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【结 构 式】 
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【分子编号】40820 【品名】tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride 【CA登记号】 |
【 分 子 式 】C17H33ClNPS 【 分 子 量 】349.948222 【元素组成】C 58.35% H 9.5% Cl 10.13% N 4% P 8.85% S 9.16% |
合成路线1
该中间体在本合成路线中的序号：(VIII)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：(VII)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3
该中间体在本合成路线中的序号：(XXIX)Assembly of the target compound: The condensation of the phosphonium salt (VII) with the aldehyde (XV) by means of NaHMDS in THF gives the adduct (XIX), which is debenzylated and hydrogenated with H2 over Pd/Al2O3 in ethanol and oxidized with NaIO4 and RuCl3 to yield the carboxylic acid (XX). The activation of (XX) with pivaloyl chloride affords the anhydride (XXI), which is condensed with the lithium oxazolidinone (XXII) to provide the cyclic amide (XXIII). The enantioselective hydroxylation of (XXIII) by means of the Davis oxaziridine and NaHMDS gives the alpha-hydroxyamide (XXIV), which is treated with N,O-dimethylhydroxylamine (XXV) to yield the methoxyamide (XXVI). The protection of the OH group of (XXVI) with Tbdms-OTf and lutidine affords the silyl ether (XXVII), which is treated with MeLi in THF, affording the methyl ketone (XXVIII). The condensation of (XXVIII) with tributyl(2-methylthiazol-4-ylmethyl)phosphonium chloride (XXIX) by means of KHMDS in THF provides the adduct (XXX).
| 【1】 Mulzer, J.; et al.; A novel highly stereoselective total synthesis of epothilone B and of its (12R,13R) acetonide. Tetrahedron Lett 2000, 41, 40, 7635. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 46168 | ((3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl)(triphenyl)phosphonium iodide | C29H40IOPSi | 详情 | 详情 | |
| (XV) | 46175 | (4S,5R)-5-[3-(benzyloxy)propyl]-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde | C17H24O4 | 详情 | 详情 | |
| (XIX) | 46176 | benzyl 3-[(4R,5R)-5-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-1-pentenyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]propyl ether; [((2S,4E)-5-[(4R,5R)-5-[3-(benzyloxy)propyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl]-2-methyl-4-pentenyl)oxy](tert-butyl)dimethylsilane | C28H48O4Si | 详情 | 详情 | |
| (XX) | 46177 | 3-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]propionic acid | C21H42O5Si | 详情 | 详情 | |
| (XXI) | 46178 | 2-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]propionic 1,1-dimethylpropionic anhydride | C26H50O6Si | 详情 | 详情 | |
| (XXII) | 46185 | [(4S,5R)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]lithium | C10H10LiNO2 | 详情 | 详情 | |
| (XXIII) | 46179 | (4S,5R)-3-[3-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C31H51NO6Si | 详情 | 详情 | |
| (XXIV) | 46180 | (4S,5R)-3-[(2S)-3-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-hydroxypropanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C31H51NO7Si | 详情 | 详情 | |
| (XXV) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (XXVI) | 46181 | (2S)-3-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-hydroxy-N-methoxy-N-methylpropanamide | C23H47NO6Si | 详情 | 详情 | |
| (XXVII) | 46182 | (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]-N-methoxy-N-methylpropanamide | C29H61NO6Si2 | 详情 | 详情 | |
| (XXVIII) | 46183 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-butanone | C28H58O5Si2 | 详情 | 详情 | |
| (XXIX) | 40820 | tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride | C17H33ClNPS | 详情 | 详情 | |
| (XXX) | 46184 | tert-butyl(dimethyl)silyl (2S)-5-[(4R,5R)-5-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl]-2-methylpentyl ether; 4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-methyl-1-butenyl]-2-methyl-1,3-thiazole | C33H63NO4SSi2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIII)The reduction of the protected (S)-ethyl lactate (I) with DIBAL in dichloromethane gives the aldehyde (II), which by a Grignard condensation with allylmagnesium bromide (III) in ethyl ether yields the homoallylic alcohol (IV). The reaction of (IV) with Tbdms-Cl and imidazole in DMF affords the silyl ether (V), which is ozonolyzed with O3 in dichloromethane/methanol to provide the aldehyde (VI), which, by a new Grignard condensation with isopropenylmagnesium bromide (VII) in THF, gives the allyl alcohol derivative (VIII). Compound (VIII) is treated with triethyl orthoacetate (refluxing xylene) in a Johnson Claisen rearrangement to yield the (E)-unsaturated ester (IX), which is debenzylated by treatment with DDQ to afford the secondary alcohol (X). The oxidation of (X) with oxalyl chloride provides the ketoester (XI), which is oxidized with AD-mix beta in tert-butanol/water to furnish the diol (XII) as an inseparable mixture of isomers. This mixture, by a Wittig condensation with the phosphonium salt (XIII) and KHMDS in THF, gives a mixture of the hydroxylactones (XIV) and (XV) that are separated by chromatography. Compound (XIV) is mesylated with MsCl and TEA and treated with K2CO3 in methanol to give the desired epoxyester (XVI). The diastereomer (XV) with wrong configuration is recovered by a double inversion: Compound (XV) is mesylated and the resulting derivative is then epoxidated with K2CO3 in methanol to yield the epoxide (XVII), which is treated with K2CO3 in methanol/water to afford the hydroxylactone (XIV) with the adequate configuration.
| 【1】 Martin, H.J.; et al.; How stable are epoxides? A novel synthesis of epothilone B. Angew Chem. Int Ed Engl 2000, 39, 3, 581. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 49259 | ethyl (2S)-2-[(4-methoxybenzyl)oxy]propanoate | C13H18O4 | 详情 | 详情 | |
| (II) | 49260 | (2S)-2-[(4-methoxybenzyl)oxy]propanal | C11H14O3 | 详情 | 详情 | |
| (III) | 10386 | Allyl(bromo)magnesium | 1730-25-2 | C3H5BrMg | 详情 | 详情 |
| (IV) | 49261 | (2S,3S)-2-[(4-methoxybenzyl)oxy]-5-hexen-3-ol | C14H20O3 | 详情 | 详情 | |
| (V) | 49262 | tert-butyl[((1S)-1-[(1S)-1-[(4-methoxybenzyl)oxy]ethyl]-3-butenyl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (1S)-1-[(1S)-1-[(4-methoxybenzyl)oxy]ethyl]-3-butenyl ether | C20H34O3Si | 详情 | 详情 | |
| (VI) | 49263 | (3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]pentanal | C19H32O4Si | 详情 | 详情 | |
| (VII) | 43649 | bromo(isopropenyl)magnesium；isopropenyl magnesium bromide；1-Methylvinylmagnesiumbromide;1-Propen-2-ylmagnesium bromide;a-Methylvinylmagnesium bromide | 13291-18-4 | C3H5BrMg | 详情 | 详情 |
| (VIII) | 49264 | (5S,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(4-methoxybenzyl)oxy]-2-methyl-1-hepten-3-ol | C22H38O4Si | 详情 | 详情 | |
| (IX) | 49265 | ethyl (E,7S,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-8-[(4-methoxybenzyl)oxy]-4-methyl-4-nonenoate | C26H44O5Si | 详情 | 详情 | |
| (X) | 49266 | ethyl (E,7S,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-4-methyl-4-nonenoate | C18H36O4Si | 详情 | 详情 | |
| (XI) | 49267 | ethyl (E,7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-8-oxo-4-nonenoate | C18H34O4Si | 详情 | 详情 | |
| (XII) | 49268 | ethyl (7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-4,5-dihydroxy-4-methyl-8-oxononanoate | C18H36O6Si | 详情 | 详情 | |
| (XIII) | 40820 | tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride | C17H33ClNPS | 详情 | 详情 | |
| (XIV) | 49269 | (5R)-5-[(1R,3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl]-5-methyldihydro-2(3H)-furanone | C21H35NO4SSi | 详情 | 详情 | |
| (XV) | 49270 | (5S)-5-[(1S,3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl]-5-methyldihydro-2(3H)-furanone | C21H35NO4SSi | 详情 | 详情 | |
| (XVI) | 49271 | methyl 3-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]propanoate | C22H37NO4SSi | 详情 | 详情 | |
| (XVII) | 49272 | methyl 3-[(2S,3R)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]propanoate | C22H37NO4SSi | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VII)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 |