Strategic Formal [5+2]-Cycloadditions Toward Heteroaryl-fused Seven-membered Rings

Georgia Tech Research Corporation, Atlanta GA

Investigators

Abstract

In this project funded by the Chemical Synthesis Program in the Division of Chemistry, Professor Stefan France of the Georgia Institute of Technology is developing new approaches to synthesize natural products, which are organic chemical compounds that are naturally produced by living organisms. The particular goal of this research project is to develop a toolbox of chemical reactions that lead to the efficient construction of molecules that contain rings of seven atoms. Professor France is applying these methods toward the synthesis of complex natural products that have a wide variety of biological activities. These natural products may serve as lead compounds for the development of new pharmaceuticals. Through this research project, Professor France is also providing high-level education and training for undergraduate and graduate students. He and his research group are also active in outreach activities to broaden the participation of underrepresented groups in science, including participating in NOBCChE and acting as a mentor for Georgia Tech FACES fellows. Heteroaryl-fused seven-membered rings are present in a large variety of natural products that play an important role in the field of drug discovery. Despite the ubiquity of this molecular structure in natural products, the efficient construction of seven-membered systems remains a synthetic methodology challenge due to vast skeletal diversity exhibited in these compounds. Consequently, the ability to synthesize these motifs in a concise, regio- and stereocontrolled manner is of high importance to organic chemists. Professor France is studying ways to develop formal [5+2] cycloadditions of heteroaryl alpha-alkylidene 1,3-dicarbonyls derivatives with alkenes to generate (hetero)aryl-fused cycloheptyl rings. To demonstrate the overall utility of the [5+2] cycloaddition approaches, Professor France is applying the newly developed methodologies in a few representative natural product syntheses. Three of the syntheses being pursued are: 1) the synthesis of azepino[1,2-a]indoles using N-indolyl alkylidene malonamides; 2) the synthesis of cyclohepta[b]indoles using indolyl alpha-alkylidene beta-ketoesters; and 3) the synthesis of cyclohepta[b]furans using furyl/benzofuryl alpha-alkylidene beta-ketoesters.