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【结 构 式】 
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【分子编号】27175 【品名】(3R)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanol 【CA登记号】 |
【 分 子 式 】C12H24O3 【 分 子 量 】216.32076 【元素组成】C 66.63% H 11.18% O 22.19% |
合成路线1
该中间体在本合成路线中的序号：(IX)C1-C6 fragment.- The reaction of 3-methyl-2-butenylmagnesium chloride (I) with propanal (II) gives racemic 4,4-dimethyl-5-hexen-3-ol (III), which was submitted to enzymatic resolution with ChiroCLEC-PC dry enzyme yielding the (R) enantiomer (IV). The esterification of (IV) with bromoacetyl bromide (V) and dimethylaniline yields the corresponding ester (VI), which is oxidized with O3 and trimethyl phosphite and cyclized with SmI2 in THF to afford chiral tetrahydropyran-2-one (VII). The reduction of (VII) with Red-Al, followed by cyclization with 2-methoxypropene (VIII) and PPTS yields the acetonide (IX), which is finally oxidized with N-methylmorpholine-N-oxide and PPTS in dichloromethane giving the target intermediate (X).
| 【1】 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 |
|---|---|---|---|---|---|---|
| (I) | 27170 | chloro(3-methyl-2-butenyl)magnesium | C5H9ClMg | 详情 | 详情 | |
| (II) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (III) | 27171 | 4,4-dimethyl-5-hexen-3-ol | C8H16O | 详情 | 详情 | |
| (IV) | 27172 | (3R)-4,4-dimethyl-5-hexen-3-ol | C8H16O | 详情 | 详情 | |
| (V) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (VI) | 27173 | (1R)-1-ethyl-2,2-dimethyl-3-butenyl 2-bromoacetate | C10H17BrO2 | 详情 | 详情 | |
| (VII) | 27174 | (4S,6R)-6-ethyl-4,5,5-trimethyltetrahydro-2H-pyran-2-one | C10H18O2 | 详情 | 详情 | |
| (VIII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (IX) | 27175 | (3R)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanol | C12H24O3 | 详情 | 详情 | |
| (X) | 27176 | 2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanone | C12H22O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIV)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 |