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【结 构 式】 
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【分子编号】11717 【品名】Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide 【CA登记号】1530-32-1 |
【 分 子 式 】C20H20BrP 【 分 子 量 】371.256562 【元素组成】C 64.7% H 5.43% Br 21.52% P 8.34% |
合成路线1
该中间体在本合成路线中的序号：(V)1) The microbiological oxidation of 3beta-hydroxyandrost-5-en-17-one (I) gives 1alpha,3beta-dihydroxyandrost-5-en-17-one (II), which is silylated with tert-butyldimethylsilyl (TBS) chloride and imidazole to the bis(silyloxy) compound (III). The dehydrogenation of (III) by bromination with N-bromosuccinimide (NBS) and dehydrobromination with 2,4,6-trimethylpyridine (TMPyr) yields 1alpha,3beta-bis(tert-butyldimethylsilyloxy)androsta-5,7-dien-17-one (IV). The Wittig condensation of (IV) with ethyltriphenylphosphonium bromide (V) by means of NaH in DMS gives the corresponding ethylidene derivative (VI), which is treated first with 9-borabicyclo[3.3.1]nonane (9-BBN) and then with H2O2 and NaOH in THF yielding a mixture of the 20(S)- and 20(R)-isomers of 1alpha,3beta-bis(tert-butyldimethylsilyloxy)pregna-5,7-dien-20-ol that was separated by preparative TLC. The 20(S)-isomer (VII) was condensed with 1-bromo-3-butene (VIII) by means of NaH in refluxing xylene affording 20(S)-(3-butenyloxy)-1alpha,3beta-bis(tert-butyldimethylsilyloxy)pregna-5,7-diene (IX), which is oxidized with O2 gas in DMF/water catalyzed by Cu2Cl2 and PdCl2 to give the corresponding 3-oxobutoxy derivative (X). The Grignard alkylation of (X) with methylmagnesium bromide in THF afforded the 20(S)-(3-hydroxy-3-methylbutoxy) derivative (XI), which was submitted to UV irradiation with a 200 W high-pressure mercury lamp in ethanol yielding the silylated 22-oxavitamin D3 derivative (XII). Finally, this compound is desilylated by a treatment with tetrabutylammonium fluoride (TBAF) in THF. 2) The addition of ethyl acrylate (XIII) to the previously reported pregna-5,7-dien-20(S)-ol (VII) by means of tetrabutylammonium hydroxide/NaOH in water/toluene gives the 2-(ethoxycarbonyl)ethoxy derivative (XIV), which by alkylation of the carbonyl function with methyllithium yields the 3-hydroxy-3-methylbutoxy derivative (XI), already obtained. 3) The addition of N,N-dimethylacrylamide (XV) to the previously reported pregna-5,7-dien-20(S)-ol (VII) by means of NaH gives the corresponding propionamide derivative (XVI), which by a Grignard alkylation with methylmagnesium bromide and CeCl3 is converted into the 3-hydroxy-3-methylbutoxy derivative (XI), already obtained.
| 【1】 Murayama, E.; Miyamoto, K.; Kubodera, N.; Mori, T.; Matsunaga, I.; Synthetic studies of vitamin D3 analogues. VIII. Synthesis of 22-oxavitamin D3 analogues. Chem Pharm Bull 1986, 34, 10, 4410-3. |
| 【2】 Kubodera, N.; Watanabe, H.; Kawanishi, T.; Matsumoto, M.; Synthetic studies of vitamin D analogues. XI. Synthesis and differentiation-inducing activity of 1alpha,25-dihydroxy-22-oxavitamin D3 analogues. Chem Pharm Bull 1992, 40, 6, 1494-9. |
| 【3】 Leeson, P.A.; Martel, A.M.; Castaner, J.; 22-Oxacalcitriol. Drugs Fut 1996, 21, 12, 1229. |
| 【4】 Kubodera, N.; Miyamoto, K.; Ochi, K.; Matsunaga, I.; Murayama, E. (Chugai Pharmaceutical Co. Ltd.); Novel vitamin D derivs. and process for producing the same. EP 0184112; JP 1986267548; JP 1986267550 . |
| 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) | 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 |
| (II) | 11714 | (1S,3R,8R,9S,10R,13S,14S)-1,3-Dihydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H28O3 | 详情 | 详情 | |
| (III) | 11715 | (1S,8R,9S,10R,13S,14S)-1,3-Bis[[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 | C31H56O3Si2 | 详情 | 详情 | |
| (IV) | 11716 | (1S,3R,9S,10R,13S,14S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-1,2,3,4,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C31H54O3Si2 | 详情 | 详情 | |
| (V) | 11717 | Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide | 1530-32-1 | C20H20BrP | 详情 | 详情 |
| (VI) | 11718 | tert-Butyl(dimethyl)silyl (1S,3R,9S,10R,13S,14S)-1-[[tert-butyl(dimethyl)silyl]oxy]-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ether; tert-Butyl([(1S,3R,9S,10R,13S,14S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-1-yl]oxy)dimethylsilane | C33H58O2Si2 | 详情 | 详情 | |
| (VII) | 11719 | (1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-ethanol | C33H60O3Si2 | 详情 | 详情 | |
| (VIII) | 11720 | 4-Bromo-1-butene | 5162-44-7 | C4H7Br | 详情 | 详情 |
| (IX) | 11721 | (1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl 3-butenyl ether; [((1S,3R,9S,10R,13S,14S,17S)-17-[(1S)-1-(3-Butenyloxy)ethyl]-3-[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-1-yl)oxy](tert-butyl)dimethylsilane | C37H66O3Si2 | 详情 | 详情 | |
| (X) | 11722 | 4-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-butanone | C37H66O4Si2 | 详情 | 详情 | |
| (XI) | 11723 | 4-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-methyl-2-butanol | C38H70O4Si2 | 详情 | 详情 | |
| (XII) | 11724 | 4-[((1S)-1-[(1S,3aS,7aS)-4-[(E)-2-((3S,5R)-3,5-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]ethyl)oxy]-2-methyl-2-butanol | C38H70O4Si2 | 详情 | 详情 | |
| (XIII) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (XIV) | 11726 | ethyl 3-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]propanoate | C38H68O5Si2 | 详情 | 详情 | |
| (XV) | 11727 | N,N-Dimethylacrylamide; N,N-Dimethyl-2-propenamide | 2680-03-7 | C5H9NO | 详情 | 详情 |
| (XVI) | 11728 | 3-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-N,N-dimethylpropanamide | C38H69NO4Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)4) The Wittig condensation of the previously reported 1alpha,3beta-bis(tert-butyldimethylsilyloxy)androst-5-en-17-one (III) with ethyltriphenylphosphonium bromide and potassium tert-butoxide gives the corresponding 17-ethylidene derivative (XVII), which is treated first with 9-borabicyclo[3.3.1]nonane (9-BBN) and then with H2O2 and NaOH in THF yielding a mixture of the 20(S)- and 20(R)-isomers of the 1alpha,3beta-bis(tert-butyldimethylsilyloxy)pregn-5-en-20-ol that was separated by preparative TLC. The 20(S)-isomer (XVIII) was condensed with N,N-dimethylacrylamide (XV) by means of NaH affording the propionamide derivative (XIX), which by a Grignard condensation with methylmagnesium bromide catalyzed by CeCl3 is converted into 1alpha,3beta-bis(tert-butyldimethylsilyloxy)-20(S)-(3-hydroxy-3-methylbutoxy)pregn-5-ene (XX). Finally, this compound is dehydrogenated as before by bromination with N-bromosuccinimide (NBS) and dehydrobromination with 2,4,6-trimethylpyridine (TMPyr) to afford the 3-hydroxy-3-methylbutoxy derivative (XI), already obtained.
| 【1】 Kubodera, N.; Active vitamin D analogs. Important and various roles by medicinal chemists during the course of development of promising candidates as useful medicines. Jpn J Org Chem 1996, 54, 2, 139-45. |
| 【2】 Leeson, P.A.; Martel, A.M.; Castaner, J.; 22-Oxacalcitriol. Drugs Fut 1996, 21, 12, 1229. |
| 【3】 Kato, M.; Mikami, T.; Ochi, K.; Watanabe, H.; Kubodera, N. (Chugai Pharmaceutical Co. Ltd.); 22-Oxacalciferol deriv. and production thereof. WO 9312083 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 11715 | (1S,8R,9S,10R,13S,14S)-1,3-Bis[[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 | C31H56O3Si2 | 详情 | 详情 | |
| (V) | 11717 | Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide | 1530-32-1 | C20H20BrP | 详情 | 详情 |
| (XI) | 11723 | 4-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-methyl-2-butanol | C38H70O4Si2 | 详情 | 详情 | |
| (XV) | 11727 | N,N-Dimethylacrylamide; N,N-Dimethyl-2-propenamide | 2680-03-7 | C5H9NO | 详情 | 详情 |
| (XVII) | 11729 | tert-Butyl([(1S,3R,8S,9S,10R,13S,14S)-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-1-yl]oxy)dimethylsilane; tert-Butyl(dimethyl)silyl (1S,3R,8S,9S,10R,13S,14S)-1-[[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-3-yl ether | C33H60O2Si2 | 详情 | 详情 | |
| (XVIII) | 11730 | (1S)-1-((1S,3R,8S,9S,10R,13S,14S,17S)-1,3-Bis[[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-yl)-1-ethanol | C33H62O3Si2 | 详情 | 详情 | |
| (XIX) | 11731 | 3-[[(1S)-1-((1S,3R,8S,9S,10R,13S,14S,17S)-1,3-Bis[[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-yl)ethyl]oxy]-N,N-dimethylpropanamide | C38H71NO4Si2 | 详情 | 详情 | |
| (XX) | 11732 | 4-[[(1S)-1-((1S,3R,8S,9S,10R,13S,14S,17S)-1,3-Bis[[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-yl)ethyl]oxy]-2-methyl-2-butanol | C38H72O4Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The oxidation of (5R)-(-)-carvone (I) with 3-chloroperbenzoic acid (3-CPB) in dichloromethane gives 5(R)-acetyl-2-methyl-2-cyclohexen-1-one (II), which is condensed with ethyltriphenylphosphonium bromide (III) by means of butyllithium in THF yielding 2-methyl-5(Z)-(1-methyl-1-propenyl)-2-cyclohexen-1-one (IV). The photochemical oxidation of (IV) in acetonitrile catalyzed by methylene blue affords (1R,4RS,5R,8S)-4,8-dimethyl-4-vinyl-2,3-dioxabicyclo[3.3.1]nonan-7-one (V), which is ozonolyzed with O3 in methanol to the corresponding aldehyde as a mixture of enantiomers, which is submitted to crystallization giving the (1S,4R,5R,8S)-isomer (VI). Finally, this compound is submitted to a Wittig condensation with 2,4-bis(trifluoromethyl)benzyltriphenylphosphonium bromide (VII) by means of sodium bis(trimethylsilyl)amide (NaBTSA) in dichloromethane.
| 【1】 Rabasseda, X.; Mealy, N.; Castaner, J.; Arteflene. Drugs Fut 1995, 20, 4, 341. |
| 【2】 Hofheinz, W.; Schmid, G.; Stohler, H. (F. Hoffmann-La Roche AG); Bicyclic peroxide. AU 8823596; EP 0311955; JP 1989132578; US 4977184 . |
| 【3】 Hofheinz, W.; Burgin, H.; Gocke, H.; Jaquet, C.; Masciadri, R.; Schmid, G.; Stohler, H.; Urwyler, H.; Ro 42-1611 (arteflene), a neweffective antimalarial: Chemical structure and biological activity. Trop Med Parasitol 1994, 45, 3, 261-5. |
| 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) | 13386 | (5R)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one; L-(-)-Carvone | 6485-40-1 | C10H14O | 详情 | 详情 |
| (II) | 13387 | (5R)-5-Acetyl-2-methyl-2-cyclohexen-1-one | C9H12O2 | 详情 | 详情 | |
| (III) | 11717 | Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide | 1530-32-1 | C20H20BrP | 详情 | 详情 |
| (IV) | 13389 | (5R)-2-Methyl-5-[(Z)-1-methyl-1-propenyl]-2-cyclohexen-1-one | C11H16O | 详情 | 详情 | |
| (V) | 13390 | (1S,5R,8S)-4,8-Dimethyl-4-vinyl-2,3-dioxabicyclo[3.3.1]nonan-7-one | C11H16O3 | 详情 | 详情 | |
| (VI) | 13391 | (1S,4R,5R,8S)-4,8-Dimethyl-7-oxo-2,3-dioxabicyclo[3.3.1]nonane-4-carbaldehyde | C10H14O4 | 详情 | 详情 | |
| (VII) | 13392 | [3,5-Bis(trifluoromethyl)benzyl](triphenyl)phosphonium bromide | C27H20BrF6P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(LXVII)In a synthetic route starting from dehydroepiandrosterone (LXVI), Wittig reaction of ketone (LXVI) with ethyl triphenylphosphonium bromide (LXVII) and potassium tert-butoxide gave the C-17 ethylidene derivative (LXVIII). Condensation of (LXVIII) with isopropyl vinyl ketone (LXIX) in the presence of dimethylaluminum chloride, followed by catalytic hydrogenation over Pt/C, yielded (LV), which was then converted into ethylene ketal (LVI). Catalytic hydrogenation of (LVI) gave compound (LXX), whose acetate ester was hydrolyzed to afford alcohol (LXXI). Oxidation of (LXXI) by means of chromic acid furnishes ketone (LXXII), from which intermediate (LX) was obtained by introduction of the 7-alpha hydroxyl group by means of microbiological oxidation employing several microorganism strains.
| 【1】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LV) | 53712 | (3S,8S,9S,10R,13R,14S,17R)-17-[(1R)-1,5-dimethyl-4-oxohexyl]-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 | n/a | C29H46O3 | 详情 | 详情 |
| (LVI) | 53739 | (3S,8S,9S,10R,13R,14S,17R)-17-[(1R)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-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 | n/a | C31H50O4 | 详情 | 详情 |
| (LX) | 53754 | (3S,8S,9S,10R,13S,14S,17S)-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | n/a | C25H38O4 | 详情 | 详情 |
| (LXVI) | 20083 | Prasterone acetate;3b-Hydroxy-5-androstene-17-one acetate；Dehydroisoandrosterone acetate;Dehydroepiandrosterone 3-acetate;Dehydroepiandrosterone acetate;(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | 853-23-6 | C21H30O3 | 详情 | 详情 |
| (LXVII) | 11717 | Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide | 1530-32-1 | C20H20BrP | 详情 | 详情 |
| (LXVIII) | 53749 | (3S,8S,9S,10R,13S,14S)-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-3-yl acetate | n/a | C23H34O2 | 详情 | 详情 |
| (LXIX) | 53750 | 4-methyl-1-penten-3-one | 1606-47-9 | C6H10O | 详情 | 详情 |
| (LXX) | 53751 | (3S,5S,8R,9S,10S,13R,14S,17R)-17-[(1R)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | n/a | C31H52O4 | 详情 | 详情 |
| (LXXI) | 53752 | (3S,5S,8R,9S,10S,13R,14S,17R)-17-[(1R)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol | n/a | C29H50O3 | 详情 | 详情 |
| (LXXII) | 53753 | (5S,8R,9S,10S,13R,14S,17R)-17-[(1R)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one | n/a | C29H48O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXVIII)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6
该中间体在本合成路线中的序号：(XIX)Synthesis of the cholestane aglycone (XXXII): The condensation of the commercial dehydroisoandrosterone (XVIII) with ethyl triphenylphosphonium bromide (XIX) and potassium tert-butoxide in refluxing THF gives the ethylidene derivative (XX), which is silylated at the 3-OH group with Tbdps-Cl and imidazole to yield the silyl ether (XXI). The reaction of (XXI) with paraformaldehyde in the presence of catalytic BF3/Et2O affords the desired homoallylic alcohol (XXII) stereoselectively. Oxidation of alcohol (XXII) with DMP in dichloromethane provides the corresponding aldehyde (XXIII), which when treated with the Grignard reagent (XXIV) of the 1-bromo-3-methyl butane in ether furnishes the adduct (XXV). The oxidation of the secondary alcohol of (XXV) with PDC in DMF/dichloromethane gives the expected ketone (XXVI), which is protected as the spiroketal (XXVIII) by reaction with ethyleneglycol (XXVII), TsOH and triethyl orthoformate. The Tbdps protecting group of (XXVIII) was now converted into the Tbdms group by desilylation with TBAF and resilylation with Tbdms-Cl and imidazole to give (XXIX). The oxidation of (XXIX) with OsO4 and pyridine in ether yields the 16alpha,17alpha-diol (XXX), which is oxidized with oxalyl chloride to afford the ketone (XXXI). The reduction of (XXXI) with NaBH4 and CeCl3 in THF provides the target 16beta,17alpha-diol (XXXII).
| 【1】 Deng, S.; et al.; First total synthesis of an exceptionally potent antitumor saponin, OSW-1. J Org Chem 1999, 64, 1, 202. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 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 |
| (XIX) | 11717 | Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide | 1530-32-1 | C20H20BrP | 详情 | 详情 |
| (XX) | 48980 | (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-ol | C21H32O | 详情 | 详情 | |
| (XXI) | 48981 | 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)diphenylsilane; tert-butyl(diphenyl)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 | C37H50OSi | 详情 | 详情 | |
| (XXII) | 48982 | (2S)-2-((3S,10R,13S)-3-[[tert-butyl(diphenyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-propanol | C38H52O2Si | 详情 | 详情 | |
| (XXIII) | 48983 | (2S)-2-((3S,10R,13S)-3-[[tert-butyl(diphenyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)propanal | C38H50O2Si | 详情 | 详情 | |
| (XXIV) | 13532 | Bromo(isopentyl)magnesium | C5H11BrMg | 详情 | 详情 | |
| (XXV) | 48984 | (2S,3S)-2-((3S,10R,13S)-3-[[tert-butyl(diphenyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-6-methyl-3-heptanol | C43H62O2Si | 详情 | 详情 | |
| (XXVI) | 48985 | (2S)-2-((3S,10R,13S)-3-[[tert-butyl(diphenyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-6-methyl-3-heptanone | C43H60O2Si | 详情 | 详情 | |
| (XXVII) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (XXVIII) | 48986 | tert-butyl([(3S,10R,13S)-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-3-yl]oxy)diphenylsilane; tert-butyl(diphenyl)silyl (3S,10R,13S)-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-3-yl ether | C45H64O3Si | 详情 | 详情 | |
| (XXIX) | 48987 | tert-butyl([(3S,10R,13S)-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-3-yl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (3S,10R,13S)-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-3-yl ether | C35H60O3Si | 详情 | 详情 | |
| (XXX) | 48988 | (3S,10R,13S,16R,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 | |
| (XXXI) | 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 | |
| (XXXII) | 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7
该中间体在本合成路线中的序号：(XVI)The bromination of the Hajos dione (XI) with t-Bu-Cu, DIBAL and Br2 in HMPA/THF gives the bromo derivative (XII), which is reduced with LiAlH(t-BuO)3 in THF to yield the diol (XIII). The dehydrobromination of (XIII) with KH in HMPA affords the epoxide (XIV), which is oxidized with pyridinium dichromate (PDC) in dichloromethane to provide the ketoepoxide (XV). The Wittig condensation of (XV) with phosphonium salt (XVI) by means of potassium tert-butoxide gives the ethylidene epoxide (XVII), which is finally opened with LiAlH4 in THF to yield the target intermediate (I).
| 【1】 Liu, W.; Daniewski, A.R.; A novel silycopper catalyst for the reductivo bromination of hajos dione. Improved preparation of a CD synthon for teh synthesis of vitamin D. J Org Chem 2001, 66, 2, 626. |
| 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) | 42566 | (3aR,4S,7aS)-1-[(Z)ethylidene]-7a-methyloctahydro-1H-inden-4-ol | C12H20O | 详情 | 详情 | |
| (XI) | 45534 | (7aS)-7a-methyl-2,3,7,7a-tetrahydro-1H-indene-1,5(6H)-dione | 17553-86-5 | C10H12O2 | 详情 | 详情 |
| (XII) | 45535 | (3aR,4S,7aS)-4-bromo-7a-methylhexahydro-1H-indene-1,5(4H)-dione | 2706-38-9 | C10H13BrO2 | 详情 | 详情 |
| (XIII) | 45536 | (1S,3aR,4S,5S,7aS)-4-bromo-7a-methyloctahydro-1H-indene-1,5-diol | C10H17BrO2 | 详情 | 详情 | |
| (XIV) | 45537 | (1aS,3aS,4S,6aR,6bR)-3a-methyloctahydro-1aH-indeno[4,5-b]oxiren-4-ol | C10H16O2 | 详情 | 详情 | |
| (XV) | 45538 | (1aS,3aS,6aR,6bR)-3a-methyloctahydro-4H-indeno[4,5-b]oxiren-4-one | C10H14O2 | 详情 | 详情 | |
| (XVI) | 11717 | Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide | 1530-32-1 | C20H20BrP | 详情 | 详情 |
| (XVII) | 45539 | (1aS,3aS,6aR,6bR)-4-[(Z)ethylidene]-3a-methyloctahydro-4H-indeno[4,5-b]oxirene | C12H18O | 详情 | 详情 |