Catalytic Anhydride Desymmetrization as a Route to Polypropionate Synthons

Colorado State University, Fort Collins CO

Investigators

Abstract

The central theme in the proposed research is to develop rapid access to fragments of polyketide natural products, a family of targets that are five times as likely to have biological activity as other natural product families. Assembly of these stereochemically complex structures has previously taken place using inherently iterative strategies that, by necessity, require many steps and very skilled hands. The approach detailed herein differs in that this science assembles significant subsections of these natural products from commercially available starting materials using a Rh-catalyzed anhydride desymmetrization. This one key step delivers 6-11 carbon sections of natural products, instead of the more typical 2-4 carbon sections, while also controlling stereochemistry in the process. With the support of this award from the Chemical Synthesis Program, Professor Tomislav Rovis of the Chemistry Department at Colorado State University will develop rapid access to fragments of polyketide natural products. These polyketides have diverse activity, including antibiotic, anticancer and angiogenesis inhibition, therapeutics that are currently a significant challenge in global health. The goal of this research program is to fill a deep apparent hole in this area of science; that is, the ability to assemble very complex structures of this family. The Rovis research group is uniquely qualified to do this because of their prior contributions. Once the hole is filled, it will enable organic and medicinal chemists, biochemists, biologists and microbiologists to generate and screen the biological efficacy of subsections of these complex molecules, privileged structures in medicinal chemistry. Beyond the interdisciplinary impact and potential, there is also the broader impact in educational benefit to undergraduates, graduates and postdoctoral fellows, whose training and instruction in becoming independent scientists is facilitated. Furthermore, these funds will also enable the participation of two members of underrepresented groups in research (one woman and one Native American, both graduate students).