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【结 构 式】 
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【分子编号】59895 【品名】2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethyl(diphenyl)phosphine oxide; {2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethyl}(oxo)diphenylphosphorane 【CA登记号】 |
【 分 子 式 】C42H71O5PSi3 【 分 子 量 】771.253002 【元素组成】C 65.41% H 9.28% O 10.37% P 4.02% Si 10.92% |
合成路线1
该中间体在本合成路线中的序号：(LVIII)The title compound was also prepared using solid-phase methodology within a parallel synthesis protocol for the construction of a combinatorial library of vitamin D3 analogues. The A-ring synthon (LVIII) was synthesized as follows. Esterification of the previously reported alcohol intermediate (L) with pivaloyl chloride gave pivalate ester (LI). Acetonide hydrolysis in (LI) and then selective mono-silylation of the resultant diol (LII) yielded (LIII). Michael addition of ethyl acrylate (LIV) to the free hydroxyl group of (LIII) furnished ester (LV). Subsequently reduction of methyl ester (LV), with simultaneous reductive cleavage of the pivaloyl group in the presence of LiAlH4 led to diol (LVI). Chlorination of the allylic alcohol of (LVI) by means of N-chlorosuccinimide and dimethylsulfide, followed by silylation of the remaining hydroxyl group gave (LVII). Conversion of chloride (LVII) into the phosphine oxide (LVIII) was then performed using a similar procedure as that for intermediate (XXXII)
| 【1】 Hijikuro, I.; Doi, T.; Takahashi, T.; Parallel synthesis of a vitamin D3 library in the solid-phase. J Am Chem Soc 2001, 123, 16, 3716. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (L) | 59888 | 2-[(3aR,7R,7aS)-7-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyl-4-methylenetetrahydro-1,3-benzodioxol-5(4H)-ylidene]-1-ethanol | C18H32O4Si | 详情 | 详情 | |
| (LI) | 59889 | 2-[(3aR,7R,7aS)-7-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyl-4-methylenetetrahydro-1,3-benzodioxol-5(4H)-ylidene]ethyl pivalate | C23H40O5Si | 详情 | 详情 | |
| (LII) | 59890 | 2-((3R,4S,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-3,4-dihydroxy-2-methylenecyclohexylidene)ethyl pivalate | C20H36O5Si | 详情 | 详情 | |
| (LIII) | 59891 | 2-((3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-2-methylenecyclohexylidene)ethyl pivalate | C26H50O5Si2 | 详情 | 详情 | |
| (LIV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (LV) | 59892 | 2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-methoxy-3-oxopropoxy)-2-methylenecyclohexylidene]ethyl pivalate | C30H56O7Si2 | 详情 | 详情 | |
| (LVI) | 59893 | 3-({(1R,2R,6R)-2,6-bis{[tert-butyl(dimethyl)silyl]oxy}-4-[(Z)-2-hydroxyethylidene]-3-methylenecyclohexyl}oxy)-1-propanol | C24H48O5Si2 | 详情 | 详情 | |
| (LVII) | 59894 | tert-butyl({(1R,2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-5-[(Z)-2-chloroethylidene]-4-methylenecyclohexyl}oxy)dimethylsilane; (1R,2R,6R)-2,6-bis{[tert-butyl(dimethyl)silyl]oxy}-4-[(Z)-2-chloroethylidene]-3-methylenecyclohexyl 3-{[tert-butyl(dimethyl)silyl]oxy}propyl ether | C30H61ClO4Si3 | 详情 | 详情 | |
| (LVIII) | 59895 | 2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethyl(diphenyl)phosphine oxide; {2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethyl}(oxo)diphenylphosphorane | C42H71O5PSi3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(LVIII)Attachment of the CD-ring synthon to the solid-phase support required the introduction of an appropriate spacer group. Coupling between methyl 4-hydroxybenzenesulfonate (LIX) and the tetrahydropyranyl-protected diol (LX) under Mitsunobu conditions afforded the alkoxy sulfonate (LXI). The sulfonate ester of (LXI) was hydrolyzed with LiCl in refluxing acetone, and the resulting sulfonic acid was converted to sulfonyl chloride (LXII) by PCl5 -in DMF. Coupling of the CD-ring alcohol (LXIII) with the sulfonyl chloride (LXII), followed by acidic tetrahydropyranyl group cleavage gave the sulfonate linker-bound CD synthon (LXIV). This was attached to a previously chlorinated diethylsilyl resin to furnish the resin-bound CD ring (LXV). Alternatively, resin (LXV) was prepared by a more general method consisting in the initial attachment of the sulfonate linker (LXII) to the resin support, and then loading alcohol (LXIII) to the resultant sulfonyl chloride resin (LXVI). Horner-Wadsworth-Emmons condensation of the resin-bound ketone (LXV) with the lithiated phosphine oxide (LVIII) yielded the triene compound (LXVII). Cleavage of the sulfonate resin and simultaneous introduction of the side chain substitution was achieved by copper-catalyzed displacement of sulfonate resin (LXVII) with the Grignard reagent (LXVIII). The silyl protecting groups were finally cleaved by treatment with CSA in aqueous methanol
| 【1】 Hijikuro, I.; Doi, T.; Takahashi, T.; Parallel synthesis of a vitamin D3 library in the solid-phase. J Am Chem Soc 2001, 123, 16, 3716. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LVIII) | 59895 | 2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethyl(diphenyl)phosphine oxide; {2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethyl}(oxo)diphenylphosphorane | C42H71O5PSi3 | 详情 | 详情 | |
| (LIX) | 59896 | methyl 4-hydroxybenzenesulfonate | C7H8O4S | 详情 | 详情 | |
| (LX) | 59897 | 9-(tetrahydro-2H-pyran-2-yloxy)-1-nonanol | C14H28O3 | 详情 | 详情 | |
| (LXI) | 59898 | methyl 4-{[9-(tetrahydro-2H-pyran-2-yloxy)nonyl]oxy}benzenesulfonate | C21H34O6S | 详情 | 详情 | |
| (LXII) | 59899 | 4-{[9-(tetrahydro-2H-pyran-2-yloxy)nonyl]oxy}benzenesulfonyl chloride | C20H31ClO5S | 详情 | 详情 | |
| (LXIII) | 59900 | (1R,3aR,7aR)-1-[(1S)-2-hydroxy-1-methylethyl]-7a-methyloctahydro-4H-inden-4-one | C13H22O2 | 详情 | 详情 | |
| (LXIV) | 59901 | (2S)-2-[(1R,3aR,7aR)-7a-methyl-4-oxooctahydro-1H-inden-1-yl]propyl 4-[(9-hydroxynonyl)oxy]benzenesulfonate | C28H44O6S | 详情 | 详情 | |
| (LXV) | 59903 | (2S)-2-[(1R,3aR,7aR)-7a-methyl-4-oxooctahydro-1H-inden-1-yl]propyl 4-({9-[hydroxy(dipropyl)silyl]nonyl}oxy)benzenesulfonate | C34H58O6SSi | 详情 | 详情 | |
| (LXVI) | 59902 | {9-[4-(methylsulfonyl)phenoxy]nonyl}(dipropyl)silanol | C22H40O4SSi | 详情 | 详情 | |
| (LXVII) | 59904 | (2S)-2-((1R,3aS,7aR)-4-{(E)-2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethylidene}-7a-methyloctahydro-1H-inden-1-yl)propyl 4-({9-[hydroxy(dipropyl)silyl]nonyl}oxy)be | C64H118O9SSi4 | 详情 | 详情 |