Asymmetric synthesis of cis-fused bicyclic pyrrolidines and pyrrolidinones via chiral polycyclic lactams

Condensation of racemic keto-ester 2 and 1.1 equiv of (R)-(-)-phenylglycinol in toluene with azeotropic removal of water and methanol gave rise to a tetracyclic lactam in greater than 90% yield. Examination of the crude reaction product by H-1 and C-13 NMR, capillary GC, and HPLC revealed this product to be a single isomer, the absolute configuration of which was determined to be that illustrated by structure 3. The tetracyclic lactam 3 was stereospecifically reduced to either the cis-fused bicyclic pyrrolidine 4 or the cis-fused bicyclic pyrrolidinone 9. The chiral auxiliaries in both 4 and 9 were removed using different, novel methodologies. This highly stereoselective reaction establishes two contiguous chiral centers via the deracemization of an achiral keto-ester. This methodology has been applied to the synthesis of (1R,5R)-2-azabicyclo[3.3.0]octane 15. This important amine is now readily available from commercial materials in only three steps.