Late Stage Stereochemical Editing to Transform the Synthesis of Bioactive Molecules

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Project Summary Chiral natural products and man-made drugs play a pivotal role in the study and treatment of a diverse spectrum of human diseases. The presence of stereogenic centers in drug candidates has been shown to correlate with diminished off-target toxicity, reduced CYP450 inhibition, and an overall enhanced probability of regulatory approval as drugs. However, despite the established importance of three-dimensionality in bioactive chemical structures, the selective synthesis of complex organic molecules containing stereogenic centers remains a venerable challenge. The research described in this proposal describes a conceptually new approach to the selective formation and revision of stereogenic centers through the stereoconvergent epimerization of C– H bonds. In contrast to the vast majority of stereoselective transformations, which establish the absolute and relative configuration of a stereogenic center during a key bond-formation step, our approach introduces the opportunity to enrich or invert individual stereocenters after bond connectivity has been finalized. Our strategy thus decouples the strategies needed to establish bond connectivity from the strategies needed to establish the three-dimensional configuration of a complex molecule. By targeting the most ubiquitous functional group, C–H bonds, this tool has expansive potential. If successful, the research program proposed here is anticipated to transform chemical synthesis, dramatically reducing the time and resources necessary to synthesize complex, bioactive molecules. Fundamental mechanistic findings revealed en route to this goal are further anticipated to contribute significantly to our ability to understand reactivity and selectivity patterns in the context of complex molecular environments. .