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【结 构 式】 
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【药物名称】(-)-Epothilone E, Epothilone E 【化学名称】[4S,7R,8S,9S,13R,14S,16S(E)]-13,14-Epoxy-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[2-[2-(hydroxymethyl)thiazol-4-yl]-1-methylvinyl]-1-oxacyclohexadecane-2,6-dione 【CA登记号】201049-37-8 【 分 子 式 】C26H39NO7S 【 分 子 量 】509.66723 |
【开发单位】GBF (Originator), Scripps Research Institute (Originator) 【药理作用】Oncolytic Drugs, Antimitotic Drugs, Epothilones, Microtubule-Stabilizing Agents |
合成路线1
Lithiation of 2,4-dibromothiazole (I) with n-BuLi at -78 C, followed by condensation with dimethylformamide gave aldehyde (II), which was reduced to alcohol (III) with NaBH4. After protection of the alcohol (III) as the tert-butyldimethylsilyl ether (IV), a second metalation with n-BuLi, and subsequent quenching with tri-n-butyltin chloride furnished stannane (V). Further desilylation of (V) by means of tetrabutylammonium fluoride yielded 2-(hydroxymethyl)-4-(tri-n-butylstannyl)thiazole (VI).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of epothilone E and analogs with modified side chains through the Stille coupling reaction. Angew Chem. Int Ed Engl 1998, 37, 1-2, 84. |
| 【2】 Nicolaou, K.C.; et al.; Total synthesis of epothilone E and related side-chain modified analogues via a stille coupling based strategy. Bioorg Med Chem 1999, 7, 5, 665. |
| 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) | 37946 | 2,4-dibromo-1,3-thiazole | C3HBr2NS | 详情 | 详情 | |
| (II) | 37947 | 4-bromo-1,3-thiazole-2-carbaldehyde | C4H2BrNOS | 详情 | 详情 | |
| (III) | 37948 | (4-bromo-1,3-thiazol-2-yl)methanol | C4H4BrNOS | 详情 | 详情 | |
| (IV) | 37949 | (4-bromo-1,3-thiazol-2-yl)methyl tert-butyl(dimethyl)silyl ether; 4-bromo-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-thiazole | C10H18BrNOSSi | 详情 | 详情 | |
| (V) | 37950 | tert-butyl(dimethyl)silyl [4-(tributylstannyl)-1,3-thiazol-2-yl]methyl ether; 2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-(tributylstannyl)-1,3-thiazole | C22H45NOSSiSn | 详情 | 详情 | |
| (VI) | 37951 | [4-(tributylstannyl)-1,3-thiazol-2-yl]methanol | C16H31NOSSn | 详情 | 详情 |
合成路线2
Asymmetric allylation of 3-iodomethacrolein (VII) with (+)-allyldiisopinocampheyl borane at -100 C provided the enantiopure alcohol (IX). Subsequent coupling of (IX) with the diastereomeric mixture of (6R,7S) and (6S,7R)-acids (X) using DCC and DMAP afforded a mixture of diastereomeric esters from which the required (6R,7S)-isomer (XI) was isolated by flash chromatography. Ring closure by means of olefin methatesis in the presence of a ruthenium initiator gave a separable mixture of E (XII) and Z (XIII) macrolactones. Subsequent desilylation of the desired Z isomer (XIII) with HF.Pyr in THF provided the macrocyclic diol (XIV). Introduction of the thiazole unit in (XIV) was carried out by Stille coupling of vinyl iodide (XIV) with thiazolyl stannane (VI) in the presence of Pd catalyst to provide (XV). Finally, epoxidation of (XV) with methylperoxycarboximidic acid, generated in situ from hydrogen peroxide and acetonitrile, furnished the title compound.
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of epothilone E and analogs with modified side chains through the Stille coupling reaction. Angew Chem. Int Ed Engl 1998, 37, 1-2, 84. |
| 【2】 Nicolaou, K.C.; et al.; Total synthesis of epothilone E and related side-chain modified analogues via a stille coupling based strategy. Bioorg Med Chem 1999, 7, 5, 665. |
| 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) | 37951 | [4-(tributylstannyl)-1,3-thiazol-2-yl]methanol | C16H31NOSSn | 详情 | 详情 | |
| (VII) | 37952 | (E)-3-iodo-2-methyl-2-propenal | C4H5IO | 详情 | 详情 | |
| (VIII) | 37953 | allyl[(1S,2R,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl][(5S,6S)-4,4,6-trimethylbicyclo[3.1.1]hept-1-yl]borane | C23H39B | 详情 | 详情 | |
| (IX) | 37954 | (1E,3S)-1-iodo-2-methyl-1,5-hexadien-3-ol | C7H11IO | 详情 | 详情 | |
| (X) | 37955 | (3S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C23H44O5Si | 详情 | 详情 | |
| (XI) | 37956 | (1S)-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate | C30H53IO5Si | 详情 | 详情 | |
| (XII) | 37957 | (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-16-[(E)-2-iodo-1-methylethenyl]-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione | C28H49IO5Si | 详情 | 详情 | |
| (XIII) | 37958 | (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-16-[(E)-2-iodo-1-methylethenyl]-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione | C28H49IO5Si | 详情 | 详情 | |
| (XIV) | 37959 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-16-[(E)-2-iodo-1-methylethenyl]-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione | C22H35IO5 | 详情 | 详情 | |
| (XV) | 37960 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-16-[(E)-2-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-1-methylethenyl]-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione | C26H39NO6S | 详情 | 详情 |
合成路线3
The oxidation of epothilon A (I) with m-chlroperbenzoic acid (MCPBA) in dichloromethane gives the corresponding N-oxide (II), which by reaction with acetic anhydride and 2,6-di-tert-butyulpyridine in dichloromethane is converted into 21-O-acetyl epothilon E (III). Finally, this compound is deacetylated with NH3 in methanol.
| 【1】 Sefkow, M.; Hofle, G. (Gesellschaft fur Biotechnologische Forschung mbH); Epothilones with a modified side chain. WO 9838192 . |
| 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) | 37961 | (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione | C26H39NO6S | 详情 | 详情 | |
| (II) | 37962 | 4-[(E)-2-[(1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-3-yl]-1-propenyl]-2-methyl-1,3-thiazol-3-ium-3-olate | C26H39NO7S | 详情 | 详情 | |
| (III) | 37963 | (4-[(E)-2-[(1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-3-yl]-1-propenyl]-1,3-thiazol-2-yl)methyl acetate | C28H41NO8S | 详情 | 详情 |
合成路线4
The condensation of 3-[2-(hydroxymethyl)thiazol-4-yl]-2-methylpropenal (I) with acetone (II) gives the racemic aldol derivative (III), which is submitted to a enantioselective retroaldol reaction catalyzed by antibodies 84G3, 85H6 or 93F3, yielding the chiral aldol (IV) with 99% ee purity. The protection of the OH groups of (IV) with TbdmsCl and imidazole affords the bis silyl ether (V), which is oxidized with Tms-OTf, trifluoroacetone and oxone to provide the hydroxyketone (VI). The reduction of (VI) with NaBH4 in methanol gives the vicinal diol (VII), which is cleaved with Pb(OAc)4 to yield the aldehyde (VIII). The Wittig reaction of (VIII) with methyltriphenylphosphonium iodide (IX) and BuLi in THF affords the olefin (X), which is desilylated with TBAF in THF and selectively monosilylated at the primary alcohol with Tbdms-Cl and DIEA to give the secondary alcohol (XI). The esterification of (XI) with the known carboxylic acid (XII) (see later) by means of EDC in dichloromethane yields the ester (XIII), which is submitted to a ring-closing metathesis catalyzed by the Grubb's catalyst in dichloromethane to afford the protected macrolactone (XIV). The desilylation of (XIV) with HF and pyridine in THF gives the precursor (XV), which is finally epoxidated with H2O2 and KHCO3 in methanol to yield the target epothilone E.
| 【1】 Sinha, S.C.; et al.; Sets of aldolase antibodies with antipodal reactivities. Formal synthesis of epothilone E by large-scale antibody-catalyzed resolution of thiazole aldol. Org Lett 1999, 1, 10, 1623. |
| 【2】 Nicolaou, K.C.; et al.; Total synthesis of epothilone E and analogs with modified side chains through the Stille coupling reaction. Angew Chem. Int Ed Engl 1998, 37, 1-2, 84. |
| 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) | 45949 | (E)-3-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-2-methyl-2-propenal | C8H9NO2S | 详情 | 详情 | |
| (II) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (III) | 45950 | (E)-4-hydroxy-6-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-5-methyl-5-hexen-2-one | C11H15NO3S | 详情 | 详情 | |
| (IV) | 45951 | (4S,5E)-4-hydroxy-6-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-5-methyl-5-hexen-2-one | C11H15NO3S | 详情 | 详情 | |
| (V) | 45952 | (4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-thiazol-4-yl]-5-methyl-5-hexen-2-one | C23H43NO3SSi2 | 详情 | 详情 | |
| (VI) | 45953 | (4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-thiazol-4-yl]-1-hydroxy-5-methyl-5-hexen-2-one | C23H43NO4SSi2 | 详情 | 详情 | |
| (VII) | 45954 | (4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-thiazol-4-yl]-5-methyl-5-hexene-1,2-diol | C23H45NO4SSi2 | 详情 | 详情 | |
| (VIII) | 45955 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-[2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-thiazol-4-yl]-4-methyl-4-pentenal | C22H41NO3SSi2 | 详情 | 详情 | |
| (IX) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (X) | 45956 | 2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-1,3-thiazole; tert-butyl(dimethyl)silyl [4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-1,3-thiazol-2-yl]methyl ether | C23H43NO2SSi2 | 详情 | 详情 | |
| (XI) | 45957 | (1E,3S)-1-[2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-thiazol-4-yl]-2-methyl-1,5-hexadien-3-ol | C17H29NO2SSi | 详情 | 详情 | |
| (XII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 | |
| (XIII) | 45958 | (1S)-1-[(E)-2-[2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-thiazol-4-yl]-1-methylethenyl]-3-butenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate | C46H85NO6SSi3 | 详情 | 详情 | |
| (XIV) | 45959 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-16-[(E)-2-[2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3-thiazol-4-yl]-1-methylethenyl]-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione | C44H81NO6SSi3 | 详情 | 详情 | |
| (XV) | 37960 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-16-[(E)-2-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-1-methylethenyl]-5,5,7,9-tetramethyloxa-13-cyclohexadecene-2,6-dione | C26H39NO6S | 详情 | 详情 |
合成路线5
The reaction of 3-methyl-2-butenylmagnesium bromide (XVI) with propanal (XVII) gives racemic hexenol (XVIII), which is submitted to enzymatic resolution with ChiroCLEC-PC dry enzyme, yielding the R-enantiomer (XIX). The esterification of (XIX) with bromoacetyl bromide (XX) and dimethylaniline (DMA) affords the corresponding ester (XXI), which is oxidized with O3 and trimethyl phosphite and cyclized with SmI2 in THF to provide the chiral tetrahydropyranone (XXII). The reduction of (XXII) with Red-Al, followed by cyclization with 2-methoxypropene (XXIII) and PPTS, gives the acetonide (XXIV), which is oxidized with PPTS and NMO to provide the protected dihydroxyketone (XXV). The condensation of the ketone (XXV) with 2(S)-methyl-6-heptenal (XXVI) by means of LDA in THF gives the hydroxyundecenone (XXVII), which is treated with pyridinium p-toluenesulfonate (PPTS) in methanol to cleave the 1,3-dioxane ring and yield the trihydroxy compound (XXVIII). The silylation of (XXVIII) with Tbdms-OTf and lutidine in dichloromethane affords the fully silylated compound (XXIX), which is selectively monodesilylated with CSA to provide the primary alcohol (XXX). Finally, this alcohol is oxidized by means of pyridinium dichromate (PDC) in DMF to furnish the target tridecenoic acid intermediate (XII).
| 【1】 Schinzer, D.; et al.; Total synthesis of (-)-epothilone A. Angew Chem. Int Ed Engl 1997, 36, 5, 523. |
| 【2】 Taylor, R.E.; et al.; A formal total synthesis of epothiolone A: Enantioselective preparation of the C1-C6 and C7-C12 fragments. J Org Chem 1998, 63, 25, 9580. |
| 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) | 27170 | chloro(3-methyl-2-butenyl)magnesium | C5H9ClMg | 详情 | 详情 | |
| (XVII) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (XVIII) | 27171 | 4,4-dimethyl-5-hexen-3-ol | C8H16O | 详情 | 详情 | |
| (XIX) | 27172 | (3R)-4,4-dimethyl-5-hexen-3-ol | C8H16O | 详情 | 详情 | |
| (XX) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (XXI) | 27173 | (1R)-1-ethyl-2,2-dimethyl-3-butenyl 2-bromoacetate | C10H17BrO2 | 详情 | 详情 | |
| (XXII) | 27174 | (4S,6R)-6-ethyl-4,5,5-trimethyltetrahydro-2H-pyran-2-one | C10H18O2 | 详情 | 详情 | |
| (XXIII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (XXIV) | 27175 | (3R)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanol | C12H24O3 | 详情 | 详情 | |
| (XXV) | 27176 | 2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanone | C12H22O3 | 详情 | 详情 | |
| (XXVI) | 27185 | (2S)-2-methyl-6-heptenal | C8H14O | 详情 | 详情 | |
| (XXVII) | 44434 | (4R,5S,6S)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-5-hydroxy-2,4,6-trimethyl-10-undecen-3-one | C20H36O4 | 详情 | 详情 | |
| (XXVIII) | 44435 | (3S,6R,7S,8S)-1,3,7-trihydroxy-4,4,6,8-tetramethyl-12-tridecen-5-one | C17H32O4 | 详情 | 详情 | |
| (XXIX) | 44436 | (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one | C35H74O4Si3 | 详情 | 详情 | |
| (XXX) | 44437 | (5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one | C29H60O4Si2 | 详情 | 详情 | |
| (XXX) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 |
合成路线6
The reaction of 2,2-dimethyl-3-oxopentanal (XXXI) with (+)-diisopinocampheyl(allyl)borane (XXXII) in ethyl ether gives the chiral beta-hydroxy ketone (XXXIII), which is protected with Tbdms-OTf to yield the silyl ether (XXXIV). The ozonolysis of the double bond of (XXXIV) affords the aldehyde (XXXV), which is oxidized with NaClO2 to the carboxylic acid (XXXVI). Finally, this compound is condensed with 2(S)-methyl-6-heptenal (VII) by means of LDA in THF to provide the intermediate tridecenoic acid (XII).
| 【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960. |
| 【2】 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 |
|---|---|---|---|---|---|---|
| (XII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 | |
| (XXXI) | 44448 | 2,2-dimethyl-3-oxopentanal | C7H12O2 | 详情 | 详情 | |
| (XXXII) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (XXXIII) | 44450 | (5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one | C10H18O2 | 详情 | 详情 | |
| (XXXIV) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XXXV) | 44452 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal | C15H30O3Si | 详情 | 详情 | |
| (XXXVI) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XXXVII) | 27185 | (2S)-2-methyl-6-heptenal | C8H14O | 详情 | 详情 |
合成路线7
The aldol condensation of 4-methoxy-alpha-methyl-cinnamaldehyde (XXXVIII) with the enol ether of 3-pentanone (XXXIX) gives the racemic aldol (rac)-(XL), which is submitted to an enantioselective retroaldol reaction catalyzed by antibody 38C2 yielding the chiral aldol (3R,4R)-(XLI). The reduction of the double bond of (XLI) with H2 over Rh/Al2O3 in THF affords the saturated hydroxyketone (XLII), which is treated with Tbdms-Cl and imidazole to provide the silyl ether (XLIII). The methylation of (XLIII) with methyl iodide and LDA in THF gives the isopropyl ketone (XLIV), which is condensed with aldehyde (XLV) by means of LDA in THF to yield the aldol (XLVI). The reaction of (XLVI) with Tbdms-Cl and imidazole affords the tris-silyl ether (XLVII), which is oxidized at the aromatic ring by means of RuCl3 and NaIO4 to provide the aldehyde (XLVIII).
| 【1】 Sinha, S.C.; Barbas, C.F. III; Lerner, R.A.; The antibody catalysis route to the total synthesis of epothilones. Proc Natl Acad Sci USA 1998, 95, 25, 14603. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)-(XL) | 45542 | (rac)-(4R*,5R*,6E)-5-hydroxy-7-(4-methoxyphenyl)-4,6-dimethyl-6-hepten-3-one | 2592-19-0 | C16H22O3 | 详情 | 详情 |
| (3R, 4R)-(XLI) | 55588 | (4R,5R,6E)-5-hydroxy-7-(4-methoxyphenyl)-4,6-dimethyl-6-hepten-3-one | C16H22O3 | 详情 | 详情 | |
| (XXXVIII) | 45540 | (E)-3-(4-methoxyphenyl)-2-methyl-2-propenoic acid | C11H12O3 | 详情 | 详情 | |
| (XXXIX) | 45541 | (E)-1-ethyl-1-propenyl dibutylborinate | C13H27BO | 详情 | 详情 | |
| (XLII) | 45543 | (4R,5S,6S)-5-hydroxy-7-(4-methoxyphenyl)-4,6-dimethyl-3-heptanone | 71-44-3 | C16H24O3 | 详情 | 详情 |
| (XLIII) | 45544 | (4R,5S,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-(4-methoxyphenyl)-4,6-dimethyl-3-heptanone | C22H38O3Si | 详情 | 详情 | |
| (XLIV) | 45545 | (4R,5S,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-(4-methoxyphenyl)-2,4,6-trimethyl-3-heptanone | C23H40O3Si | 详情 | 详情 | |
| (XLV) | 45546 | 3-[[tert-butyl(dimethyl)silyl]oxy]propanal | 570-24-1 | C9H20O2Si | 详情 | 详情 |
| (XLVI) | 45547 | (5S,6R,9S)-9-hydroxy-5-[(1S)-2-(4-methoxyphenyl)-1-methylethyl]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disilapentadecan-7-one | 18063-02-0 | C32H60O5Si2 | 详情 | 详情 |
| (XLVII) | 45547 | (5S,6R,9S)-9-hydroxy-5-[(1S)-2-(4-methoxyphenyl)-1-methylethyl]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disilapentadecan-7-one | 18063-02-0 | C32H60O5Si2 | 详情 | 详情 |
| (XLVIII) | 45549 | (3S,4S,5R,8S)-4,8,10-tris[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyl-6-oxodecanal | C32H68O5Si3 | 详情 | 详情 |
合成路线8
The condensation of (XLVIII) with phosphonate (XLIX) by means of NaH in THF furnishes the unsaturated ester (L). The reduction of the double bond of (L) with H2 over Rh/Al2O3, followed by reduction of the ester group with DIBAL and oxidation of the resulting alcohol with DMP, gives rise to the aldehyde (LI). The Wittig condensation of (LI) with phosphonium salt (LII) by means of BuLi in THF yields the terminal olefin (LIII), which is selectively desilylated with TsOH to afford the primary alcohol (LIV). Finally, this compound is oxidized to the target carboxylic acid intermediate (XII) with DMP and NaClO2 in dichloromethane/THF.
| 【1】 Sinha, S.C.; Barbas, C.F. III; Lerner, R.A.; The antibody catalysis route to the total synthesis of epothilones. Proc Natl Acad Sci USA 1998, 95, 25, 14603. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IL) | 35909 | ethyl 3-(diethoxyphosphoryl)propanoate | 3699-67-0 | C9H19O5P | 详情 | 详情 |
| (XII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 | |
| (XLVIII) | 45549 | (3S,4S,5R,8S)-4,8,10-tris[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyl-6-oxodecanal | C32H68O5Si3 | 详情 | 详情 | |
| (L) | 45550 | ethyl (E,5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxo-2-dodecenoate | 2463-77-6 | C36H74O6Si3 | 详情 | 详情 |
| (LI) | 45551 | (5S,6S,7R,10S)-6,10,12-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7,9,9-tetramethyl-8-oxododecanal | 94-59-7 | C34H72O5Si3 | 详情 | 详情 |
| (LII) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (LIII) | 44436 | (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one | C35H74O4Si3 | 详情 | 详情 | |
| (LIV) | 44437 | (5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one | C29H60O4Si2 | 详情 | 详情 |