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【结 构 式】 
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【分子编号】13817 【品名】methyl 5-[(3aS,5R,6S,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate 【CA登记号】 |
【 分 子 式 】C34H64O4Si2 【 分 子 量 】593.05076 【元素组成】C 68.86% H 10.88% O 10.79% Si 9.47% |
合成路线1
该中间体在本合成路线中的序号：(XCIII)8) The condensation of the cyclopentenone (LXXXI) with the organocuprate (LXXXII) gives the condensed enolate (LXXXIII), which is coupled with 3-(trimethylsilyl)-2-propynyl iodide (LXXXIV) to yield the acetylenic cyclopentanone (LXXXV). The methylenation of (LXXXV) with Zn/CH2Br2/TiCl4 as before gives compound (LXXXVI), which by selective hydroboration as usual is converted into the hydroxymethyl derivative (LXXXVII). The selective desilylation of the protected acetylene of (LXXXVII) affords (LXXXVIII), which is oxidized as usual to the corresponding aldehyde (LXXXIX). The reductive cyclization of (LXXXIX) gives the bicyclic alcohol (XC), which is treated with tosyl chloride and DMAP in dichloromethane to yield (XCI). Finally, this compound is alkylated with methyl 4-iodobutyrate (XCII)/Zn/Cu2(CN)2 in THF affording the bisilylated clinprost derivative (XCIII) that was desilylated with TBAF as usual. 9) The alkylation of the exocyclic methylene double bond of the bicyclic alcohol (XC) can also be performed by treating (XC) first with diethyl chlorophosphate and BuLi, and then with 4-iodobutyrate (XCII)/Zn/Cu2Cl2 in THF to obtain the previously reported bisilylated clinprost (XCIII). 10) The preceding alkylation of bicyclic alcohol (XC) can also be performed using p-toluenesulfonyl chloride instead of diethyl chlorophosphate.
| 【1】 Graul, A.; Leeson, P.; Castaner, J.; Clinprost. Drugs Fut 1997, 22, 6, 608. |
| 【2】 Tanaka, T.; Bannai, K.; Hazato, A.; Koga, M.; Kurozumi, S.; Kato, Y.; Short synthesis of isocarbacyclin by regioselective SN2' alkylation of bicyclic allylic esters with zinc-copper reagents. Tetrahedron 1991, 47, 10-11, 1861-76. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LXXXI) | 13805 | (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one | C11H20O2Si | 详情 | 详情 | |
| (LXXXII) | 13806 | Bis[3(S)-(tert-Butyldimethylsilyloxy)-1(E)-octenyl] copper magnesium chloride | C39H82O5 | 详情 | 详情 | |
| (LXXXIII) | 13807 | (3R,4R)-4-[[(tert-Butyl)(dimethyl)silyl]oxy]-3-((E,3S)-3-[[(tert-butyl)(dimethyl)silyl]oxy]-1-octenyl)-1-cyclopenten-1-ol chloromagnesium salt | C25H49ClMgO3Si2 | 详情 | 详情 | |
| (LXXXIV) | 13808 | (3-Iodo-1-propynyl)(trimethyl)silane | C6H11ISi | 详情 | 详情 | |
| (LXXXV) | 13809 | (2R,3R,4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-3-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-[3-(trimethylsilyl)-2-propynyl]cyclopentanone | C31H60O3Si3 | 详情 | 详情 | |
| (LXXXVI) | 13810 | tert-Butyl[((1S,2E)-3-[(1R,2R,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-methylene-2-[3-(trimethylsilyl)-2-propynyl]cyclopentyl]-1-pentyl-2-propenyl)oxy]dimethylsilane | C32H62O2Si3 | 详情 | 详情 | |
| (LXXXVII) | 13811 | [(1S,2S,3S,4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-3-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-[3-(trimethylsilyl)-2-propynyl]cyclopentyl]methanol | C32H64O3Si3 | 详情 | 详情 | |
| (LXXXVIII) | 13812 | [(1S,2S,3S,4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-3-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-(2-propynyl)cyclopentyl]methanol | C29H56O3Si2 | 详情 | 详情 | |
| (LXXXIX) | 13813 | (1S,2R,3R,4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-3-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-(2-propynyl)cyclopentanecarbaldehyde | C29H54O3Si2 | 详情 | 详情 | |
| (XC) | 13814 | (1R,3aS,4S,5R,6aS)-5-[[tert-Butyl(dimethyl)silyl]oxy]-4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-methyleneoctahydro-1-pentalenol | C29H56O3Si2 | 详情 | 详情 | |
| (XCI) | 13815 | ([(1S,2E)-3-[(1S,2R,3aS,6aS)-2-[[tert-Butyl(dimethyl)silyl]oxy]-5-(chloromethyl)-1,2,3,3a,6,6a-hexahydro-1-pentalenyl]-1-pentyl-2-propenyl]oxy)(tert-butyl)dimethylsilane | C29H55ClO2Si2 | 详情 | 详情 | |
| (XCII) | 13816 | Methyl 4-iodobutyrate; Methyl 4-iodobutanoate | 14273-85-9 | C5H9IO2 | 详情 | 详情 |
| (XCIII) | 13817 | methyl 5-[(3aS,5R,6S,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C34H64O4Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XCIII)11) The alkylation of the exocyclic methylene double bond of the fully protected bicyclic triol (XCIV) with 4,4-bis(phenylsulfonyl)butyric acid methyl ester (XCV) by means of NaH and catalyzed by a palladium complex gives (XCVI), which is desulfonated by treatment with magnesium in dry methanol to yield the bisilylated clinprost (XCIII). Finally, this compound is desilylated with TBAF as usual.
| 【1】 Graul, A.; Leeson, P.; Castaner, J.; Clinprost. Drugs Fut 1997, 22, 6, 608. |
| 【2】 Hari, A.; Tanaka, T.; Okamura, N.; Sakauchi, K. (Teijin Ltd.); Isocarbacyclin derivs. and their preparation. JP 1988303962 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XCIII) | 13817 | methyl 5-[(3aS,5R,6S,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C34H64O4Si2 | 详情 | 详情 | |
| (XCIV) | 13818 | (1R,3aS,4S,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-methyleneoctahydro-1-pentalenyl acetate | C31H58O4Si2 | 详情 | 详情 | |
| (XCV) | 13819 | methyl 4,4-bis(phenylsulfonyl)butanoate | C17H18O6S2 | 详情 | 详情 | |
| (XCVI) | 13820 | methyl 5-[(3aS,5R,6S,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]-4,4-bis(phenylsulfonyl)pentanoate | C46H72O8S2Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XCIII)12) The ketalization of (R)-2-(2-oxocyclopentyl)acetic acid methyl ester (XCVII) with butane-2,3-diol gives the expected acetal (XCVIII), which is converted into the beta-keto ester (XCIX) in the usual way. Transesterification of (XCIX) with benzyl alcohol yields the benzyl ester (C), which is converted into the alpha-diazo ester (CI) with p-toluenesulfonyl azide. The cyclization of (CI) by means of rhodium acetate in dichloromethane affords the bicyclic keto ester (CII), which is condensed with 3(S)-(TBDMS-O)-1(E)-octenyl mercury (CIII) by means of lead tetraacetate giving the alkylated bicyclic beta-keto ester (CIV). The decarboxylation of (CIV) with Raney Ni and triethylamine in ethanol yields the bicyclic ketone (CV), which is reduced with NaBH4 and deacetalized with HCl to afford the hydroxy ketone (CVI). The silylation of the hydroxy group of (CVI) with TBDMS-Cl and DMAP in DMF gives the disilylated ketone (CVII), which is treated with diphenyl disulfide and lithium bis(trimethylsilyl)amide in THF/HMPT yielding the sulfenylated enol (CVIII). The oxidation of (CVIII) with m-chloroperbenzoic acid (MCPBA) affords the corresponding sulfonated enol (CIX), which is condensed with methyl 4-iodobutyrate (CX) by means of t-BuOK in DMSO giving the dialkylated bicyclic ketone (CXI). The reduction of (CXI) with NaBH4 in methanol, followed by mesylation with mesyl chloride yields the alpha-mesyloxy sulfone (CXII), which by a reductive elimination with Na-Hg in methanol is converted into the bisilylated clinprost (XCIII). Finally, this compound is desilyated with TBAF as usual.
| 【1】 Graul, A.; Leeson, P.; Castaner, J.; Clinprost. Drugs Fut 1997, 22, 6, 608. |
| 【2】 Hashimoto, S.; Shinoda, T.; Ikegami, S.; A simple synthesis of (+)-isocarbacyclin via a convergent process. J Chem Soc Chem Commun 1988, 17, 1137-9. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 24048 | 2,3-butanediol | 513-85-9 | C4H10O2 | 详情 | 详情 | |
| (CI) | 13825 | 2-Diazo-4-[(6R)-2,3-dimethyl-1,4-dioxaspiro[4.4]non-6-yl]-3-oxobutyric acid benyzl ester | C20H24N2O5 | 详情 | 详情 | |
| (CII) | 13826 | (3'aS,6'aS)-4,5-Dimethyl-5'-oxoperhydrospiro[1,3-dioxolane-2,1'-pentalen]-4'-ylcarboxylic acid benzyl ester | C20H24O5 | 详情 | 详情 | |
| (CIII) | 13827 | ((E,3S)-3-[[tert-Butyl(dimethyl)silyl]oxy]-1-octenyl)mercury | C14H29HgOSi | 详情 | 详情 | |
| (CIV) | 13828 | (3'aS,6'aS)-4,5-Dimethyl-4'-[3-[tert-butyl(dimethyl)silyloxy]-1(E)-octenyl]-5'-oxoperhydrospiro[1,3-dioxolane-2,1'-pentalen]-4'-ylcarboxylic acid benzyl ester | C34H52O6Si | 详情 | 详情 | |
| (CV) | 13829 | (3'aS,6'aS)-4,5-Dimethyl-4'-[3-[tert-butyl(dimethyl)silyloxy]-1(E)-octenyl]perhydrospiro[1,3-dioxolane-2,1'-pentalen]-5'-one | C26H46O4Si | 详情 | 详情 | |
| (CVI) | 13830 | (3aR,4R,5R,6aS)-4-((E,3S)-3-[[tert-Butyl(dimethyl)silyl]oxy]-1-octenyl)-5-hydroxyhexahydro-1(2H)-pentalenone | C22H40O3Si | 详情 | 详情 | |
| (CVII) | 13831 | (3aR,4R,5R,6aS)-5-[[tert-Butyl(dimethyl)silyl]oxy]-4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)hexahydro-1(2H)-pentalenone | C28H54O3Si2 | 详情 | 详情 | |
| (CVIII) | 13832 | (3aR,4R,5R,6aS)-5-[[tert-Butyl(dimethyl)silyl]oxy]-4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-(phenylsulfanyl)-3,3a,4,5,6,6a-hexahydro-1-pentalenol | C34H58O3SSi2 | 详情 | 详情 | |
| (CIX) | 13833 | (3aR,4R,5R,6aS)-5-[[tert-Butyl(dimethyl)silyl]oxy]-4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-(phenylsulfonyl)-3,3a,4,5,6,6a-hexahydro-1-pentalenol | C34H58O5SSi2 | 详情 | 详情 | |
| (CX) | 13834 | Methyl 5-iodovalerate; Methyl 5-iodopentanoate | 14273-88-2 | C6H11IO2 | 详情 | 详情 |
| (CXI) | 13835 | methyl 5-[(2R,3aR,4R,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-1-oxo-2-(phenylsulfonyl)octahydro-2-pentalenyl]pentanoate | C40H68O7SSi2 | 详情 | 详情 | |
| (CXII) | 13836 | methyl 5-[(1R,2R,3aR,4R,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-1-[(methylsulfonyl)oxy]-2-(phenylsulfonyl)octahydro-2-pentalenyl]pentanoate | C41H72O9S2Si2 | 详情 | 详情 | |
| (XCIII) | 13817 | methyl 5-[(3aS,5R,6S,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C34H64O4Si2 | 详情 | 详情 | |
| (XCVII) | 13821 | methyl 2-[(1R)-2-oxocyclopentyl]acetate | C8H12O3 | 详情 | 详情 | |
| (XCVIII) | 13822 | methyl 2-[(6R)-2,3-dimethyl-1,4-dioxaspiro[4.4]non-6-yl]acetate | C12H20O4 | 详情 | 详情 | |
| (XCIX) | 13823 | methyl 4-[(6R)-2,3-dimethyl-1,4-dioxaspiro[4.4]non-6-yl]-3-oxobutanoate | C14H22O5 | 详情 | 详情 | |
| (C) | 13824 | benzyl 4-[(6R)-2,3-dimethyl-1,4-dioxaspiro[4.4]non-6-yl]-3-oxobutanoate | C20H26O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XCIII)15) The synthesis of the 11beta-tritiated clinprost can be performed as follows: The disilylated compound (XCIII), already reported in Scheme 7, is carefully treated with TBAF in THF and the resulting mixture of 11- and 15-monosilylated compounds is separated by column chromatography over silicagel in hexane/ethylacetate giving the 15-O-silylated compound (CXX), which is oxidized with CrO3/Pyr in dichloromethane yielding the ketonic compound (CXXI). The reduction of (CXXI) with NaB3H4 and CeCl3 in diglyme affords the 11-tritiated compound (CXXII) as an epimeric mixture on the 11-carbon, which was resolved by column chromatography giving enantiomerically pure (CXXII). Finally, this compound is desilylated with TBAF as usual.
| 【1】 Graul, A.; Leeson, P.; Castaner, J.; Clinprost. Drugs Fut 1997, 22, 6, 608. |
| 【2】 Sugiura, S.; Kurozumi, S.; Ikegami, S.; Synthesis of tritium-labelled isocarbacyclin derivatives, radiolabelled prostaglandin I1 analogs (1). J Label Compd Radiopharm 1995, 38, 2, 129-38. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (CXX), (CXIX) | 13846 | methyl 5-[(3aS,5R,6S,6aS)-6-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-5-hydroxy-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C28H50O4Si | 详情 | 详情 | |
| (CXXI) | 13847 | methyl 5-[(3aS,6S,6aS)-6-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-5-oxo-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C28H48O4Si | 详情 | 详情 | |
| (CXIX) | 63807 | methyl 5-[6-(3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-octenyl)-5-hydroxy-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C28H50O4Si | 详情 | 详情 | |
| (XCIII) | 13817 | methyl 5-[(3aS,5R,6S,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C34H64O4Si2 | 详情 | 详情 |