Advancing Enantioselective Carbanion Chemistry Through Complex Molecule Synthesis

With the support of the Chemical Synthesis program in the Division of Chemistry, Professor Armen Zakarian of the University of California, Santa Barbara will study synthetic methods for leveraging carbanions, carbons with a negative charge, in highly selective and complex transformations. The proposal will leverage designer amine bases for the selective generation and reaction of the carbanions derived from medicinally relevant scaffolds, leading to important bond formations in a highly selective fashion. The importance and power of these methods will be demonstrated in the synthesis of biologically active complex molecules. The proposed research will improve the way chemists access challenging molecules, with applications from medicinal to materials research. It will also serve as an invaluable platform for the training of students at all levels, from high school to graduate students. Such specialized training in stereocontrolled synthetic chemistry will help to produce the future workforce with synthetic expertise to tackle problems at the chemistry/biology interface with longer term implications for fields such as medicine, pharmaceuticals and new materials. Under this award, the Zakarian group will apply the assembly chemistry of readily accessible chiral lithium amide bases (CLAs) to the development of stereoselective transformations with carbonyl and heterocycle-derived carbanions. While such reactions with enolates have precedent, applications of non-enolate carbanions mediated by CLAs have much more limited precedent and remain underdeveloped. This project will advance both types of these transformations, which can be rendered towards the construction of multiple stereocenters with high enantio-, regio-, and diastereocontrol in a modular format. Applications of this methodology in the synthesis of alkaloids of Lycopodium family and heterodimeric bisindole alkaloids bousigonine A and bisleuconothine A will subject the utility of the proposed methods to the test in the rigorous context of complex molecule synthesis, so as to confirm their reliability and scalability as a practical source of enantioenriched intermediates for organic synthesis. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.