Probing Reactivity and Mechanism of Alkyl Transmetallation in Palladium-Catalyzed Cross-Coupling Reactions

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Cross-coupling reactions, where two molecules are coupled to produce a new molecule, are routinely employed by synthetic chemists in efforts to produce new drug candidates. However, these reactions are not especially well-suited for the synthesis of chiral molecules, e.g., molecules with three-dimensional structures that can exist as non-superimposable mirror images, similar to your right and left hands. Because these different mirror images usually display distinct properties, precise control of their three-dimensional structure is essential in the drug discovery process. One mirror image may serve as the active therapeutic agent, while the other may prove harmful to biological systems or may significantly reduce the efficacy of the active one. Dr. Mark Biscoe is investigating new strategies and catalysts to produce only the desired mirror image structure of molecules produced by cross-coupling reactions. This work is contributing to the improved safety and efficacy of new drug candidates. Dr. Biscoe is also active in projects that are designed to increase the diversity of students participating in the STEM fields. Summer research internships for high school and undergraduate students constitute an important part of these outreach activities. With funding from the Chemical Catalysis Program of the Chemistry Division, Dr. Mark Biscoe of the City College of New York is exploring the factors that control the reactivity and mechanism of alkyl transmetallation in palladium-catalyzed cross-coupling reactions. These studies utilize a combination of catalytic and stoichiometric processes, stereochemical probes, modern data analysis techniques, and DFT calculations to deconvolute the factors that influence the rate and stereochemistry of the transmetallation process. Particular focus is placed on the transmetallation of alkyltin (alkylcarbastannatrane) and alkylboron nucleophiles, with the ultimate goal of developing new, robust methods to employ optically active alkyltin and alkylboron nucleophiles in stereospecific cross-coupling reactions. These studies expand our fundamental understanding of transmetallation in transition metal-catalyzed reactions involving alkyl coupling partners, and facilitate the development of new, stereospecific chemical transformations through the exploitation of this knowledge. Additionally, these activities include summer research internships designed to increase the participation of underrepresented and minority groups in STEM fields.