A Radical Pathway Toward C-F Bond Functionalization: Direct Fluorine-Atom Transfer

About This Grant

Project Summary/Abstract The incorporation of carbon–fluorine (C–F) bonds into active pharmaceutical ingredients (APIs) can dramatically enhance their pharmacokinetic properties. The beneficial influence of C–F bonds on the success of small-molecule therapeutics has led to the incorporation of fluorine in approximately 20% of all pharmaceuticals. In line with this demand for C–F bonds, significant synthetic efforts focusing on fluorination strategies have led to the wide availability of organofluorine compounds as synthetic building blocks. However, C–F bonds often represent stagnant, persistent end products due to their exceptional strength and inertness. A general strategy for C–F bond functionalization would transform these linkages into useful synthetic linchpins for further product elaboration. For example, widely available trifluoromethyl groups (–CF3) could be utilized to construct valuable, difficult-to-access gem-difluoro motifs (–CF2R), which are of interest in medicinal chemistry as bioisosteres. Existing methods for C–F bond functionalization almost exclusively rely on two-electron, polar pathways of bond deconstruction that often require harsh conditions, which limits the functional group compatibility of these methods. Single-electron strategies toward C–F bond functionalization would be highly desirable, as radical cross-coupling is a powerful platform for the construction of complex molecular architectures. Thus, this proposal seeks to develop single-electron pathways toward C–F bond functionalization. The objective of this proposal will be met via the design of fluorophilic radical reagents based upon phosphorous, silicon, boron, and aluminum. Electrochemical redox will activate these radical reagents to promote fluorine-atom abstraction from C–F bonds. The resultant C-centered radicals will be harnessed for useful C–C and C–X bond formations. The proposed research is expected to constitute a significant advance in C–F functionalization methodology, as it will allow for 1) the introduction of organofluorine electrophiles into the pool of radical precursors, 2) the streamlined synthesis of medicinally relevant –CF2R motifs, and 3) the late-stage modification of fluorine-containing motifs in APIs. The Baran Lab at The Scripps Research Institute is the ideal environment for the execution of the proposed research. The Baran Group are experts in radical methodology and will provide broad training in organic chemistry, including methodology development, electrosynthesis, and retrosynthetic analysis. Furthermore, the training environment in the Baran Lab at Scripps will facilitate communication with end users of the developed synthetic techniques, including industrial chemists. This training will enable further identification of synthetic challenges that, if solved, would meaningfully improve human health by enhancing the efficiency of small- molecule therapeutic synthesis. These factors distinguish Scripps as the ideal institution to pursue the proposed ambitious research goals, as well as to develop the skills necessary for a future career in academic research.