New Reactions for Targeting the Akuammiline Alkaloids

Dartmouth College, Hanover NH

Investigators

Abstract

This project is jointly funded by the Chemical Synthesis program and the Established Program to Stimulate Competitive Research to support the research of Professor Jimmy Wu of Dartmouth College. Dr. Wu is developing new chemical synthesis of organic compounds with unique chemical structures. This research is leading to the discovery of molecules with important physical and/or biological properties. To accomplish these goals, Prof. Wu invents new reactions that can be applied to the synthesis of a class of anti-diabetic compounds that are found in the seeds of the Akuamma trees which grow in western Africa. In collaboration with Professor Lori Loeb of the Department of Computer Science at Dartmouth, Professor Wu is also producing a series of short, animated films focused on important concepts in organic chemistry and other STEM topics. The target audience is middle school, high school, and college students, as well as the general public. The fourth animation in this series is currently in production and tells the story of exenatide, an FDA-approved drug for type 2 diabetes that was first discovered in the saliva of the Gila monster. Professor Wu is actively pursuing advances in heterocyclic chemistry within the context of the total synthesis of complex natural products from the akuamma family of indoline alkaloids. His strategy makes use of reactions recently developed in his research group as key steps in the synthesis. These reactions include the dearomative indole 3+2 annulation reaction and nucleophile-intercepted Beckmann fragmentation, among others. At least one member of these compounds possesses anti-diabetic properties and is thought to work by dual inhibition of the sodium/glucose co-transporters SGLT1 and SGLT2. Additionally, Professor Wu is using fundamental knowledge gleaned from these syntheses as the basis for preparing complex heterocyclic scaffolds that populate novel chemical space. The broader scientific impacts of this award are multi-fold, with the most obvious being advances in understanding both type 1 and type 2 diabetes. In addition, benefits arise from the use of these newly invented reactions by others in the chemical community in synthetic endeavors unrelated to the akuammilines. 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.