Vernolepine, preparation

Synthesis of a m-decalin system by the asymmetric cyclization[38] has been carried out with high enantioselectivity[142,143,147,148], Using BINAP as a chiral ligand, 91% ee was achieved in the asymmetric cyclization of 177 to give 178. In order to achieve an efficient asymmetric cyclization, selection of the reaction conditions is crucial, and sometimes added Ag salts play an important role[148], A catalytic asymmetric cyclization of 179 to prepare the key intermediate enone 180 for vernolepin synthesis has been carried out[149]. Highly efficient asymmetric cyclization of 181 to give the tetralin system 182 has been applied to the synthesis of (-)-eptazocine (183)[150], Hydrindans are synthesized in 86% ee[151]. 

Epoxides - The first indication of the synthetic utility of metalated carboxylic acids resulted from efforts to prepare steroidal aldosterone inhibitors from spiroepoxides.39 Model studies indicated that the reaction fails as a result of severe steric hindrance in either the epoxide or carboxylic acid and that monosubstitution occurs for the same reason.39 The reaction has been used in a key step of an elegant synthesis of vernolepin, 5. 40 Forcing conditions are required, and, in contrast to acid dianions, anions of unactivated esters fail to react with epoxides.39 41... 

Heck coupling. An intramolecular Heck coupling is a convenient way to prepare 4-methylcoumarin and related compounds. Through ligand exchange with a chiral BINAP to mediate cyclization, an intermediate for vernolepin is accessible in... 

Further work by Schlessinger s group on approaches to vernolepin has revealed that t-butyl dilithioacetoacetate is a preferable reagent to dilithioacetate for the stereoselective synthesis of fused butyrolactones, originally developed by Danishefsky, from a-hydroxy-epoxides. The greater stereoselectivity of this reagent allows the preparation of pure c/s-fused lactones from /ran -a-hydroxy-epoxides (Scheme 10). 

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