Copper-Catalyzed Enantioselective Addition of Styrene-Derived Nucleophiles to Thiocarbenium Ions by Ligand-Controlled Chemoselective Hydrocupration

Massachusetts Institute Of Technology, Cambridge MA

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Abstract

Project Summary/Abstract The current state of organic and medicinal chemistry is centered on developing methodologies that have the ability to precisely install a breadth of functionality over a range of chemical space. Specifically, the ability to install diverse functionality at the start of a synthesis is very powerful as diversity oriented synthesis can lead to the rapid formation of chemical libraries. On the other hand, the importance of late stage diversification is of equal significance because the physiochemical properties of a drug candidate can be easily tuned to provide adequate cell permeability, lifetimes and potency. In 2012, all of the top 10 selling drugs contained sulfur functionality and upon their examination and other known therapeutic agents incorporating sulfur a lack of stereochemical information was observed. Specifically, thioether skeletons more often than not lack stereochemistry at the sulfur bearing carbon especially vicinal stereogenic centers because no streamline methods are currently available to access them. As sulfur functionality is often the crucial component of the therapeutic agent the ability to install stereochemistry at this location is very significant because it could dramatically alter its biological properties. The theme of the research planned in this proposal is the development of a coupling technology that provides expeditious access to highly diverse enantioenriched thioether scaffolds containing vicinal stereocenters. Of equal significance is the ability to access other bio- relevant sulfur skeletons through the constructive elaboration of chiral thioether libraries. Furthermore, this chemistry is predicted to be highly enantioselective which makes it even more suitable for the pharmaceutical industry because essentially all medications must be prepared as enantiopure products. To accomplish these goals our plan starts with developing a late stage diversification protocol by performing initial investigations on oxidized thioether scaffold ?sulfoxide system? that allows for the reaction parameters to be optimized. Secondly, early stage methodologies will be developed to access thioethers in a highly programmable manner from three commercially available reagents (aldehyde, thiol and alkene). We then wish to demonstrate the generality and robustness of this technology in both early and late stage drug discovery by selecting a relevant pharmaceutical target and diversifying its core into the realm of the described chemical space. Overall, the success of this chemistry is expected to fill the present-day void in accessing such compounds in both the academic and industrial settings alike.