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【结 构 式】

【分子编号】40827

【品名】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

【CA登记号】

【 分 子 式 】C30H57NO2SSi2

【 分 子 量 】552.02512

【元素组成】C 65.27% H 10.41% N 2.54% O 5.8% S 5.81% Si 10.18%

与该中间体有关的原料药合成路线共 7 条

合成路线1

该中间体在本合成路线中的序号:(XVI)

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

1 Mulzer, J.; Ohler, E.; Mantoulidis, A. (Schering AG); Method for producing epothilone B and derivs., and intermediate products for this method. WO 0023452 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 40815 (3S)-3-hydroxydihydro-2(3H)-furanone 19444-84-9 C4H6O3 详情 详情
(II) 40816 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]dihydro-2(3H)-furanone C10H20O3Si 详情 详情
(III) 40817 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyltetrahydro-2-furanol C11H24O3Si 详情 详情
(IV) 40818 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-2-pentanone C11H24O3Si 详情 详情
(V) 63907 1,3-dichloroacetone C3H4Cl2O 详情 详情
(VI) 19170 ethanethioamide 62-55-5 C2H5NS 详情 详情
(VII) 40819 4-(chloromethyl)-2-methyl-1,3-thiazole C5H6ClNS 详情 详情
(VIII) 40820 tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride C17H33ClNPS 详情 详情
(IX) 40821 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol C16H29NO2SSi 详情 详情
(X) 40822 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal C16H27NO2SSi 详情 详情
(XI) 18816 ethyl 2-(diethoxyphosphoryl)propanoate 3699-66-9 C9H19O5P 详情 详情
(XII) 40823 ethyl (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate C21H35NO3SSi 详情 详情
(XIII) 40824 (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol C19H33NO2SSi 详情 详情
(XIV) 40825 tert-butyl(dimethyl)[[(2S)-2-methyl-4-(phenylsulfonyl)butyl]oxy]silane; (3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl phenyl sulfone C17H30O3SSi 详情 详情
(XV) 40826 (1R,3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-1-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl phenyl sulfone; 4-[(1E,3S,5Z,8R,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-8-(phenylsulfonyl)-1,5-undecadienyl]-2-methyl-1,3-thiazole C36H61NO4S2Si2 详情 详情
(XVI) 40827 tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole C30H57NO2SSi2 详情 详情
(XVII) 40828 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol C24H43NO2SSi 详情 详情
(XVIII) 40829 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal C24H41NO2SSi 详情 详情
(XIX) 40830 (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone C21H46O3Si2 详情 详情
(XX) 40831 (7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one C45H87NO5SSi3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XXVII)

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

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3

该中间体在本合成路线中的序号:(III)

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

1 Nicolaou, K.C.; et al.; Synthesis of epothilones A and B in solid and solution phase. Nature 1997, 387, 6630, 268.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 44459 [(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide C34H43INOPSSi 详情 详情
(II) 46121 (6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2-heptanone C14H30O2Si 详情 详情
(III) 40827 tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole C30H57NO2SSi2 详情 详情
(IV) 40828 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol C24H43NO2SSi 详情 详情
(V) 40829 (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal C24H41NO2SSi 详情 详情
(VI) 43166 (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid C15H30O4Si 详情 详情
(VII) 46118 (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(VIII) 40834 (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C45H85NO6SSi3 详情 详情
(IX) 40835 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid C39H71NO6SSi2 详情 详情
(X) 40836 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C39H69NO5SSi2 详情 详情
(XI) 40837 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C27H41NO5S 详情 详情
(XII) 31501 3,3-dimethyl-1,2-dioxirane C3H6O2 详情 详情

合成路线4

该中间体在本合成路线中的序号:(XVII)

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).

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5

该中间体在本合成路线中的序号:(XXVII)

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).

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6

该中间体在本合成路线中的序号:(III)

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.

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7

该中间体在本合成路线中的序号:(XVII)

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).

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
Extended Information