First highly regio- and diastereoselective [3+2] cycloaddition of chiral nonracemic Fischer carbene complexes with azomethine ylides: An enantioselective synthesis of (+)-rolipram

A new procedure for the synthesis of 1,3,4-trisubstituted and 1,4-disubstit uted pyrrolidin-2-one derivatives in an enantios elective fashion is report ed. The 1,3-dipolar cycloaddition of ()menthol and (+/-)-8-phenylmenthol de rived Fischer alkoxy alkenyl carbene complexes with in situ generated funct ionalized azomethine ylides gives the corresponding cycloadducts as chelate d tetracarbonyl Fischer carbene complexes. Only one regioisomer is detected in all cases, and the diastereoselectivity of the reaction is very high wh en (-)-8-phenylmenthol derived carbenes are employed. Oxidation and further transformation of the cycloadducts provide an easy access to pyrrolidin-2- ones. The anti-inflammatory and antidepressant drug (+)-Rolipram is readily prepared in four steps in a 20 % overall yield by taking advantage of this newly developed methodology.