GOALI: CAS: Iron-Catalyzed Suzuki-Miyaura Cross Coupling Using Pseudohalide Alkyl Electrophiles

Boston College, Chestnut Hill MA

Investigators

Abstract

With the support of the Chemical Catalysis program in the Division of Chemistry, Professor Jeffery Byers of Boston College, in close collaboration with partners at the Sanofi pharmaceutical company, is studying a new method to assemble complex molecules with relevance to the pharmaceutical industry. The new method involves readily available raw materials and more abundant, iron-based catalysts in contracts to the precious metal-based catalysts, typically palladium-based, that are almost always used for the targeted reactions. Additionally, the method provides greater control over the three-dimensional structure of the product molecules, a critically important characteristic desired in most drugs. To complement the scientific goals of the proposal, the partnership between Boston College and Sanofi will be leveraged to educate the general public about the values of sustainable chemistry and its role in the pharmaceutical industry through town hall meetings and student visits to Sanofi. Under this GOALI award, the Byers research group at Boston College and their collaborators at Sanofi Pharma will work to develop Suzuki-Miyaura cross-coupling reactions of alkyl pseudo-halides with aryl boronic and alkyl boronic esters and/or boranes catalyzed by iron-based complexes. The Suzuki-Miyaura cross coupling reaction is one of the most widely used C–C bond-forming reactions in academic and industrial chemistry. However, palladium-based catalysts have limited reactivity with sp3-hybridized substrates, which has resulted in an over-representation of flat molecules being investigated as therapeutic candidate molecules in pharmaceutical chemistry circles. It is hoped that by introducing Fe-based catalysts, a wider array of sp3-hybridized substrates will be accessible. Replacing the alkyl halide electrophile in these reactions with alkyl pseudo-halides is expected to have significant impact in the pharmaceutical industry as alkyl pseudo-halides are conveniently prepared from alcohols, which, due to their stability and low toxicity, are well represented in compound libraries in the pharmaceutical industry. The project will take advantage of the high and medium throughput instrumentation that is at Sanofi for the development of aryl-alkyl and alkyl-alkyl cross coupling reactions and enantioselective and/or enantiospecific cross coupling reactions. Moreover, in situ monitoring of reactions will facilitate in depth mechanistic investigations, which are lacking in the field of iron-catalyzed cross-coupling reactions. 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.