Expanding the scope of the nucleophile catalyzed aldol lactonization (NCALl) process and transformations of the resulting beta-lactones

Expanding the uses of the NCAL and finding the spectrum of substrates best suited for such a transformation has been the main effort of my research. Previous studies had focused on aldedydes as the requisite functionality that would provide the needed electrophilicity in order to complete the aldol; however, recent advancements have introduced ketones as a viable carbonyl. With an established protocol in hand, I set out to explore various substrates that could yield Beta-lactones in good to moderate yields such as amino acid derivatives, diones, and large cyclic formations as well as simple, straight chain acids with varying groups Alpha to the ketone. In general, I was able to establish a basic framework of substrates that are highly and/or moderately susceptible towards the NCAL and current studies continue to further expand the scope. In addition to making Beta-lactones, I investigated alkyl cuprates as soft nucleophiles to afford addition at the Beta carbon yielding a variety of acids. Substrates for cuprate additions have been expanded to bulkier and multi-cyclic Beta-lactones and applied to the synthesis of a Merck IND intermediate. Additions to bi- and tri-chloro Beta-lactones due to the presence of the resulting moity in natural products are currently being studied.