|
【结 构 式】 
|
【分子编号】16818 【品名】(3S,8R,9S,10R,13S,14S)-3-[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one 【CA登记号】 |
【 分 子 式 】C25H42O2Si 【 分 子 量 】402.69278 【元素组成】C 74.57% H 10.51% O 7.95% Si 6.97% |
合成路线1
该中间体在本合成路线中的序号：(VII)Prasterone can be obtained by two related ways: 1) The acetylation of cholesterol (I) with refluxing acetic anhydride gives the corresponding acetate (II), which is brominated with Br2 in acetic acid to the dibromide (III). The oxidation of (III) with CrO3 in acetic acid followed by debromination with Zn in the same solvent and treatment with semicarbazide and sodium acetate in ethanol/water affords 3beta-acetoxyandrost-5-en-17-one semicarbazone (IV), which is finally hydrolyzed with 5N H2SO4 in refluxing ethanol. 2) The partial silylation of androst-5-ene-3beta,17beta-diol (V) with tert-butyldimethylsilyl chloride and imidazole in DMF yields the 3beta-silyloxy derivative (VI), which is oxidized with CrO3-pyridine complex in pyridine affording 3-(tert-butyldimethylsilyloxy)androst-5-en-17-one (VII). Finally, this compound is deprotected with hot acetic acid/water/THF or with tetrabutylammonium fluoride in THF.
| 【1】 Fernholz, E.; Wallis, E.S.; The preparation of dehydroandrosterone from cholesterol. J Am Chem Soc 1935, 57, 1504-6. |
| 【2】 Castañer, J.; Mealy, N.; Rabasseda, X.; Prasterone. Drugs Fut 1995, 20, 6, 575. |
| 【3】 Ruzicka, L.; Wettstein, A.; Sexual hormones: Synthetic preparation of the male sexual hormones trans-dehydroandrosterone and androstene-3,17-dione. Helv Chim Acta 1935, 18, 986-95. |
| 【4】 Fernholz, E.; Wallis, E.S.; The constitution of dehydro-androsterone and its preparation from cholesterol. J Am Chem Soc 1935, 57, 1379-80. |
| 【5】 Hosoda, H.; Fishman, J.; Fukushima, D.K.; Convenient, high yield conversion of androst-5-ene-3beta,17beta-diol to dehydroisoandrosterone. J Org Chem 1973, 38, 24, 4209-11. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32057 | tert-butyl(chloro)dimethylsilane | 18162-48-6 | C6H15ClSi | 详情 | 详情 | |
| (I) | 16812 | (+)-Cholesterol; (+)-(3S,8S,9S,10R,13R,14S,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol | 14868-17-8 | C27H46O | 详情 | 详情 |
| (II) | 16813 | (3S,8S,9S,10R,13R,14S,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | 604-35-3 | C29H48O2 | 详情 | 详情 |
| (III) | 16814 | (3S,8S,9S,10R,13R,14S,17R)-5,6-dibromo-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C29H48Br2O2 | 详情 | 详情 | |
| (IV) | 16815 | (3S,8R,9S,10R,13S,14S)-17-[(E)-2-(aminocarbonyl)hydrazono]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C22H33N3O3 | 详情 | 详情 | |
| (V) | 16816 | (3S,8R,9S,10R,13S,14S,17S)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diol; 3beta,17beta-Dihydroxyandrost-5-ene; 5-Androstene-3beta,17beta-diol | 521-17-5 | C19H30O2 | 详情 | 详情 |
| (VI) | 16817 | (3S,8R,9S,10R,13S,14S,17S)-3-[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ol | C25H44O2Si | 详情 | 详情 | |
| (VII) | 16818 | (3S,8R,9S,10R,13S,14S)-3-[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C25H42O2Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVII)Synthesis of the cholestane aglycon (XXXVI): The protection of the OH group of dehydroisoandrosterone (XXVI) with Tbdms-Cl and imidazole gives the silyl ether (XXVII), which is condensed with ethyl triphenylphosphonium bromide (XXVIII) and potassium tert-butoxide in refluxing THF to yield the ethylidene compound (XXIX). The hydroxylation of (XXIX) with SeO2 and TBHP affords the 16alpha-hydroxy compound (XXX), which by a Swern oxidation is converted into the ketone (XXXI). The condensation of (XXXI) with the intermediate cuprate (XXV) provides the adduct (XXXII), which is treated with ethyleneglycol (XXXIII) and PPTS to give the spiroketal (XXXIV). The oxidative cleavage of the enol acetate of (XXXIV) with tBu-OK and Davis reagent yields the alpha-hydroxyketone (XXXV), which is finally reduced with LiAlH4 to afford the desired cholestane aglycon (XXXVI).
| 【1】 Jin, Z.; Yu, W.; A new strategy for the stereoselective introduction of steroid side chain via alpha-alkoxy vinyl cuprates: Total synthesis of a highly potent antitumor natural product OSW-1. J Am Chem Soc 2001, 123, 14, 3369. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXV) | 48957 | C54H99CuNO4 | 详情 | 详情 | ||
| (XXVI) | 11713 | Dehydroepiandrosterone;prasterone；(3S,8R,9S,10R,13S,14S)-3-Hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | 53-43-0 | C19H28O2 | 详情 | 详情 |
| (XXVII) | 16818 | (3S,8R,9S,10R,13S,14S)-3-[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C25H42O2Si | 详情 | 详情 | |
| (XXVIII) | 11717 | Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide | 1530-32-1 | C20H20BrP | 详情 | 详情 |
| (XXIX) | 48958 | tert-butyl(dimethyl)silyl (3S,10R,13S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl ether; tert-butyl([(3S,10R,13S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl]oxy)dimethylsilane | C27H46OSi | 详情 | 详情 | |
| (XXX) | 48959 | (3S,10R,13S,16R)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-16-ol | C27H46O2Si | 详情 | 详情 | |
| (XXXI) | 48960 | (3S,10R,13S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(E)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,17-tetradecahydro-16H-cyclopenta[a]phenanthren-16-one | C27H44O2Si | 详情 | 详情 | |
| (XXXII) | 48961 | (3S,10R,13S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(1S,2Z)-2-(cyclohexyloxy)-1,5-dimethyl-2-hexenyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate | C41H68O4Si | 详情 | 详情 | |
| (XXXIII) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (XXXIV) | 48962 | (3S,10R,13S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate | C37H62O5Si | 详情 | 详情 | |
| (XXXV) | 48963 | (3S,10R,13S,17S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-hydroxy-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,17-tetradecahydro-16H-cyclopenta[a]phenanthren-16-one | C35H60O5Si | 详情 | 详情 | |
| (XXXVI) | 48964 | (3S,10R,13S,16S,17S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16,17-diol | C35H62O5Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXVI)Synthesis of the target cholestane glycoside. The reaction of 3-beta-hydroxy-5-androsten-17-one (XXV) with Tbdms-Cl gives the silyl ether (XXVI), which is condensed with phosphorane (XXVII), yielding the ethylidene derivative (XXVIII). The oxidation of (XXVIII) by means of SeO2 and tert-butyl hydroperoxide affords the alcohol (XXIX), which is submitted to a Swern oxidation to provide the enone (XXX). The condensation of (XXX) with the intermediate vinyl bromide (XXIV) by means of CuCN, LiCl and Tms-Cl gives the non isolated intermediate (XXXI), which is treated with acetyl chloride to yield the enol acetate (XXXII). The reaction of (XXXII) with ethyleneglycol and PPTS in dichloromethane affords the ethylene ketal (XXXIII), which is submitted to a stereoselective oxidation with Davis reagent and t-BuOK to provide the hydroxy ketone (XXXIV). The stereoselective reduction of (XXXIV) by means of LiAlH4 in dichloromethane leads to the dihydroxy compound (XXXV).
| 【1】 Yu, W.; Jin, Z.; Total synthesis of the anticancer natural product OSW-1. J Am Chem Soc 2002, 124, 23, 6576. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (XXIV) | 48956 | (E)-1-bromo-4-methyl-1-pentenyl cyclohexyl ether; 1-[[(E)-1-bromo-4-methyl-1-pentenyl]oxy]cyclohexane | C12H21BrO | 详情 | 详情 | |
| (XXV) | 11713 | Dehydroepiandrosterone;prasterone；(3S,8R,9S,10R,13S,14S)-3-Hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | 53-43-0 | C19H28O2 | 详情 | 详情 |
| (XXVI) | 16818 | (3S,8R,9S,10R,13S,14S)-3-[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C25H42O2Si | 详情 | 详情 | |
| (XXVII) | 60152 | ethylidene(triphenyl)phosphorane | C20H19P | 详情 | 详情 | |
| (XXVIII) | 60153 | tert-butyl(dimethyl)silyl (3S,8S,9S,10R,13S,14S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl ether; tert-butyl({(3S,8S,9S,10R,13S,14S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl}oxy)dimethylsilane | C27H46OSi | 详情 | 详情 | |
| (XXIX) | 60154 | (3S,8R,9S,10R,13S,14S,16R)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-16-ol | C27H46O2Si | 详情 | 详情 | |
| (XXX) | 60155 | (3S,8R,9S,10R,13S,14S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(E)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,17-tetradecahydro-16H-cyclopenta[a]phenanthren-16-one | C27H44O2Si | 详情 | 详情 | |
| (XXXI) | 60156 | tert-butyl(dimethyl)silyl (3S,8R,9S,10R,13S,14S)-17-[(1S,2Z)-2-(cyclohexyloxy)-1,5-dimethyl-2-hexenyl]-10,13-dimethyl-16-[(trimethylsilyl)oxy]-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ether; tert-butyl({(3S,8R,9S,10R,13S,14S)-17-[(1S,2Z)-2-(cyclohexyloxy)-1,5-dimethyl-2-hexenyl]-10,13-dimethyl-16-[(trimethylsilyl)oxy]-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl}oxy)dimethylsilane | C42H74O3Si2 | 详情 | 详情 | |
| (XXXII) | 60157 | (3S,8R,9S,10R,13S,14S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(1S,2Z)-2-(cyclohexyloxy)-1,5-dimethyl-2-hexenyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate | C41H68O4Si | 详情 | 详情 | |
| (XXXIII) | 60158 | (3S,8R,9S,10R,13S,14S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate | C37H62O5Si | 详情 | 详情 | |
| (XXXIV) | 60159 | (3S,8R,9S,10R,13S,14S,17S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-hydroxy-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,17-tetradecahydro-16H-cyclopenta[a]phenanthren-16-one | C35H60O5Si | 详情 | 详情 | |
| (XXXV) | 60160 | (3S,8R,9S,10R,13S,14S,16S,17S)-3-{[tert-butyl(dimethyl)silyl]oxy}-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16,17-diol | C35H62O5Si | 详情 | 详情 |