Synthesis and Modification of Natural Products through Inert Bond Cleavage Reactions

Project Summary Medicinal chemists have consistently sought inspiration from natural products and their synthetic derivatives when exploring potential therapeutic lead compounds. These compounds frequently exhibit polycyclic architectures with numerous Csp3 stereocenters, contributing to heightened molecular rigidity. Additionally, clinical candidates which contain many stereocenters, topologically rich molecules, have been shown to exhibit less off-target effects. However, many synthetic methods solely modify the periphery of a molecule, which results in negligible three- dimensional change to the core scaffold. This proposal aims to develop protocols to alter the molecular topology of biologically active molecules; therefore, providing access to untapped chemical space and novel approaches to potentially improve a clinical candidate’s biological properties (Project 1). This project centers around developing several photochemical deconstructive epimerization protocols, involving an initial C–C bond cleavage, formation of a radical intermediate, and C–C bond reformation with the altered stereochemistry. This new mode of precision molecular editing may enable the opportunity to rapidly modify existing natural product and therapeutic libraries as well as the ability to synthesize compounds that would previously be challenging to access without lengthy de novo syntheses. Nevertheless, certain secondary metabolites are isolated from natural sources in minute quantities, which may limit the potential for direct modifications to a core scaffold. To overcome this hurdle, we also seek to develop new convergent retrosynthetic strategies that allow for the rapid and scalable total syntheses of natural products (Project 2). Our second proposal aims to utilize common, stable, and widely available precursors, such as alcohols and amines, for the direct execution of convergent fragment coupling reactions. By in situ cleavage of these inert C–C and C–heteroatom bonds, a radical intermediate is formed which we harness in various coupling reactions. We will further employ these protocols in the synthesis of several biologically active terpenoids.