Harnessing the Latent Potential of Radical Migration to Drive Synthetic Innovation

Project Summary/Abstract This proposal will exploit the unique and latent features of radical-mediated migrations to underpin new synthetic transformations designed to facilitate the discovery and manufacture of medicines. Using this approach, we aim to make significant advances in olefin difunctionalizations and stereoselective α-functionalizations of carbonyls. These reaction classes have enormous potential in pharmaceutical synthesis, but technical complications with their transition-metal catalysts have restricted the products they can directly access. To address these limitations, we will develop new conceptual platforms that promote these transformations and are compatible with medicinally valuable motifs that have heretofore presented challenges. In the context of olefin alkyl–arylation and amino–arylation, we have shown that a radical-migration-based design affords clear improvements over established strategies. Using this approach, our alkyl–arylation protocol enables (1) the use of mono- to tetrasubstituted olefins without activating or directing groups, (2) alkylation with diversifiable partners, (3) the formation of quaternary benzylic centers, (4) the broad use of N-rich heteroaromatic groups, and (5) good diastereocontrol. All five of these key outcomes are nearly unprecedented in metal-catalyzed alkyl–arylations of unbiased olefins, and they result directly from the method’s radical-migration-based design. Amino–arylation features similar advantages. Future work will comprehensively demonstrate the utility of these methods, develop more accessible reagents, and the introduce a further suite of amino–functionalization reactions. We will also translate this open-shell approach to the stereoselective α-functionalization of carbonyls. In this setting, we will develop and implement simple ‘chiral chaperones’ that are well-poised to deliver aromatics and other key functional groups to the α-position of carbonyl compounds after a radical-generation step. Since these transformations have struggled to introduce N-rich heteroaryl groups stereoselectively – a task for which radical- mediated migrations hold particular promise – this approach will unlock access to a broad range of stereodefined carbonyls bearing these privileged pharmacophores, in addition to α- and β-amino acids.