Progress toward the total synthesis of stemocurtisine and asymmetric synthesis of endoperoxide anticancer agents via Bronsted acid cascade catalysis

A viable route toward the pyrido-azepine core of stemocurtisine involving an N-heterocyclic carbene catalyzed Stetter reaction has been realized. The key steps involve a formal [3+2] cycloaddition of enones with isocyanoacetates and a catalytic asymmetric intramolecular Stetter reaction. Additionally, a diastereoselective intramolecular Stetter reaction was achieved to access highly substituted pyrrolidines.;Asymmetric Bronsted acid catalyzed cascade reactions were also investigated. A diastereoselective acetalization/oxa-Micahel cascade has been developed to provide dioxolanes and oxazolidines using diphenylphosphinic acid as a catalyst. The enantioselective variant of this reaction was explored with minor success.;The desymmetrization of p-peroxyquinols using a Bronsted acid catalyzed acetalization/oxa-Michael cascade was achieved in high yields and selectivities for a variety of aliphatic and aryl aldehydes. Mechanistic studies suggest that the reaction proceeds through a dynamic kinetic resolution of the peroxy-hemiacetal intermediate. The resulting 1,2,4-trioxane products were derivatized and show potent cytotoxicity toward specific cancer cells.