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【结 构 式】 
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【分子编号】47614 【品名】2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)-1-ethanol 【CA登记号】 |
【 分 子 式 】C21H42O3Si2 【 分 子 量 】398.73368 【元素组成】C 63.26% H 10.62% O 12.04% Si 14.09% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Synthesis of phosphine oxide (XIV): Epoxidation of l-carvone (I) with H2O2 and LiOH in methanol gives the epoxide (II), which is reduced with L-Selectride in THF to yield the alcohol (III). Oxidation of the isopropenyl group of (III) with OsO4, KIO4, MCPBA and HOAc affords the acetate (IV), which is hydrolyzed to the diol (V) with MeONa in methanol. Protection of the two OH groups of (V) with TBDMS-Cl and imidazole provides the bis-silyl ether (VI), which is oxidized with periodic acid in ethyl ether to give the aldehyde (VII). Compound (VII) is submitted to a Wittig condensation with CBr4, PPh3 and Zn in dichloromethane to yield the dibromovinyl compound (VIII), which is converted into the acetylenic vinyl triflate (X) by treatment with LDA in THF followed by the triflic imide (IX). Cyclization of triflate (X) by means of Pd(OAc)2 and PPh3, followed by carbonylation with CO in methanol provides the methyl ester (XI) as a 2:1 mixture of the Z- and E-isomers. Photoisomerization of this mixture (XIa-b) under the Hoffman-La Roche conditions (presence of 9-fluorenone) gives the Z-isomer (XII) in a high yield. Reduction of ester (XII) with DIBAL in toluene provides the primary alcohol (XIII), which is finally converted into the phosphine oxide (XIV) by known methods.
| 【1】 Mourino, A.; et al.; Efficient and versatile synthesis of A-ring precursors of 1alpha,25-dihydroxyvitamin D3 and analogues. Application to the synthesis of Lythgoe-Roche phosphine oxide. Tetrahedron Lett 1997, 38, 26, 4713. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIa),(XII) | 52149 | methyl 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetate | C22H42O4Si2 | 详情 | 详情 | |
| (XIb) | 52150 | methyl 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetate | C22H42O4Si2 | 详情 | 详情 | |
| (I) | 13386 | (5R)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one; L-(-)-Carvone | 6485-40-1 | C10H14O | 详情 | 详情 |
| (II) | 52141 | (1R,4R,6R)-4-isopropenyl-1-methyl-7-oxabicyclo[4.1.0]heptan-2-one | C10H14O2 | 详情 | 详情 | |
| (III) | 52142 | (1R,2S,4S,6R)-4-isopropenyl-1-methyl-7-oxabicyclo[4.1.0]heptan-2-ol | C10H16O2 | 详情 | 详情 | |
| (IV) | 52143 | (1R,3S,5S,6S)-5-hydroxy-6-methyl-7-oxabicyclo[4.1.0]hept-3-yl acetate | C9H14O4 | 详情 | 详情 | |
| (V) | 52144 | (1S,2S,4S,6R)-1-methyl-7-oxabicyclo[4.1.0]heptane-2,4-diol | C7H12O3 | 详情 | 详情 | |
| (VI) | 52145 | tert-butyl[((1R,2S,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-7-oxabicyclo[4.1.0]hept-2-yl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (1R,2S,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-7-oxabicyclo[4.1.0]hept-2-yl ether | C19H40O3Si2 | 详情 | 详情 | |
| (VII) | 52146 | (3S,5S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-6-oxoheptanal | C19H40O4Si2 | 详情 | 详情 | |
| (VIII) | 52147 | (3S,5R)-8,8-dibromo-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-7-octen-2-one | C20H40Br2O3Si2 | 详情 | 详情 | |
| (IX) | 34685 | N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 145100-51-2 | C7H3ClF6N2O4S2 | 详情 | 详情 |
| (X) | 52148 | (2S,4R)-2,4-bis[[tert-butyl(dimethyl)silyl]oxy]-1-methylene-6-heptynyl trifluoromethanesulfonate | C21H39F3O5SSi2 | 详情 | 详情 | |
| (XIII) | 47614 | 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)-1-ethanol | C21H42O3Si2 | 详情 | 详情 | |
| (XIV) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Oxidation of hydroxylated diene (I) with m-CPBA followed by acetylation provides epoxide (II), which is then converted to the corresponding hydroxy derivative (III) by means of SeO2 and PyO in dioxane followed by isomer separation. Treatment of compound (III) with t-butyldimethylsilyl chloride and imidazole in DMF yields the 5,7-bis-protected derivative (IV), which reacts in THF with tungsten hexachloride (WCl6) and BuLi in hexane/THF to furnish compound (V). Hydrolysis of acetate (V) with NaOH in MeOH provides alcohol (VI), which is then converted into the corresponding chloro derivative (VII) by treatment with N-chlorosuccinimide (NCS) and dimethylsulfide (Me2S) in CH2Cl2. Treatment of compound (VII) with potassium diphenylphosphide (PPh2K) in THF and aqueous H2O2 in CH2Cl2 gives diphenylphosphine oxide (VIII), which is condensed in THF with hexahydro indenone derivative (IX) by means of n-BuLi in hexane to afford compound (X). Finally, derivative (X) is deprotected by treatment with tetrabutyl ammonium fluoride in THF to yield the desired product.
| 【1】 Kiegiel, J.; et al.; Chemical conversion of vitamin D3 to its 1,25-dihydroxy metabolite. Tetrahedron Lett 1991, 32, 43, 6057. |
| 【2】 Batcho, A.D.; Hennessy, B.M.; Uskokovic, M.R. (F. Hoffmann-La Roche AG); Vitamin D3 analogs. WO 0104089 . |
| 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) | 47609 | 2-((5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)-1-ethanol | C15H28O2Si | 详情 | 详情 | |
| (II) | 47610 | ((2R,3S,7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-4-methylene-1-oxaspiro[2.5]oct-2-yl)methyl acetate | C17H30O4Si | 详情 | 详情 | |
| (III) | 47611 | ((2R,3S,5S,7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4-methylene-1-oxaspiro[2.5]oct-2-yl)methyl acetate | C17H30O5Si | 详情 | 详情 | |
| (IV) | 47612 | ((2R,3S,5S,7S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methylene-1-oxaspiro[2.5]oct-2-yl)methyl acetate | C23H44O5Si2 | 详情 | 详情 | |
| (V) | 47613 | 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl acetate | C23H44O4Si2 | 详情 | 详情 | |
| (VI) | 47614 | 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)-1-ethanol | C21H42O3Si2 | 详情 | 详情 | |
| (VII) | 47615 | tert-butyl(dimethyl)silyl (1R,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-[(E)-2-chloroethylidene]-4-methylenecyclohexyl ether; tert-butyl([(1R,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-[(E)-2-chloroethylidene]-4-methylenecyclohexyl]oxy)dimethylsilane | C21H41ClO2Si2 | 详情 | 详情 | |
| (VIII) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 | |
| (IX) | 47616 | (3aR,7aS)-1-[(1R)-1,5-dimethyl-5-[(trimethylsilyl)oxy]hexyl]-7a-methyl-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one | C21H38O2Si | 详情 | 详情 | |
| (X) | 47617 | C41H78O4Si3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)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 |
合成路线4
该中间体在本合成路线中的序号：(XIII)The intermediate phosphine oxide (XIV) has been obtained as follows: The epoxidation of l-carvone (I) with H2O2 and LiOH in methanol gives the epoxide (II), which is reduced with L-Selectride in THF to yield the alcohol (III). The oxidation of the isopropenyl group of (III) with OsO4, KIO4, MCPBA and HOAc affords the acetate (IV), which is hydrolyzed to the diol (V) with NaOMe in methanol. The protection of the two OH groups of (V) with Tbdms-Cl and imidazole provides the bis-silyl ether (VI), which is oxidized with periodic acid in ethyl ether to give the ketoaldehyde (VII). The aldehyde group of (VII) is subjected to a Wittig condensation with CBr4, PPh3 and Zn in dichloromethane to yield the dibromovinyl compound (VIII), which by treatment with LDA and the triflic imide (IX) in THF affords the acetylenic vinyl triflate (X). The cyclization of (X) by means of Pd(OAc)2 and PPH3, followed by carbonylation in methanol, provides the methyl ester (XI) as a 2:1 mixture of the (Z)- and (E)-isomers. The photoisomerization of this mixture under the Hoffmann-La Roche conditions (presence of 9-fluorenone) gives a high yield of the (Z)-isomer (XII), which is reduced with DIBAL in toluene to give the primary alcohol (XIII). Finally, this compound is converted into the target phosphine oxide (XIV) is performed by known methods.
| 【1】 Mourino, A.; et al.; Efficient and versatile synthesis of A-ring precursors of 1alpha,25-dihydroxyvitamin D3 and analogues. Application to the synthesis of Lythgoe-Roche phosphine oxide. Tetrahedron Lett 1997, 38, 26, 4713. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIa),(XII) | 52149 | methyl 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetate | C22H42O4Si2 | 详情 | 详情 | |
| (XIb) | 52150 | methyl 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetate | C22H42O4Si2 | 详情 | 详情 | |
| (I) | 13386 | (5R)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one; L-(-)-Carvone | 6485-40-1 | C10H14O | 详情 | 详情 |
| (II) | 52141 | (1R,4R,6R)-4-isopropenyl-1-methyl-7-oxabicyclo[4.1.0]heptan-2-one | C10H14O2 | 详情 | 详情 | |
| (III) | 52550 | 1-methyl-4-(1-methylethenyl)-7-oxabicyclo[4.1.0]heptan-2-ol | C10H16O2 | 详情 | 详情 | |
| (IV) | 52143 | (1R,3S,5S,6S)-5-hydroxy-6-methyl-7-oxabicyclo[4.1.0]hept-3-yl acetate | C9H14O4 | 详情 | 详情 | |
| (V) | 52144 | (1S,2S,4S,6R)-1-methyl-7-oxabicyclo[4.1.0]heptane-2,4-diol | C7H12O3 | 详情 | 详情 | |
| (VI) | 52145 | tert-butyl[((1R,2S,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-7-oxabicyclo[4.1.0]hept-2-yl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (1R,2S,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-7-oxabicyclo[4.1.0]hept-2-yl ether | C19H40O3Si2 | 详情 | 详情 | |
| (VII) | 52146 | (3S,5S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-6-oxoheptanal | C19H40O4Si2 | 详情 | 详情 | |
| (VIII) | 52147 | (3S,5R)-8,8-dibromo-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-7-octen-2-one | C20H40Br2O3Si2 | 详情 | 详情 | |
| (IX) | 34685 | N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 145100-51-2 | C7H3ClF6N2O4S2 | 详情 | 详情 |
| (X) | 52148 | (2S,4R)-2,4-bis[[tert-butyl(dimethyl)silyl]oxy]-1-methylene-6-heptynyl trifluoromethanesulfonate | C21H39F3O5SSi2 | 详情 | 详情 | |
| (XIII) | 47614 | 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)-1-ethanol | C21H42O3Si2 | 详情 | 详情 | |
| (XIV) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 |