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【结 构 式】 
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【分子编号】57139 【品名】(1S,4S,6S)-4-{[tert-butyl(dimethyl)silyl]oxy}-7-oxabicyclo[4.1.0]heptan-2-one 【CA登记号】 |
【 分 子 式 】C12H22O3Si 【 分 子 量 】242.39038 【元素组成】C 59.46% H 9.15% O 19.8% Si 11.59% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of the chiral cyclohexenone (I) with H2O2 and NaOH in methanol gives the epoxide (II), which is submitted to a Wittig olefination with the phosphonium bromide (III) and KHMDS in toluene to yield the bromomethylene derivative (IV). The opening of the epoxide ring by means of DIBAL in hexane affords the cyclohexanol (V), which is silylated with Tbdms-Cl and imidazole to provide the bis silyl ether (VI). The reaction of (VI), triisopropyl borate and pinacol by means of t-BuLi in ethyl ether gives the boronic ester (VII), which is condensed with alkyl bromide intermediate (VIII) and catalyzed by PdCl2(dppf) and KOH in THF/water to yield the silylated precursor (IX). Finally, this compound is desilylated by means of aq. HF in THF to provide the target 1-alpha,25-dihydroxy-19-nor-vitamin D3. Alternatively, the intermediate (VIII) is reacted with triisiopropyl borate and pinacol, as before, to give the boronic ester (X), which is condensed with the cyclohexylidenemethyl bromide (VI) and catalyzed by PdCl2(dppf) and KOH in THF/water to yield the already reported silylated precursor (IX).
| 【1】 Hanazawa, T.; et al.; Novel synthetic approach to 19-nor-1alpha,25-dihydroxyvitamin D3 and its derivatives by Suzuki-Miyaura coupling in solution and on solid support. Org Lett 2001, 3, 24, 3975. |
| 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) | 57138 | (5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclohexen-1-one | C12H22O2Si | 详情 | 详情 | |
| (II) | 57139 | (1S,4S,6S)-4-{[tert-butyl(dimethyl)silyl]oxy}-7-oxabicyclo[4.1.0]heptan-2-one | C12H22O3Si | 详情 | 详情 | |
| (III) | 57140 | (bromomethyl)(trimethyl)phosphonium bromide | C4H11Br2P | 详情 | 详情 | |
| (IV) | 57141 | ({(1S,3R,6R)-5-[(E)-bromomethylidene]-7-oxabicyclo[4.1.0]hept-3-yl}oxy)(tert-butyl)dimethylsilane; (1S,3R,6R)-5-[(E)-bromomethylidene]-7-oxabicyclo[4.1.0]hept-3-yl tert-butyl(dimethyl)silyl ether | C13H23BrO2Si | 详情 | 详情 | |
| (V) | 57142 | (1R,5R)-3-[(Z)-bromomethylidene]-5-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol | C13H25BrO2Si | 详情 | 详情 | |
| (VI) | 57143 | (1R,5R)-3-(bromomethylene)-5-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl tert-butyl(dimethyl)silyl ether; [((1R,5R)-3-(bromomethylene)-5-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)oxy](tert-butyl)dimethylsilane | C19H39BrO2Si2 | 详情 | 详情 | |
| (VII) | 57144 | tert-butyl(dimethyl)silyl (1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]cyclohexyl ether; tert-butyl({(1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]cyclohexyl}oxy)dimethylsilane | C25H51BO4Si2 | 详情 | 详情 | |
| (VIII) | 57145 | (5R)-5-{(1R,7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl}-1,1-dimethylhexyl trimethylsilyl ether; [((5R)-5-{(1R,7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl}-1,1-dimethylhexyl)oxy](trimethyl)silane | C22H41BrOSi | 详情 | 详情 | |
| (IX) | 57147 | [((1R,5R)-3-[2-((1R,7aR)-1-{(1R)-1,5-dimethyl-5-[(trimethylsilyl)oxy]hexyl}-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene]-5-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)oxy](tert-butyl)dimethylsilane; (5R)-5-{(1R,7aR)-4-[(E)-2-((3R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}cyclohexylidene)ethylidene]-7a-methyloctahydro-4H-inden-1-yl}-1,1-dimethylhexyl trimethylsilyl ether | C41H80O3Si3 | 详情 | 详情 | |
| (X) | 57146 | (5R)-5-{(1R,7aR)-7a-methyl-4-[(E)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylidene]octahydro-1H-inden-1-yl}-1,1-dimethylhexyl trimethylsilyl ether; [((5R)-5-{(1R,7aR)-7a-methyl-4-[(E)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylidene]octahydro-1H-inden-1-yl}-1,1-dimethylhexyl)oxy](trimethyl)silane | C28H53BO3Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The epoxidation of the chiral cyclohexenone (I) with H2O2 and NaOH in methanol gives the epoxide (II), which is condensed with triethyl phosphonoacetate (III) by means of NaH in THF to yield the cyclohexylidene acetate (IV). The regioselective opening of the epoxide ring of (V) by means of formic acid, Pd2(dba)3 and Bu3P in chloroform affords the cyclohexanol derivative (V), which is silylated by means of Tbdms-Cl and imidazole to provide the fully silylated compound (VI). The reduction of the ester group of (VI) by means of DIBAL in toluene gives the primary alcohol (VII) (1), which is treated with NCS and Me2S in dichloromethane to yield the chloride compound (VIII). The reaction of (VIII) with lithium diphenylphosphide, followed by oxidation with H2O2 affords the phosphine oxide (IX), which is condensed with the known synthon (X) by means of BuLi in THF to provide the silylated precursor (XI). Finally, this compound is desilylated by means of TBAF in THF to afford the target 1-alpha,25-dihydroxy-19-nor-vitamin D3.
| 【1】 Hanazawa, T.; et al.; Efficient and practical synthesis of the A-ring precursor of 19-nor-1alpha,25-dihydroxyvitamin D3 and its (3C- or 2H-labeled derivative. Org Lett 2001, 3, 14, 2205. |
| 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) | 57138 | (5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclohexen-1-one | C12H22O2Si | 详情 | 详情 | |
| (II) | 57139 | (1S,4S,6S)-4-{[tert-butyl(dimethyl)silyl]oxy}-7-oxabicyclo[4.1.0]heptan-2-one | C12H22O3Si | 详情 | 详情 | |
| (III) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (IV) | 57148 | ethyl 2-((1R,4R,6S)-4-{[tert-butyl(dimethyl)silyl]oxy}-7-oxabicyclo[4.1.0]hept-2-ylidene)acetate | C16H28O4Si | 详情 | 详情 | |
| (V) | 57149 | ethyl 2-((3R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxycyclohexylidene)acetate | C16H30O4Si | 详情 | 详情 | |
| (VI) | 49047 | ethyl 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)acetate | C22H44O4Si2 | 详情 | 详情 | |
| (VII) | 49048 | 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)-1-ethanol | C20H42O3Si2 | 详情 | 详情 | |
| (VIII) | 57150 | tert-butyl(dimethyl)silyl (1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-(2-chloroethylidene)cyclohexyl ether; tert-butyl{[(1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-(2-chloroethylidene)cyclohexyl]oxy}dimethylsilane | C20H41ClO2Si2 | 详情 | 详情 | |
| (IX) | 30302 | [2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl(diphenyl)phosphine oxide | C32H51O3PSi2 | 详情 | 详情 | |
| (X) | 47151 | ethyl 4-[[4-(benzyloxy)-2-hydroxy-3,6-dimethylbenzoyl]oxy]-2-hydroxy-3,6-dimethylbenzoate | C27H28O7 | 详情 | 详情 | |
| (XI) | 57147 | [((1R,5R)-3-[2-((1R,7aR)-1-{(1R)-1,5-dimethyl-5-[(trimethylsilyl)oxy]hexyl}-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene]-5-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)oxy](tert-butyl)dimethylsilane; (5R)-5-{(1R,7aR)-4-[(E)-2-((3R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}cyclohexylidene)ethylidene]-7a-methyloctahydro-4H-inden-1-yl}-1,1-dimethylhexyl trimethylsilyl ether | C41H80O3Si3 | 详情 | 详情 |