-2-methyl-1,3-thiazole; methyl (2S,6S)-3-methyl-6-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,6-dihydro-2H-pyran-2-yl ether n/a C14H19NO2S 详情 详情
(XIII) 54344 (2Z,5S,6E)-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadiene-1,5-diol n/a C13H19NO2S 详情 详情
(XIV) 54345 (1E,3S,5Z)-7-bromo-2,6-dimethyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-heptadien-3-ol n/a C13H18BrNOS 详情 详情
(XV) 46147 4-((1E,3S,5Z)-7-bromo-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; (1S,3Z)-5-bromo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl tert-butyl(dimethyl)silyl ether C19H32BrNOSSi 详情 详情
(XVI) 27301 methylene(triphenyl)phosphorane C19H17P 详情 详情
(XVII) 46148 [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide C38H49BrNOPSSi 详情 详情

合成路线52

The reaction of the glucoside (I) with Me2CuLi in THF gives the methyl derivative (II), which is oxidized with oxalyl chloride in DMSO to yield the tetrahydropyranone (XVIII). The treatment of (XVIII) with TEA in dichloromethane/methanol causes isomerization of the methyl group of (XVIII) to (XIX), which is reduced with NaBH4 in methanol/DMF to afford the secondary alcohol (XX). The cleavage of the benzylidene protecting group of (XX) with H2 over Pd/C in ethyl acetate provides the trihydroxy compound (XXI), which is regioselectively monosilylated at the primary OH group with Tbdms-Cl and pyridine to gives the silyl ether (XXII). The epoxidation of (XXII) by the orthoester method yields the epoxide (XXIII), which is opened with dimethylmagnesium in ethyl ether to afford the methylated secondary alcohol (XXIV). The desilylation of (XXIV) by means of TBAF in THF provides the dihydroxy compound (XXV), which is regioselectively brominated with CBr4 and PPh3 to give the bromomethyl compound (XXVI). The silylation of the remaining OH group of (XXVI) with Tbdms-Cl and imidazole in DMF yields the silyl ether (XXVII), which is treated with Zn in hot isopropanol/water to open the tetrahydropyran ring to afford, with simultaneous dehydrobromination, the unsaturated aldehyde (XXVIII). The reduction of (XXVIII) with NaBH4 provides the corresponding alcohol (XXIX), which is silylated with Tbdms-Cl as before to give the fully silylated diol (XXX). The oxidation of the terminal double bond of (XXX) first with OsO4 and then with H5IO6 yields the aldehyde (XXXI), which is condensed with the Grignard reagent (XXXII) to afford the secondary alcohol (XXXIII). The oxidation of (XXXIII) with TPAP and NMO in acetonitrile provides the ketone (XXXIV), which is oxidized at its terminal double bond with OsO4 and H5IO6 to give the carbaldehyde (XXXV). The condensation of (XXXV) with the lithium derivative of tert-butyl acetate (XXXVI), followed by silylation of the intermediate alcohol, yields the nonanoic ester (XXXVII), which is regioselectively monodesilylated with PPTS in ethanol to afford the primary alcohol (XXXVIII).

参考文献 中间体
【1】 Potier, P.; Ermolenko, M.S.; Synthesis of epothilones B and D from D-glucose. Tetrahedron Lett 2002, 43, 16, 2895.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 54335 (1aR,2S,3aR,6R,7aS,7bS)-2-methoxy-6-phenylhexahydrooxireno[2',3':4,5]pyrano[3,2-d][1,3]dioxine; (1aR,2S,3aR,6R,7aS,7bS)-6-phenylhexahydrooxireno[2',3':4,5]pyrano[3,2-d][1,3]dioxin-2-yl methyl ether n/a C14H16O5 详情 详情
(II) 54336 (2R,4aR,6S,7S,8S,8aS)-6-methoxy-7-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ol n/a C15H20O5 详情 详情
(XVIII) 54346 (2R,4aR,6S,7R,8aR)-6-methoxy-7-methyl-2-phenyltetrahydropyrano[3,2-d][1,3]dioxin-8(4H)-one n/a C15H18O5 详情 详情
(XIX) 54347 (2R,4aR,6S,7S,8aR)-6-methoxy-7-methyl-2-phenyltetrahydropyrano[3,2-d][1,3]dioxin-8(4H)-one n/a C15H18O5 详情 详情
(XX) 54348 (2R,4aR,6S,7R,8S,8aS)-6-methoxy-7-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ol n/a C15H20O5 详情 详情
(XXI) 54349 (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-methoxy-5-methyltetrahydro-2H-pyran-3,4-diol n/a C8H16O5 详情 详情
(XXII) 54350 (2R,3S,4S,5R,6S)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methoxy-5-methyltetrahydro-2H-pyran-3,4-diol n/a C24H34O5Si 详情 详情
(XXIII) 54351 tert-butyl{[(1S,2R,4S,5R,6S)-4-methoxy-5-methyl-3,7-dioxabicyclo[4.1.0]hept-2-yl]methoxy}diphenylsilane; tert-butyl(diphenyl)silyl [(1S,2R,4S,5R,6S)-4-methoxy-5-methyl-3,7-dioxabicyclo[4.1.0]hept-2-yl]methyl ether n/a C24H32O4Si 详情 详情
(XXIV) 54352 (2S,3R,4R,5R,6S)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol n/a C25H36O4Si 详情 详情
(XXV) 54353 (2S,3R,4R,5R,6S)-2-(hydroxymethyl)-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol n/a C9H18O4 详情 详情
(XXVI) 54354 (2S,3R,4R,5R,6S)-2-(bromomethyl)-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol C9H17BrO3 详情 详情
(XXVII) 54355 (2S,3R,4R,5S,6S)-6-(bromomethyl)-4-{[tert-butyl(dimethyl)silyl]oxy}-3,5-dimethyltetrahydro-2H-pyran-2-yl methyl ether; {[(2S,3S,4R,5R,6S)-2-(bromomethyl)-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-yl]oxy}(tert-butyl)dimethylsilane C15H31BrO3Si 详情 详情
(XXVIII) 54356 (2R,3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dimethyl-5-hexenal C14H28O2Si 详情 详情
(XXIX) 54357 (2S,3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dimethyl-5-hexen-1-ol C14H30O2Si 详情 详情
(XXX) 42381 (5S,6R)-2,2,3,3,6,9,9,10,10-nonamethyl-5-[(1R)-1-methyl-2-propenyl]-4,8-dioxa-3,9-disilaundecane; tert-butyl(dimethyl)silyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-hexenyl ether C20H44O2Si2 详情 详情
(XXXI) 42702 (2R,3S,4S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethylpentanal C19H42O3Si2 详情 详情
(XXXII) 27170 chloro(3-methyl-2-butenyl)magnesium C5H9ClMg 详情 详情
(XXXIII) 54358 (5S,6S,7S)-6,8-bis{[tert-butyl(dimethyl)silyl]oxy}-3,3,5,7-tetramethyl-1-octen-4-ol C24H52O3Si2 详情 详情
(XXXIV) 54359 (5R,6S,7S)-6,8-bis{[tert-butyl(dimethyl)silyl]oxy}-3,3,5,7-tetramethyl-1-octen-4-one C24H50O3Si2 详情 详情
(XXXV) 54360 (4R,5S,6S)-5,7-bis{[tert-butyl(dimethyl)silyl]oxy}-2,2,4,6-tetramethyl-3-oxoheptanal C23H48O4Si2 详情 详情
(XXXVI) 15593 [2-(tert-butoxy)-2-oxoethyl]lithium C6H11LiO2 详情 详情
(XXXVII) 54361 tert-butyl (3S,6R,7S,8S)-3,7,9-tris{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8-tetramethyl-5-oxononanoate C35H74O6Si3 详情 详情
(XXXVIII) 54362 tert-butyl (3S,6R,7S,8S)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-9-hydroxy-4,4,6,8-tetramethyl-5-oxononanoate C29H60O6Si2 详情 详情

合成路线53

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

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

合成路线54

The reaction of the oxime (I) with the 1-methylallyl alcohol (II) by means of Et-MgBr gives the isoxazoline (III), which is condensed with 2-methylthiazole-4-carbaldehyde (IV) by means of DBU and LiCl in acetonitrile to yield the adduct (V). The oxidation of (V) with TPAP and NMO affords the methyl ketone (VI), which is condensed with the Grignard reagent (VII) in THF to provide the tertiary alcohol (VIII). The protection of (VIII) by means of Tes-OTf gives the silylated compound (IX), which is oxidated with SmI2 in THF to yield the beta-hydroxy ketone (X). The reduction of (X) with Et3B and NaBH4 in THF/methanol affords the beta-diol (XI), which is treated with SOCl2, TEA and TBAF to provide the epoxide derivative (XII). The silylation of both OH groups of (XII) by means of Tes-Cl and TEA in dichloromethane furnishes the bis-silyl ether (XIII), which is selectively monodesilylated by means of AcOH in THF/water to give the primary alcohol (XIV). The oxidation of this alcohol by means of TPAP and NMO yields the carbaldehyde (XV).

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) 60651 dipropyl (1S)-2-chloro-2-(hydroxyimino)-1-methylethylphosphonate C9H19ClNO4P 详情 详情
(II) 49287 (2R)-3-buten-2-ol 33447-72-2 C4H8O 详情 详情
(III) 60652 diethyl (1S)-1-{(5R)-5-[(1R)-1-hydroxyethyl]-4,5-dihydro-3-isoxazolyl}ethylphosphonate C11H22NO5P 详情 详情
(IV) 44455 2-methyl-1,3-thiazole-4-carbaldehyde C5H5NOS 详情 详情
(V) 49289 (1R)-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-1-ethanol C12H16N2O2S 详情 详情
(VI) 49290 1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-1-ethanone C12H14N2O2S 详情 详情
(VII) 49291 bromo[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]magnesium C15H33BrMgOSi 详情 详情
(VIII) 49292 (2R,6S)-6-methyl-2-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-7-[(triisopropylsilyl)oxy]-2-heptanol C27H48N2O3SSi 详情 详情
(IX) 49293 (5R)-5-[(1R,5S)-1,5-dimethyl-1-[(triethylsilyl)oxy]-6-[(triisopropylsilyl)oxy]hexyl]-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydroisoxazole; (1R,5S)-1,5-dimethyl-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-6-[(triisopropylsilyl)oxy]hexyl triethylsilyl ether C33H62N2O3SSi2 详情 详情
(X) 60653 (E,5R,6R,10S)-5-hydroxy-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-6-[(triethylsilyl)oxy]-11-[(triisopropylsilyl)oxy]-1-undecen-3-one C33H63NO4SSi2 详情 详情
(XI) 49294 (E,3S,5R,6R,10S)-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-6-[(triethylsilyl)oxy]-11-[(triisopropylsilyl)oxy]-1-undecene-3,5-diol C33H65NO4SSi2 详情 详情
(XII) 60654 (2S,3E)-1-{(2S,3R)-3-[(4S)-5-hydroxy-4-methylpentyl]-3-methyloxiranyl}-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-buten-2-ol C18H29NO3S 详情 详情
(XIII) 60655 (2S)-2-methyl-5-((2R,3S)-2-methyl-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-methyl-3-{(4S)-4-methyl-5-[(triethylsilyl)oxy]pentyl}oxiranyl)-3-[(triethylsilyl)oxy]-1-butenyl}-1,3-thiazole C30H57NO3SSi2 详情 详情
(XIV) 49297 (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-pentanol C24H43NO3SSi 详情 详情
(XV) 49278 (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal C24H41NO3SSi 详情 详情

合成路线55

The condensation of (XV) with the chiral ketone (XVI) by means of LDA in TH gives the aldol (XVII). The protection of the OH group of (XVII) with Troc-Cl and pyridine yields compound (XVIII), which is oxidized at the vinyl group by means of OsO4, NaIO4, selectively monodesilylated with HF and pyridine, and further oxidated with NaClO2 to afford the hydroxyacid (XIX). The Yamaguchi macrolactonization of (XIX) by means of 2,4,6-trichlorobenzoyl chloride provides the macrocyclic lactone (XX). Elimination of the Troc protecting group of (XX) by means of Zn and NH4Cl gives the silylated precursor (XXI), which is finally deprotected by means of HF and pyridine to yield the target epothilone B.

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
(XV) 49278 (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal C24H41NO3SSi 详情 详情
(XVI) 44451 (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one C16H32O2Si 详情 详情
(XVII) 49298 (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one C40H73NO5SSi2 详情 详情
(XVIII) 60656 trityl (3S,4R,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}-4,6,6-trimethyl-3-[(1S)-1-methyl-4-((2R,3S)-2-methyl-3-{(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl}oxiranyl)butyl]-5-oxo-9-decenoate C61H89NO6SSi2 详情 详情
(XIX) 60657 (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]-2-methyloxiranyl}-4,4,6,8-tetramethyl-5-oxo-7-[2-oxo-2-(trityloxy)ethyl]undecanoic acid C54H73NO8SSi 详情 详情
(XX) 60658 trityl 2-{(1S,3S,7S,10R,11S,12S,16R)-7-{[tert-butyl(dimethyl)silyl]oxy}-8,8,10,12,16-pentamethyl-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 C54H71NO7SSi 详情 详情
(XXI) 49303 (1S,3S,7S,10R,11S,12S,16R)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione C33H55NO6SSi 详情 详情

合成路线56

The aldol condensation of 2,2-dimethyl-3-oxopentanal (I) with acetylsultam (II) by means of Et3B/OTf and DIEA gives the aldol adduct (III), which is treated with Tbdms-OTf to yield the silyl ether (IV). The TiCl4 catalyzed aldol reaction between ketone (IV) with the intermediate aldehyde (V) affords the aldol adduct (VI), which is treated with Tbdms-OTf to provide the silylated adduct (VII). Finally the cleavage of the sultam group of (VII) by means of LiO2H furnishes the already known carboxylic acid intermediate (VIII)

参考文献 中间体
【1】 Altmann, K.-H.; et al.; The total synthesis and biological assessment of trans-epothilone A. Helv Chim Acta 2002, 85, 11, 4086.
【2】 Koch, G.; Loiseleur, O.; Fuentes, D.; Jantsch, A.; Altmann, K.-H.; Diastereoselective titanium enolate aldol reaction for the total synthesis of epothilones. Org Lett 2002, 4, 22, 3811.
【3】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 44448 2,2-dimethyl-3-oxopentanal C7H12O2 详情 详情
(II) 62591 4-acetyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione C10H15NO3S 详情 详情
(III) 62592 4-[(3S)-3-hydroxy-4,4-dimethyl-5-oxoheptanoyl]-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione C17H27NO5S 详情 详情
(IV) 62593 4-((3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4,4-dimethyl-5-oxoheptanoyl)-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione C23H41NO5SSi 详情 详情
(V) 62594 (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[(triethylsilyl)oxy]-6,10-undecadienal C24H41NO2SSi 详情 详情
(VI) 62595 4-{(3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[(triethylsilyl)oxy]-12,16-heptadecadienoyl}-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione C47H82N2O7S2Si2 详情 详情
(VII) 62596 4-{(3S,6R,7S,8S,12Z,15S,16E)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[(triethylsilyl)oxy]-12,16-heptadecadienoyl}-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione C53H96N2O7S2Si3 详情 详情
(VIII) 62597 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-[(triethylsilyl)oxy]-12,16-heptadecadienoic acid C45H85NO6SSi3 详情 详情

合成路线57

The intermediate chiral epoxide (III) has been obtained as follows. The Sharpless epoxidation of 3-buten-2(R)-ol (I) gives the chiral epoxide (II), which is protected with Pmb-Br and NaH to yield the target epoxide intermediate (III).

参考文献 中间体
【1】 Jung, J.-K.; Kache, R.; Vines, K.K.; Zheng, Y.-S.; Avery, M.A.; Total synthesis of epothilones B and D amenable to large-scale preparation. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 121.
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) 49287 (2R)-3-buten-2-ol 33447-72-2 C4H8O 详情 详情
(II) 52577 1-(2-oxiranyl)-1-ethanol n/a C4H8O2 详情 详情
(III) 52578 methyl 4-({[1-(2-oxiranyl)ethyl]oxy}methyl)phenyl ether; 2-[1-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]oxirane C2H5NS 详情 详情

合成路线58

The intermediate phosphonate (X) has been obtained as follows. The cyclization of thioacetamide (IV) with ethyl 3-bromopiruvate (V) in ethanol gives 2-methylthiazole-4-carboxylic acid ethyl ester (VI), which is reduced by means of LiAlH4 in ethyl ether to yield the carbinol (VII). The bromination of (VII) with CBr4 and PPh3 in CCl4 affords the 4-bromomethyl-2-methylthiazole (VIII), which is finally condensed with triethyl phosphite (IX) to provide the target phosphonate intermediate (X). Alternatively, the cyclization of thioacetamide (IV) with 1,3-dichloroacetone (XI) gives 4-(chloromethyl)-2-methylthiazole (XII), which is condensed with triethyl phosphite (IX) to also provide the target phosphonate intermediate (X).

参考文献 中间体
【1】 Jung, J.-K.; Kache, R.; Vines, K.K.; Zheng, Y.-S.; Avery, M.A.; Total synthesis of epothilones B and D amenable to large-scale preparation. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 121.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 19170 ethanethioamide 62-55-5 C2H5NS 详情 详情
(V) 63904 propyl 3-bromo-2-oxopropanoate C6H9BrO3 详情 详情
(VI) 63905 propyl 2-methyl-1,3-thiazole-4-carboxylate C8H11NO2S 详情 详情
(VII) 63906 (2-methyl-1,3-thiazol-4-yl)methanol C5H7NOS 详情 详情
(VIII) 63909 4-(bromomethyl)-2-methyl-1,3-thiazole C5H6BrNS 详情 详情
(IX) 15487 triethyl phosphite 122-52-1 C6H15O3P 详情 详情
(X) 63908 dipropyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C11H20NO3PS 详情 详情
(XI) 63907 1,3-dichloroacetone C3H4Cl2O 详情 详情
(XII) 40819 4-(chloromethyl)-2-methyl-1,3-thiazole C5H6ClNS 详情 详情

合成路线59

Synthesis of the target epothilone D. The condensation of 4-methyl-4-pentenyl bromide (XIII) with propyne (XIV) and 1-hexynyl lithium (XV) by means of CuBr in DMSO/ethyl ether gives the copper complex (XVI), which is condensed with the chiral epoxide (III) to yield the chiral unsaturated alcohol (XVII). The protection of the free OH group of (XVII) with Sem-Cl and DIEA in dichloromethane affords compound (XVIII). The selective cleavage of the Pmb-protecting group of (XVIII) by means of DDQ, followed by oxidation of the resulting alcohol with oxalyl chloride provides the methyl ketone (XIX), which is condensed with the intermediate phosphonate (X) by means of BuLi in THF to give the adduct (XX). The hydroxylation of the terminal vinylene double bond of (XX) by means of (Ipc)2BH and LiOH yields the primary alcohol (XXI), which is oxidized with (COCl)2, PTAP or DMP to afford the corresponding aldehyde (XXII). The condensation of aldehyde (XXII) with the known carboxylic acid (XXIII) by means of LDA in THF provides the linear adduct (XXIV), which is treated with Troc-Cl to protect the free OH group of (XXIV) yielding carboxylic acid (XXV).

参考文献 中间体
【1】 Jung, J.-K.; Kache, R.; Vines, K.K.; Zheng, Y.-S.; Avery, M.A.; Total synthesis of epothilones B and D amenable to large-scale preparation. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 121.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 52578 methyl 4-({[1-(2-oxiranyl)ethyl]oxy}methyl)phenyl ether; 2-[1-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]oxirane C2H5NS 详情 详情
(X) 52614 dimethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C7H12NO3PS 详情 详情
(XIII) 52575 5-bromo-2-methyl-1-pentene C6H11Br 详情 详情
(XIV) 51602 1-Propyne C3H4 详情 详情
(XV) 63910 1-hexynyllithium C6H9Li 详情 详情
(XVI) 52576 (2,6-dimethyl-1,6-heptadienyl)(1-hexynyl)copper C15H24Cu 详情 详情
(XVII) 52579 6,10-dimethyl-2-({[4-(methyloxy)phenyl]methyl}oxy)-5,10-undecadien-3-ol C21H32O3 详情 详情
(XVIII) 54299 (3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-1-(4-methoxyphenyl)-3,10,10-trimethyl-2,5,7-trioxa-10-silaundecane; 4-{(3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-3,10,10-trimethyl-2,5,7-trioxa-10-silaundec-1-yl}phenyl methyl ether n/a C27H46O4Si 详情 详情
(XIX) 54301 (3S,5Z)-6,10-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5,10-undecadien-2-one n/a C19H36O3Si 详情 详情
(XX) 54302 2-methyl-4-((1E,3S,5Z)-2,6,10-trimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-1,5,10-undecatrienyl)-1,3-thiazole; (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl [2-(trimethylsilyl)ethoxy]methyl ether n/a C24H41NO2SSi 详情 详情
(XXI) 54303 (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methoxy}-6,10-undecadien-1-ol n/a C24H43NO3SSi 详情 详情
(XXII) 34304 (2S)-3-[3-[bis(2-chloroethyl)amino]phenyl]-2-[[(2S)-3-(4-fluorophenyl)-2-(formylamino)propanoyl]amino]propionic acid C23H26Cl2FN3O4 详情 详情
(XXIII) 43166 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid C15H30O4Si 详情 详情
(XXIV) 54305 (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid n/a C39H71NO7SSi2 详情 详情
(XXV) 54306 (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid n/a C42H72Cl3NO9SSi2 详情 详情

合成路线60

The selective cleavage of the Sem protecting group of (XXV) by means of MgBr2, MeNO2 and BuSH gives the hydroxyacid (XXVI), which is submitted to macrolactonization by means of 2,4,6-trichlorobenzoyl chloride and TEA in THF to yield the protected macrolactone (XXVII). The treatment of (XXVII) with Zn and NH4Cl cleaves the Troc protecting group of to yield lactone (XXVIII), which is treated with HF and pyridine to afford epothilone D (XXIX). Finally, this compound is epoxidated by means of MCPBA or DMDO to provide the target epothilone B.

参考文献 中间体
【1】 Jung, J.-K.; Kache, R.; Vines, K.K.; Zheng, Y.-S.; Avery, M.A.; Total synthesis of epothilones B and D amenable to large-scale preparation. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 121.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXV) 54306 (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid n/a C42H72Cl3NO9SSi2 详情 详情
(XXVI) 54307 (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-12,16-heptadecadienoic acid n/a C36H58Cl3NO8SSi 详情 详情
(XXVII) 52590 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-2,6-dioxooxa-13-cyclohexadecen-8-yl 2,2,2-trichloroethyl carbonate C36H56Cl3NO7SSi 详情 详情
(XXVIII) 63911 (4S,7R,8S,9S,16S)-4-{[tert-butyl(dimethyl)silyl]oxy}-8-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C33H55NO5SSi 详情 详情
(XXIX) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情
Extended Information