Rhodium(II)-Mediated O-H or N-H Insertion Tandem Conia-Ene Cyclizations: Application Towards the Synthesis of the Welwitindolinone Alkaloids

Colorado State University, Fort Collins CO

Investigators

Abstract

With this award, the Chemical Synthesis Program is supporting Professor John L. Wood of the Department of Chemistry at Colorado State University to develop new methods for the formation of oxygen- and nitrogen-containing heterocycles via a rhodium(II)-mediated O-H/N-H insertion tandem Conia-ene cyclization. Since its discovery, the Conia-ene cyclization has presented a method for assembling carbocycles from linear substrates containing an enol and pendant olefinic moiety. This rearrangement remains synthetically underdeveloped because of the harsh reaction conditions required for its application. Recent advances in metal-catalyzed Conia-ene cyclizations have made this reaction more amenable for synthetic use, however the reaction is still limited to underfunctionalized, linear precursors. One metal that has not been explored is rhodium(II). Rhodium(II) is well known for its dediazotization ability in carbene chemistry, but few examples exists where it behaves as a pi-Lewis acid that would help initiate a rearrangement such as a Conia-ene cyclization. Tandem reactions are synthetically attractive for their efficiency and tendency to generate minimal waste. The development of this reaction sequence will create a new synthetic tool for the construction of target compounds that possess interesting biological and structural properties including complex natural products. Specifically, the proposal outlines a strategy utilizing the newly developed method for the synthesis of the welwitindolinone B/D family. Syntheses of theses compounds could generate intermediates that possess medicinally relevant activities. In terms of Broader Impacts, the PI will build on his notable track record in training undergraduate, graduate, and postdoctoral fellows through the scholarly pursuit of methods development and its application to the construction of complex molecular targets. It is expected that these individuals will have a positive influence on the academic community, pharmaceutical industry and allied scientific fields in the general areas of matter by design and controlled molecular synthesis.