A Unified Synthetic Approach Toward the Kalihinanes
This dissertation describes our efforts toward developing a unified synthesis of the kalininane family of antimalarial marine isocyanoterpenes. Chapter 1 focuses on the isolation, structure determination, subclass specification, biological activity, and proposed biogenesis of the kalihinanes. Additionally, methods for the synthesis of isonitriles and previous syntheses of kalihinanes and related isocyanoterpenes are described.
Chapter 2 describes our divergent synthetic plan, featuring an oxa Michael/Robinson annulation sequence and a Piers-type annulation for the rapid synthesis of the decalin framework of the kalihinanes. This strategy was validated with a formal synthesis of 10 isocyano 4 cadinene, and was subsequently applied toward the synthesis of kalihinanes bearing a pendant tetrahydropyran (kalihinol A) or tetrahydrofuran (kalihinol B). While the synthesis of the tetrahydropyran-containing kalihinanes has yet to be accomplished, our efforts toward tetrahydrofuran-containing kalihinanes culminated in the first synthesis of kalihinol B. An unexpected hydride shift has thwarted efforts to extend the synthesis to other tetrahydrofuran containing kalihinanes.
Chapter 3 focuses on the application of our strategy to the synthesis of unnatural kalihinane analogues. Several analogues have been prepared and subjected to an antiplasmodial assay. All of the synthetic isocyanoterpenes exhibited antiplasmodial activity against drug sensitive and drug-resistant strains of Plasmodium falciparum (IC50 < 1.2 µM). Furthermore, kalihinane-based small-molecule probes have been prepared, and will be used for protein profiling in P. falciparum.