|
【结 构 式】 
|
【分子编号】47723 【品名】(1S,3aS,4S,7aS)-1-[(1S)-1,5-dimethyl-5-[(triethylsilyl)oxy]hexyl]-7a-methyloctahydro-1H-inden-4-yl phenyl sulfone; ([(5S)-5-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-1,1-dimethylhexyl]oxy)(triethyl)silane 【CA登记号】 |
【 分 子 式 】C30H52O3SSi 【 分 子 量 】520.89258 【元素组成】C 69.18% H 10.06% O 9.21% S 6.16% Si 5.39% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Asymmetric Robinson annulation of 2-methylcyclopentane-1,3-dione (II) with (phenylsulfanyl)methyl vinyl ketone (I) using R-(+)-phenylalanine as the catalyst afforded the chiral bicyclic dione (III). Oxidation of the sulfide group of (III) by means of m-chloroperbenzoic acid gave sulfone (IV). This was reduced with LiAlH4 to the trans-hydrindane derivative (V), which was further oxidized to ketone (VI) with Jones reagent. The indaneacetic ester (VII) was obtained by Horner-Emmons condensation of ketone (VI) with triethyl phosphonoacetate, followed by catalytic hydrogenation. Treatment of (VII) with bromide (VIII) in the presence of LDA provided an inseparable mixture (IX and X) of alkylated compounds at the alpha position of the ester and sulfone functions, respectively. Ester reduction of this mixture by means of DIBAL afforded the mixture of alcohols (XI) and (XII), which were separated by chromatography. The desired alcohol (XI) was reduced to the methyl derivative (XIII) via conversion to the corresponding mesylate, which was then reduced by treatment with lithium triethyl borohydride.
| 【1】 Marczak, S.; et al.; Synthesis and biological activity of the 1alpha,25-dihydroxyvitamin D3 diastereomer with unnatural configuration at the rings C/D side-chain moiety. Bioorg Med Chem Lett 2001, 11, 1, 63. |
| 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) | 47713 | 1-(phenylsulfanyl)-3-buten-2-one | C10H10OS | 详情 | 详情 | |
| (II) | 24232 | 2-methyl-1,3-cyclopentanedione | 765-69-5 | C6H8O2 | 详情 | 详情 |
| (III) | 47714 | (7aR)-7a-methyl-4-(phenylsulfanyl)-2,3,7,7a-tetrahydro-1H-indene-1,5(6H)-dione | C16H16O2S | 详情 | 详情 | |
| (IV) | 47715 | (7aR)-7a-methyl-4-(phenylsulfonyl)-2,3,7,7a-tetrahydro-1H-indene-1,5(6H)-dione | C16H16O4S | 详情 | 详情 | |
| (V) | 47716 | (3aS,4S,7aR)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-ol | C16H22O3S | 详情 | 详情 | |
| (VI) | 47717 | (3aS,4S,7aR)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-one | C16H20O3S | 详情 | 详情 | |
| (VII) | 47718 | ethyl 2-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]acetate | C20H28O4S | 详情 | 详情 | |
| (VIII) | 47719 | (4-bromo-1,1-dimethylbutoxy)(triethyl)silane; 4-bromo-1,1-dimethylbutyl triethylsilyl ether | C12H27BrOSi | 详情 | 详情 | |
| (IX) | 47720 | ethyl (2S)-2-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-6-methyl-6-[(triethylsilyl)oxy]heptanoate | C32H54O5SSi | 详情 | 详情 | |
| (X) | 47721 | ethyl 2-[(1S,3aS,7aS)-7a-methyl-4-[4-methyl-4-[(triethylsilyl)oxy]pentyl]-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]acetate | C32H54O5SSi | 详情 | 详情 | |
| (XI) | 47729 | (2S)-2-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-6-methyl-6-[(triethylsilyl)oxy]-1-heptanol | C30H52O4SSi | 详情 | 详情 | |
| (XII) | 47722 | 2-[(1S,3aS,7aS)-7a-methyl-4-[4-methyl-4-[(triethylsilyl)oxy]pentyl]-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-1-ethanol | C30H52O4SSi | 详情 | 详情 | |
| (XIII) | 47723 | (1S,3aS,4S,7aS)-1-[(1S)-1,5-dimethyl-5-[(triethylsilyl)oxy]hexyl]-7a-methyloctahydro-1H-inden-4-yl phenyl sulfone; ([(5S)-5-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-1,1-dimethylhexyl]oxy)(triethyl)silane | C30H52O3SSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The oxidation of the ring A precursor alcohol (XIV) with Dess-Martin reagent gave rise to a mixture of aldehyde (XV) and its cyclic tautomer, the pyran derivative (XVI). Coupling of this mixture with the lithium anion of sulfone (XIII), followed by quenching with acetyl chloride, furnished the target beta-acetoxy sulfone adduct (XVII) accompanied by the silyl-acetyl exchange product (XVIII). Reductive cleavage of the phenylsulfonyl group by means of sodium amalgam yielded the desired O-triethylsilyl triene (XIX) along with some O-acetyl byproduct. Finally, desilylation of (XIX) with tetrabutylammonium fluoride provided the title triol derivative, which was separated from its C-25 acetate byproduct by flash chromatography.
| 【1】 Marczak, S.; et al.; Synthesis and biological activity of the 1alpha,25-dihydroxyvitamin D3 diastereomer with unnatural configuration at the rings C/D side-chain moiety. Bioorg Med Chem Lett 2001, 11, 1, 63. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 47723 | (1S,3aS,4S,7aS)-1-[(1S)-1,5-dimethyl-5-[(triethylsilyl)oxy]hexyl]-7a-methyloctahydro-1H-inden-4-yl phenyl sulfone; ([(5S)-5-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-1,1-dimethylhexyl]oxy)(triethyl)silane | C30H52O3SSi | 详情 | 详情 | |
| (XIV) | 47614 | 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)-1-ethanol | C21H42O3Si2 | 详情 | 详情 | |
| (XV) | 47724 | 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetaldehyde | C21H40O3Si2 | 详情 | 详情 | |
| (XVI) | 47725 | tert-butyl(dimethyl)silyl (6R,8S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5,6,7,8-tetrahydro-1H-isochromen-8-yl ether; tert-butyl[((6R,8S)-8-[[tert-butyl(dimethyl)silyl]oxy]-5,6,7,8-tetrahydro-1H-isochromen-6-yl)oxy]dimethylsilane | C21H40O3Si2 | 详情 | 详情 | |
| (XVII) | 47726 | 1-[(1S,3aS,7aS)-1-[(1S)-1,5-dimethyl-5-[(triethylsilyl)oxy]hexyl]-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-4-yl]-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl acetate | C53H94O7SSi3 | 详情 | 详情 | |
| (XVIII) | 47727 | (5S)-5-[(1S,3aS,7aS)-4-[1-(acetoxy)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl]-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-1,1-dimethylhexyl acetate | C49H82O8SSi2 | 详情 | 详情 | |
| (XIX) | 47728 | (5S)-5-[(1S,3aS,7aS)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-4H-inden-1-yl]-1,1-dimethylhexyl triethylsilyl ether; [((1R,5S)-3-[(Z)-2-((1S,3aS,7aS)-1-[(1S)-1,5-dimethyl-5-[(triethylsilyl)oxy]hexyl]-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene]-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylenecyclohexyl)oxy](tert-butyl)dimethylsilane | C45H86O3Si3 | 详情 | 详情 |