Enantioselective total synthesis of (-)-kaitocephalin, and, The design and synthesis of a scaffold for kaitocephalin analogues and glutamate receptor ligands using a natural product-based library approach

Chapter 1 of this dissertation reviews the chemistry and biology of the disubstituted pyrrolidine alkaloid (-)-kaitocephalin, the first naturally occurring ionotropic glutamate receptor antagonist. The isolation, structure elucidation, and biological activity of (-)-kaitocephalin are presented, and the previous chemical syntheses of kaitocephalin are summarized. This chapter also reviews recent methodologies for the construction of 2,5-disubstituted pyrrolidines in enantiomerically pure form. The synthetic examples illustrated in this review provide a context for the research projects described in the remainder of this dissertation, which investigate the asymmetric synthesis of the disubstituted pyrrolidine alkaloid (-)-kaitocephalin and related analogues.; Chapter 2 of this dissertation details the development and successful implementation of a stereocontrolled strategy for the total chemical synthesis of (-)-kaitocephalin, which was accomplished in 11 steps (8 isolated and purified intermediates) in 7% overall yield. The scalable synthetic route described herein profits from the strategic utilization of substrate-controlled manipulations for the iterative installation of the requisite stereocenters. The key transformations include a diastereoselective modified Claisen condensation, a chemo- and diastereoselective reduction of a beta-keto ester, and the substrate-directed hydrogenation of a dehydroamino ester derivative. During the course of our investigations, a novel dynamic resolution---cyclization reaction was discovered for the efficient assembly of the kaitocephalin 2,5-disubstituted pyrrolidine core. The flexible synthetic strategy highlighted herein also permits for the divergent generation of kaitocephalin analogues, which are useful for establishing the structure-activity relationships of this unique glutamate receptor antagonist. The second project included in this chapter details a synthesis plan for the generation of a focused library of glutamate receptor ligands based a scaffold that emulates kaitocephalin. The syntheses of the kaitocephalin library scaffold prototypes were achieved utilizing the chemistry developed for the total synthesis of (-)-kaitocephalin.