Synthesis of Heterocyclic Natural Products

The primary objective of this research program is to continue to develop a combination of novel synthetic methods and new strategies for the synthesis of bioactive heterocycles and alkaloid natural products. Under the support of the Chemical Synthesis Program of the Chemistry Division, Prof. Weinreb at Pennsylvania State University will conduct target oriented total syntheses of a number of structurally unique and complex nitrogen-containing natural products. Moreover, new synthetic methodology involving inter- and intramolecular conjugate additions to nitrosoalkenes will be explored including delineating stereochemical features of the process. Methodology will also be investigated for effecting catalytic enantioselective conjugate additions of carbon and heteronucleophiles to nitrososalkenes. This work aims to provide widely useful new methodology for alpha-alkylation of aldehydes and ketones via an 'Umpolung' process. Intermolecular versions of conjugate additions of carbon nucleophiles to nitrosoalkenes will constitute key steps in total syntheses of some of the vallesamine class of indole alkaloids. Studies will be conducted on the use of an intramolecular Michael addition of a nitrosoalkene in an enantioselective total synthesis of the unique indole alkaloid actinophyllic acid, a potent inhibitor of the enzyme carboxypeptidase U.

Emphasis will be placed upon producing and refining methodology having potentially broad applicability and practical value to organic and medicinal chemists involved in synthesis of chemotherapeutic agents. Pharmaceutical research and drug development has a multibillion dollar annual impact on the US economy, and its success is heavily dependent on synthetic methodology provided by academic laboratories. The PI will continue to disseminate the results of the research conducted under this grant by presenting seminars at pharmaceutical companies and conferences in both the US and abroad. In addition, this grant will provide practical training for M.S. and Ph.D. students in sophisticated synthetic organic and heterocyclic chemistry. The young scientists to be trained under this NSF grant will eventually take research positions in the chemical industry, most often in pharmaceutical or other health-related corporations, thereby having an important economic impact as well as providing significant health benefits to the populations of the US and the world.