Development of new dynamic kinetic asymmetric transformations: Asymmetric allylic alkylations of allenes, vinylaziridines and progress towards the total synthesis of lasonolide A

For the cost effective and efficient preparation of biologically significant molecules, the development of atom economic asymmetric transformations is highly desirable. In accordance with to the above objective, the development and application of several catalyzed dynamic kinetic asymmetric transformations (DYKATs) is described.; The palladium catalyzed dynamic kinetic asymmetric allylic alkylations of vinyl aziridines efficiently provided chiral amines in high enantioselectivity. In particular, the highly enantioselective cycloaddition with acetoacetates and isocyanates to vinylaziridines furnished chiral dihydropyrroles and imidazolidinones in moderate to excellent yields. The asymmetric addition of imides to vinylaziridines also proceeded in both high enantioselectivity and yield to generate synthetically differentiate vicinal dimines. In order to demonstrate the utility of the DYKAT, the concise asymmetric formal synthesis of balanol was accomplished by application of the asymmetric addition with imido dicarboxylates.; Further demonstrating the effectiveness of the aziridine DYKAT processes, the methodology was applied to the first total synthesis of (+)-pseudodistomin D. The absolute stereochemistry of the natural product was efficiently established by the asymmetric cycloaddition with isocyanates. This stereocenter was utilized to direct the formation of all other stereocenters in the alkaloid. A novel diastereo- and chemoselective Ag(I) catalyzed hydroamination and subsequent reduction method was developed to efficiently construct the piperidine core.; The highly enantioselective dynamic kinetic asymmetric allylic alkylation of allenes with amine and malonate nucleophiles further demonstrated the generality of the Trost ligands. In the DYKAT process, a significant base effect on the enantioselectivity was observed. This dependence was most pronounced with the amine nucleophiles, and the asymmetric induction could be reversed by the choice of the base. A Rh(I) catalyzed [4+2] cycloaddition of the DYKAT products with complete chirality transfer to multiple stereocenters show cased the synthetic utility of the methodology.; In an effort to develop a concise approach towards (-)-lasonolide A, synthetic efforts towards its total synthesis were initiated by application and development of other group methodologies. The efficient asymmetric synthesis of the northern tetrahydropyran was accomplished by application of the dinuclear zinc catalyzed asymmetric aldol reaction with an ynone. The absolute stereochemistry of the southern tetrahydropyran was established through an enzymatic dynamic kinetic asymmetric reduction.