Advances of Methodology and Design for the Synthesis of Complex Polycyclic Natural Products

Indiana University, Bloomington IN

Investigators

Abstract

The Chemical Synthesis Program of the Chemistry Division supports the project by Professor David Williams. Professor Williams is a faculty member in the Department of Chemistry at Indiana University. He is developing new classes of ring-forming reactions to carry out highly efficient preparations of complex, polycyclic molecules. The goal of the research is to develop new reactions and concise strategies that permit the rapid construction of substances that incorporate multiple rings. Studies are directed to natural products that have been isolated in extremely small quantities. These substances have important biological uses for treatment of cancer and hypertension. This research project seeks to design and develop new reactions that provide efficient synthetic pathways for the preparation of these bioactive substances. This research fundamentally advances chemistry as a platform for drug discovery. The Williams laboratory offers state-of-the-art training and mentoring in the field of synthetic organic chemistry. A blend of predoctoral students, postdoctoral fellows, and undergraduate participants, including many women and underrepresented minorities, make up the Williams' research group. All individuals receive training and mentoring to enable future opportunities as next-generation scientists. The goal of this research program is to develop new methodologies for the annulation of highly substituted, five-membered carbocycles in complex molecular arrangements. Direct applications are sought to devise concise synthetic pathways to bioactive natural products. Two lines of investigation are being pursued to achieve these goals: anionic electrocyclization reactions and transition metal catalysis. Studies are underway to explore effective methods to engage pentadienyl carbanions in ring-forming processes. Palladium and nickel-catalyzed reactions are studied to link cross-coupling processes with molecular reorganization via pi-allyl intermediates. Another aspect of the research investigates new metal-catalyzed rearrangements of strained cyclopropylidene systems to advance annulation reactions that are applied to the synthesis of bioactive terpenes. The project interfaces well with important subtopics in chemical biology and medicinal chemistry. The research is well suited for the education of scientists at all levels. Professor Williams' group is well positioned to provide the highest level of education and training for students underrepresented in science. A variety of outreach activities are part of the project. The broader impact of these scientific results benefit society by enabling the discovery of new pharmaceuticals.