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【结 构 式】

【药物名称】(-)-Desoxyepothilone B, Epothilone D, Desoxyepothilone B, R-1492, KOS-862, dEpoB, NSC-703147

【化学名称】(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxacyclohexadec-13-ene-2,6-dione

【CA登记号】189453-10-9

【 分 子 式 】C27H41NO5S

【 分 子 量 】491.69552

【开发单位】GBF (Originator), Kosan (Originator), Roche (Licensee), Memorial Sloan-Kettering Cancer Center (Codevelopment)

【药理作用】Breast Cancer Therapy, Colorectal Cancer Therapy, Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Solid Tumors Therapy, Antimitotic Drugs, Epothilones, Microtubule-Stabilizing Agents

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合成路线1

Treatment of diketoester (I) with trimethylsilyl diazomethane and diisopropyl ethylamine produced enol ether (II). This was condensed with (S)-2-methyl-4-pentenal (III) in the presence of LDA at -120 C to afford the aldol condensation product (IV) as the major isomer. Protection of the 7-hydroxyl group of (IV) with trichloroethoxycarbonyl chloride gave carbonate (V). Enol ether of (V) was then hydrolyzed with p-TsOH in acetone to provide diketoester (VI). Hydroboration of the terminal olefin of (VI) with 9-borabicyclo[3.3.1]nonane gave organoborane (VII). Then, Suzuki coupling of (VII) with vinyl iodide (VIII), followed by acid hydrolysis of the silyl protecting group, provided the thiazolyl heptadecadienoate (IX). Asymmetric hydrogenation of 3-keto group of (IX) in the presence of the modified Noyori's catalyst [RuCl2(R)-BINAP)]2[Et3N] furnished the desired 3-(S) alcohol (X).

参考文献 中间体
【1】 Harris, C.R.; et al.; New chemical synthesis of the promising cancer chemotherapeutic agent 12,13-desoxyepothilone B: Discovery of a surprising long-range effect on the diastereoselectivity of an aldol condensation. J Am Chem Soc 1999, 121, 30, 7050.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
13664 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate 17341-93-4 C3H2Cl4O2 详情 详情
(I) 26239 tert-butyl 4,4-dimethyl-3,5-dioxoheptanoate C13H22O4 详情 详情
(II) 26240 tert-butyl (Z)-3-methoxy-4,4-dimethyl-5-oxo-2-heptenoate C14H24O4 详情 详情
(III) 26241 (2S)-2-methyl-4-pentenal C6H10O 详情 详情
(IV) 26242 tert-butyl (2Z,6R,7S,8S)-7-hydroxy-3-methoxy-4,4,6,8-tetramethyl-5-oxo-2,10-undecadienoate C20H34O5 详情 详情
(V) 26243 tert-butyl (2Z,6R,7S,8S)-3-methoxy-4,4,6,8-tetramethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-2,10-undecadienoate C23H35Cl3O7 详情 详情
(VI) 26244 tert-butyl (6R,7S,8S)-4,4,6,8-tetramethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-10-undecenoate C22H33Cl3O7 详情 详情
(VII) 26245 tert-butyl (6R,7S,8S)-11-(9-borabicyclo[3.3.1]non-9-yl)-4,4,6,8-tetramethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]undecanoate C30H48BCl3O7 详情 详情
(VIII) 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
(IX) 26247 tert-butyl (6R,7S,8S,12Z,15S,16E)-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-12,16-heptadecadienoate C34H50Cl3NO8S 详情 详情
(X) 26248 tert-butyl (3S,6R,7S,8S,12Z,15S,16E)-3,15-dihydroxy-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-heptadecadienoate C34H52Cl3NO8S 详情 详情

合成路线2

Further treatment of (X) with Et3SiOTf and 2,6-lutidine protected both 3- and 15-hydroxyl groups as the triethylsilyl ethers and cleaved the tert-butyl ester to yield carboxylic acid (XI). The bis(triethylsilyl)-protected diol (XI) was selectively hydrolyzed to the required 15-hydroxy acid (XII) upon treatment with cold 0.12 M HCl in MeOH. Macrolactonization of (XII) was then performed by means of 2,4,6-trichlorobenzoyl chloride, Et3N and DMAP yielding (XIII). Removal of the trichloroethoxycarbonyl protecting group from the resulting lactone (XIII) employing SmI2 and a catalytic amount of NiI2 in THF at -78 C yielded (XIV). Finally, desilylation of (XIV) with HF-pyridine afforded the target compound.

参考文献 中间体
【1】 Harris, C.R.; et al.; New chemical synthesis of the promising cancer chemotherapeutic agent 12,13-desoxyepothilone B: Discovery of a surprising long-range effect on the diastereoselectivity of an aldol condensation. J Am Chem Soc 1999, 121, 30, 7050.
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) 26248 tert-butyl (3S,6R,7S,8S,12Z,15S,16E)-3,15-dihydroxy-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-heptadecadienoate C34H52Cl3NO8S 详情 详情
(XI) 26249 (3S,6R,7S,8S,12Z,15S,16E)-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-3,15-bis[(triethylsilyl)oxy]-12,16-heptadecadienoic acid C42H72Cl3NO8SSi2 详情 详情
(XII) 26250 (3S,6R,7S,8S,12Z,15S,16E)-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]-3-[(triethylsilyl)oxy]-12,16-heptadecadienoic acid C36H58Cl3NO8SSi 详情 详情
(XIII) 26251 (4S,7R,8S,9S,16S)-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-2,6-dioxo-4-[(triethylsilyl)oxy]oxa-13-cyclohexadecen-8-yl 2,2,2-trichloroethyl carbonate C36H56Cl3NO7SSi 详情 详情
(XIV) 26252 (4S,7R,8S,9S,16S)-8-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-[(triethylsilyl)oxy]oxa-13-cyclohexadecene-2,6-dione C33H55NO5SSi 详情 详情

合成路线3

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
【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4

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
【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5

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6

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 to provide 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7

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
【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8

Compound (XXX) is treated with TBAF in THF to afford the hydroxyacid (XXXI). The macrolactonization of (XXXI) was carried out with the Yamaguchi method using 2,4,6-trichlorobenzoyl chloride , TEA and DMAP in THF to yield the silylated macrolactone (XXXII), which is finally deprotected with TFA in dichloromethane to afford the target epothilone D.

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

合成路线9

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10

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11

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12

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 finally desilylated with HF and pyridine in THF, furnishing the target epothilone D.

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

合成路线13

Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) catalyzed by (S)(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to 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.
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14

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 provides the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane, furnishing the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of 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15

Hydrolysis of the dimethylacetal group of (XXVIII) with Ts-OH in dioxane/water yields the corresponding aldehyde (XXIX), which is submitted to a 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 de 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 finally deprotected with HF/pyridine in THF, providing the target epothilone D.

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
(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

合成路线16

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
【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17

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18

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
【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19

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). Finally, the desilylation of (XXXIV) with HF in pyridine/THF affords the target epothilone D

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

合成路线20

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, yielding 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, providing 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21

The condensation of the known ketone (XVII) (2) 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22

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). Finally, the selective hydrogenation of the disubstituted double bond of (XXX) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane yields the target epothilone D.

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

合成路线23

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) (1). Finally, the selective hydrogenation of the disubstituted double bond of (X) by means of potassium azodicarboxylate (DKAD) and HOAc in dichloromethane provides the target epothilone D.

参考文献 中间体
【1】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684.
【2】 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.
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

合成路线24

The desepoxidation of epothilone B (I) by means of WCl6 and n-BuLi in THF gives the target epothilone D.

参考文献 中间体
【1】 Johnson, J.A.; Kim, S.-H. (Bristol-Myers Squibb Co.); A process for the reduction of oxiranyl epothilones to olefinic epothilones. WO 0071521 .
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) 42208 (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-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 C27H41NO6S 详情 详情

合成路线25

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26

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27

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 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 to furnish the target epothilone D.

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28

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29

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30

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31

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 finally desilylated with HF and pyridine to provide the target epothilone D.

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

合成路线32

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). Finally, the cyclization of (XIV) by means of benzenesulfonyl chloride and pyridine gives the target epothilone D.

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

合成路线33

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 finally desilylated by means of TBAF in THF to yield the target epothilone D.

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

合成路线34

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
【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

合成路线35

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 AcOH 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36

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 give 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37

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 finally hydrogenated by means of 2,4,6-tri-isopropylbenzenesulfonyl hydrazide and TEA in refluxing ethyl ether to afford the target epothilone D.

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

合成路线38

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39

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40

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41

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(XXVII) to yield lactone (XVIII), which is finally treated with HF and pyridine to afford the target epothilone D

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