A New Approach to Kainoids through Tandem Michael Reaction Methodology: Application to the Enantioselective Synthesis of (+)- and (−)-α-Allokainic Acid and to the Formal Synthesis of (−)-α-Kainic Acid

A convergent, one-pot construction of functionalized pyrrolidine ring systems has been developed. The method is based on a tandem Michael reaction initiated by an intermolecular conjugate addition of a nitrogen nucleophile to an electrophilic olefin followed by trapping of the generated enolate by a built-in α,β-unsaturated acceptor. After model studies verified the feasibility of the process and gave information about its stereochemical outcome, the strategy was successfully applied to kainoid synthesis. The construction of the basic pyrrolidine skeleton of all the members of the family requires coupling of a suitable electrophilic subunit with a common donor‒acceptor fragment containing the nitrogen nucleophile. Thus, the enantioselective synthesis of (+)-α-allokainic acid (2) and the formal synthesis of its C-4 epimer (-)-α-kainic acid (1), have been accomplished using methyl vinyl ketone and 2-nitro-3-methyl-1,3-butadiene, respectively, as electrophilic partners of (S)-4-(benzylami...