Stereoselective construction of X-azabicyclo[ m.2.1]alkanes by [3+2]-cycloaddition of non-stabilized cyclic azomethine ylides: synthesis of enantiopure constrained amino acids and formal total synthesis of optically active epibatidine

Abstract

A new and general strategy for the stereoselective construction of X-azabicyclo[ m.2.1]alkanes has been developed by the [3+2]-cycloaddition of cyclic azomethine ylides with suitable achiral dipolarophiles. The cyclic azomethine ylides, where the whole of the ylide conjugation is in the ring, have been generated by the sequential double desilylation of the N-alkyl-α,α′-bis(trimethylsilyl) cyclic amines utilizing Ag(I)F as one electron oxidant. The structural rigidity of cyclic azomethine ylides has allowed preferential facial discrimination by the dipolarophile resulting into very good exo/ endo selectivity. The exo/ endo selectivity associated with these cycloadditions has been further exploited to access optically pure X-azabicyclo[ m.2.1]alkanes by carrying out the cycloadditions with the Oppolzer's acryloyl dipolarophile. Application of this methodology is demonstrated by the construction of few constrained amino acids related to azabicyclic structural framework and the formal total synthesis of optically active epibatidine.