合成路线1

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).