Optimization and extensions of the nucleophile catalyzed aldol-lactonization (NCAL) process for bicyclic beta-lactone synthesis: applications to piperidine, pyrrolidine, and gamma-lactam-fused beta-lactones

Abstract

The intramolecular nucleophile catalyzed aldol-lactonization (NCAL) process was optimized successfully. A variety of C9-acylated cinchona alkaloids were synthesized and used for NCAL reactions with non-activated aldehydes. New pyridinium salts, derivatives of Mukaiyama’s reagent, led to marked improvements in efficiency for the catalytic, asymmetric NCAL process while maintaining high enantioselectivity. Larger scale versions of the catalytic, asymmetric NCAL reaction were also developed allowing practical access to chiral bicyclic b-lactones. As an extension of the intramolecular NCAL process, pyrrolidine and piperidine fused blactones were synthesized. Simple g-lactam fused b-lactones were synthesized as a model study for omuralide, salinosporamide A, and derivative synthesis. Synthesis of asubstituted aldehyde acids was extensively studied but steric effects from both acid and amine moieties led to great difficulties in this approach.