Leveraging the Persistent Radical Effect in the Synthesis of Resveratrol Natural Products

Abstract

The use of radicals as intermediates in total synthesis has evolved since their initial use in the latter half of the twentieth century. Our group has long been interested in harnessing the power of radicals in the total synthesis of biologically interesting natural products. Chapter 1 summarizes recent advances in radical generation from metal hydride methodologies has shifted to “greener” techniques including catalytic metal-mediated systems, electrochemical and photoredox-mediated processes, and applications of these techniques in natural product total synthesis. Chapter 2 details the evolution of the persistent radical effect in total synthesis, wherein persistent and transient radicals will undergo a selective cross-coupling if they are generated in equal rates. Our group has leveraged this phenomenon in our own total synthesis efforts towards resveratrol dimers and tetramers, through the use of a persistent radical equilibrium that exists between quinone methide dimers and their corresponding persistent phenoxyl radicals. Leveraging this equilibrium, Chapter 2 describes a simple, diastereoselective protocol for accessing trans-2,3-diaryl-dihydrobenzofurans through efficient cross-coupling of persistent quinone radicals and transient phenoxyl radicals. DFT calculations have provided insight into the reaction pathway. This methodology allows us to access a wide array of trans-2,3-dihydrobenzofurans. Finally, Chapter 3 describes our efforts towards applying this method in the total synthesis of C10-C8' resveratrol dimers, specifically ε-viniferin, which serves as a precursor to the majority of higher order resveratrol oligomers. Through acid-mediated cyclizations, protected ε-viniferin can be converted to natural product dimers ampelopsin F and ampelopsin D. This chapter concludes with the future directions of this project, including our efforts towards resveratrol trimers.