Grant: Discovery Grants Program - Individual

The tetrasubstituted alkene functionality is an important scaffold that appears in many molecules of interest. Many bioactive natural products contain this moiety, as do many relevant synthetic compounds, including pharmaceuticals and functional materials. However, producing single isomers of tetrasubstituted alkenes (or other highly substituted alkenes) has been challenging, since many chemical processes that lead to this class of molecules are not very stereoselective. The overarching goal of the proposed research program is to take advantage of photoredox catalysis to develop a new strategy to produce highly substituted olefins with full regio- and stereochemical control, starting from a very common precursor: malonic acid. While developing this strategy, we also want to add value to various intermediates (mostly brominated alkenes) that will be generated to produce other challenging moieties. We will also use our developed strategy to prepare bioactive compounds and analogs that will be tested by collaborators. In the next five years, we want to explore this synthetic strategy by optimizing the different steps for preparing tetrasubstituted alkenes with aryl and alkyl substituents. This strategy starts by converting malonic acid into a 2-(dibromomethylene)malonate. This compound serves as a template for the construction of the desired olefin, since it already has the double bond of the final target, and bears four functionalities that eable cross-coupling reactions. First, a gem-dibromoalkene will be used to place the first two substituents (R1, R2) via two consecutive monocoupling steps. Various sets of conditions will be developed using Suzuki-Miyaura coupling to install aryl groups, and a robust metallaphotoredox cross-electrophile coupling platform to install alkyl groups. Second, the malonate moiety will serve as a precursor for two other C-Br bonds that will be generated later and that will be used for the installation of the last two substituents (R3, R4) via the same cross-coupling reactions. To this end, different decarboxylative bromination reactions will have to be developed to generate the two C-Br bonds consecutively from the diester functionality. Once our strategy is fully optimized to accommodate alkyl and aryl groups, we plan to show its full potential by preparing six unprecedented tamoxifen analogues that will also be tested for potential action against breast cancer. In parallel, my group will also be working on an innovative new double decarboxylative bromination reaction that can convert a 2-(dibromomethylene)malonate into a gem-dibromoalkene. Overall, working on this program over the next 5 years will lead us to develop reliable methods to synthesize compounds of interest that have been challenging to produce thus far. Since our strategy will, over time, be expanded to the installation of many other types of substituents, the number of compounds we can produce with this methodology will increase in the long term.