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【结 构 式】

【分子编号】40829

【品名】(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

【CA登记号】

【 分 子 式 】C24H41NO2SSi

【 分 子 量 】435.74658

【元素组成】C 66.15% H 9.48% N 3.21% O 7.34% S 7.36% Si 6.45%
与该中间体有关的原料药合成路线共 17 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17

合成路线1

该中间体在本合成路线中的序号：(XVIII)

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
合成目标
【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

该中间体在本合成路线中的序号：(XVIII)

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
合成目标
【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
中间体序号 中间体编号 品名 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3

该中间体在本合成路线中的序号：(XVIII)

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
合成目标
【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
中间体序号 中间体编号 品名 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4

该中间体在本合成路线中的序号：(XXIX)

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

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
中间体序号 中间体编号 品名 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5

该中间体在本合成路线中的序号：(V)

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
合成目标
【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6

该中间体在本合成路线中的序号：(XIX)

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
合成目标
【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7

该中间体在本合成路线中的序号：(XIX)

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
合成目标
【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8

该中间体在本合成路线中的序号：(XVII)

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
合成目标
【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9

该中间体在本合成路线中的序号：(XI)

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
合成目标
【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10

该中间体在本合成路线中的序号：(XVIII)

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/acetonitrile 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 methanol. Finally, this compound is reduced with DIBAL in toluene to afford the target aldehyde intermediate (XVIII).

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
中间体序号 中间体编号 品名 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11

该中间体在本合成路线中的序号：(XVIII)

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), which is finally deprotected with TFA in dichloromethane to provide the target epothilone D.

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
中间体序号 中间体编号 品名 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12

该中间体在本合成路线中的序号：(XXIX)

Assembly of the final product: The condensation of SAMP hydrazone (XVII) with 4-(benzyloxy)butyl iodide (XVIII) by means of LDA in THF gives the chiral 2-methylhexanal hydrazone (XIX), which is ozonolyzed in dichloromethane, yielding the free aldehyde (XX). The reduction of (XX) with NaBH4 in methanol affords the corresponding alcohol (XXI), which is protected with Tbdms-Cl and TEA in dichloromethane, providing the silyl ether (XXII). The hydrogenolysis of (XXII) with H2 over Pd/C in THF furnishes the alcohol (XXIII), which is oxidized to the aldehyde (XXIV) with oxalyl chloride, DMSO and TEA in dichloromethane. The condensation of aldehyde (XXIV) with the intermediate phosphonium salt (XVI) by means of NaHMDS in THF gives the silylated diol (XXV), which is selectively monodesilylated with CSA in dichloromethane/methanol to yield the primary alcohol (XXVI). The oxidation of (XXVI) with SO3/pyridine, DMSO and TEA in dichloromethane affords the corresponding aldehyde (XXVII), which is condensed with the oxoacid intermediate (VI) by means of LDA in THF to provide the linear heptadecadienoic acid (XXVIII) as a diastereomeric mixture that is separated at the carboxylic acid (XXX) step. The fully silylation of (XVIII) with Tbdms-OTf and lutidine in dichloromethane gives the tetrasilyloxy compound (XXIX), which is stepwise desilylated first with K2CO3 in methanol to yield the carboxylic acid (XXX).

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
中间体序号 中间体编号 品名 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13

该中间体在本合成路线中的序号：(V)

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 finally deprotected with TFA in dichloromethane to provide the target epothilone D.

参考文献 中间体
合成目标
【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 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

合成路线14

该中间体在本合成路线中的序号：(XIX)

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
合成目标
【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15

该中间体在本合成路线中的序号：(XIX)

Assembly of the target compound: 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
合成目标
【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16

该中间体在本合成路线中的序号：(XVII)

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
合成目标
【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17

该中间体在本合成路线中的序号：(XI)

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 finally yield the target epothilone D.

参考文献 中间体
合成目标
【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
Extended Information