Radical redox catalysis by Ti complexes

Cornell University, Ithaca NY

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Abstract

Project Summary This proposal focuses on uncovering new radical-based methodologies that facilitate the synthesis of bioactive compounds. Organic radicals are highly reactive species with unique chemoselectivities that complement canonical two-electron chemistry. Recently, the emergence of new reaction strategies that leverage single-electron redox events and harness radical intermediates for the selective functionalization of organic molecules has provided chemists with useful tools for solving contemporary synthetic problems. However, the highly reactive nature of many organic radicals has made it difficult to impart catalyst-control over the regio- and stereoselectivity of these fleeting intermediates, especially when complex reaction systems are concerned. In particular, catalytic stereoselective reactions involving free radical intermediates remain limited, and the discovery of such processes is highly desirable. To provide new radical-based platforms for reaction discovery and synthetic innovation, we developed catalytic strategies that leverage the unique redox features of low-valent Ti complexes to achieve redox-neutral and net-reductive transformations, and through catalyst innovation, we demonstrated that free-radical-mediated reactions can be made highly enantioselective. These promising results prompted us to continue to invent novel catalytic and reaction strategies that can effectively harness radical intermediates and provide powerful tools for solving a wide range of longstanding synthetic problems. In the parent proposal, we aim to build upon our previous success but move our research into new grounds. In each of the projects targeted herein, we aim to advance a new approach that employ radical-based catalysts or reagents to address a prominent challenge in organic synthesis. The transformations targeted in this grant are either currently unknown or display salient limitations in reaction scope or selectivity. Among the specific reactions that we aim to develop in the context of this grant are: enantioselective cycloadditions, enantioselective epoxide isomerizations, oxidative desymmetrization of alcohols, enantioselective ⍺-oxidation of amides, and site-selective functionalization of aliphatic C–H bonds. In addition, in-depth studies using canonical physical organic and electroanalytical techniques will provide insights into the reaction mechanisms. The development and mechanistic understanding of these proposed transformations will represent significant advances for the field of organic synthesis.