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项目整合精选>>>Coleonol, Boforsin, Colforsin, Forskolin, M-410, L-751362B, HL-362
Coleonol, Boforsin, Colforsin, Forskolin, M-410, L-751362B, HL-362
佛司可林Chemical Name: [3R-(3alpha,4abeta,5beta,6beta,6aalpha,10alpha,10abeta,10balpha]-5-Acetoxy-6,10,10b-trihydroxy-3,4a,7,7,10a-pentamethyl-3-vinylperhydronaphtho[2,1-b]pyran-1-one
CAS No. 66575-29-9
项目整合开发状态: Phase II
项目研究机构: Aventis Pharma (Originator), Brown University (Originator), Nippon Kayaku (Originator)
合成路线:The synthesis of a key intermediate for a new total synthesis of forskolin has been reported:The methylation of 3-hydroxy-2-methyl-2-cyclohexenone (I) with dimethyl sulfate and potassium carbonate in refluxing acetone gives the methoxy compound (II),which is dimethylated by successive treatments with lithium diisopropylamide (LDA) and methyl iodide yielding 3-methoxy-2,6,6-trimethyl-2-cyclohexenone (III).The reaction of (III) with vinylmagnesium bromide in THF affords 2,4,4-trimethyl-3-vinyl-2-cyclohexenone (IV),which is reduced with LiAlH4 in ethyl ether to the cyclohexenol (V).The esterification of (V) with 2-butynoic acid (VI) by means of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) in dichloromethane gives the ester (VII),which is cyclized in refluxing decane to the dienic lactone (VIII).The reduction of (VIII) with LiAlH4 in ethyl ether yields the diol (IX),which is selectively epoxidized with tert-butyl hydroperoxide and VO(acac)2 as catalyst to the monoepoxide (X).The ketalization of (X) with benzaldehyde dimethyl ketal and POCl3 or p-toluenesulfonic acid gives the benzylidene ketal (XI).The cleavage of the ketal ring of (XI) either with LiBF4/BH3.THF or with LiBH4/BF3.Et2O yields the benzyl ether (XII),which is selectively silylated with tert-butyldimethylsilyl chloride (TBDMS-Cl) in DMF to the mono-silyl ether (XIII).The oxidation of the secondary alcohol of (XIII) with CrO3-pyridine in dichloromethane affords the corresponding ketone (XIV),which is debenzylated by hydrogenation with H2 over Pd/C in ethanol giving the dihydroxyketone (XV).The protection of (XV) with 2-methoxypropene and POCl3 in CCl4 yields the acetonide (XVI),which is dehydrogenated by successive treatments first with LDA and phenylselanyl chloride and then with H2O2 in dichloromethane/pyridine to afford the enone (XVII).The cis-configuration of enone (XVII) was isomerized to the trans-isomer by treatment with basic alumina in refluxing toluene yielding compound (XVIII) used as the starting intermediate in a total synthesis of forskolin (Delpech,B.et al.Tetrahedron Lett 1996,37(7): 1019).
📌 参考资料/链接：
参考文献标题:Total synthesis of forskolin.1
文献作者:Calvo,D.; Lett,R.; Delpech,B.
参考来源:Tetrahedron Lett 1996,37(7),1015
📄 详细内容
合成路线:A total synthesis of forskolin has been reported:The intermediate enone (I) [obtained as final product (XVIII) in Delpech,B.et al.Tetrahedron Lett 1996,37(7): 1015] is reduced with diisobutylaluminum hydride (DIBAL) in hexane/ethyl ether giving the corresponding alcohol (II),which is esterified with N,N-dimethylcarbamoyl chloride and butyllithium in THF yielding the carbamate (III).The reaction of (III) with m-chloroperbenzoic acid (MCPBA) and NaHCO3 in dichloromethane affords the epoxide (IV),which is cleaved with BF3.Et2O in ether affording the trans-diol (V).Elimination of the carbamoyl group of (V) by treatment with LiAlH4 in ethyl ether eliminates also partially the silyl group,so the mixture obtained is resilylated to give the silylated triol (VI).The carbonylation of (VI) with carbonyldiimidazole (CDI) in refluxing toluene yields the cyclic carbonate (VII),which is desilylated by treatment with tetrabutylammonium fluoride (TBAF) in THF to afford the diol (VIII).The Swern oxidation of the primary alcohol of (VIII) gives the corresponding aldehyde (IX),which is condensed with propynyllithium (X) in THF to yield the corresponding addition product (XI).The Collins oxidation of the secondary alcohol of (XI) affords the propargyl ketone (XII),which is cyclized by means of Cs2CO3 in acetonitrile to the naphthopyrone derivative (XIII).The alkylation of (XIII) with lithium divinyl cuprate and BF3.Et2O gives the vinylated compound (XIV),which is treated with NaOH in methanol to eliminate the cyclic carbonate group giving the dihydroxyketone (XVI).Elimination of the acetonide group of (XVI) with p-toluenesulfonic acid in methanol/dichloromethane affords the tetrahydroxyketone (XVII),which is finally selectively acetylated with acetic anhydride and pyridine to forskolin.
参考文献标题:Total synthesis of forskolin.2
文献作者:Calvo,D.; Delpech,B.; Lett,R.
参考来源:Tetrahedron Lett 1996,37(7),1019
产品链接: CAS No. 66575-29-9››