Cyclization Strategies and Methodologies Toward the Synthesis of Complex Natural Products

With the support of the Chemical Synthesis (SYN) Program in the Division of Chemistry, Professor David Williams of Indiana University (IU-Bloomington) will develop new methods and strategies for the construction of complex, bio-active molecules. These concepts are important for two principal reasons. There is a need to devise more efficient procedures for the assembly of molecular complexity while finding environmentally benign reagents and reactions.

Secondly, there is need to expand the limits of structural chemistry to identify new scaffolds that are biologically active, both as a tools for chemical biology and as potential hit or even lead compounds for medicinal chemistry. Multi-step synthesis pathways will be explored for the preparation of bio-active natural products; this project is especially focused on metal-catalyzed cyclization reactions of reactive compounds as a feature that may lead to the formation of two or more rings in a single reaction.

Educational aspects of this project are geared to broadly develop students as problem-solvers in the field of organic chemistry. Most of the graduates from this laboratory experience are employed in the pharmaceutical and biotechnology industries. Societal benefits will include the recruitment and participation of under-represented individuals and women in all aspects of the research.

Summer research opportunities will also be available for undergraduate participants in this research project.

This research project seeks to forge new ground in synthetic methodology and particularly in strategies for cyclization reactions. Transition metal-catalyzed reactions of strained cyclopropanes and cyclopropenes will be explored as a key element in the design of new pathways for the synthesis of complex, bio-active natural products. The proposed activities are expected to advance knowledge regarding the synthesis of substituted cyclopropanes and the effective incorporation of these reactive building blocks into complex molecular architectures.

These investigations will also examine the propensity for reorganization of small ring metallacycles to form more stable pi-allyl metal intermediates in cyclization processes. Project objectives seek to devise a reaction cascade concluding with intramolecular [3+2] and [2+2+1] cyclizations. Studies are also planned on reaction scope and stereoselectivity through the examination of electronic and steric factors imposed by the catalyst and its ligands.

New synthesis strategies are proposed for the efficient construction of tricyclic cyathanes and fusicoccanes, as well as for completion of the synthesis of daphnicyclidin A. The project is a significant component of the Indiana University Department of Chemistry STEM (Science, Technology, Engineering and Mathematics) commitment with an emphasis on access for women and underrepresented individuals through the IU ACS Bridging Program.

Broader scientific impacts are expected through planned collaborations with scientists in allied disciplines including biology, animal sciences, neuroscience and medicine. Overall, this project aims to advance fundamental organic chemistry methodology and strategy and to provide a superior platform for student training in modern synthetic chemistry.

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.