An asymmetric approach towards 3-spiropiperidines

In the last few years, asymmetric intramolecular aza-Michael cyclisations have become a well-established method in the synthesis of nitrogen heterocycles. Chiral phosphoric acids (CPA) are known to be versatile catalysts in a variety of asymmetric reactions and have provided access to enantioenriched scaffolds present in natural products and pharmaceutical drugs. Previous work in the Clarke group established the crucial role played by thioesters as Michael acceptors in the aza-Michael reactions catalyzed by CPA resulting in high yields and enantioselectivities in the synthesis of substituted pyrrolidines. The work presented in this thesis expands on the methodology for the synthesis of substituted piperidines. Extensive optimization was required to increase the yield and maintain high enantioselectivity of the piperidines formed. Each of the changes in the thioester functionality, ring substitution, catalyst, time, temperature, and solvent affected the outcome of the reaction and were used to arrive at the final optimized reaction conditions. The methodology was then applied to synthesize a range of 3-spiropiperidines from readily available starting materials resulting in good yields and excellent enantioselectivities.