Persistent Radicals in Natural Product Synthesis: A Biomimetic Approach to Resveratrol Oligomers

Since their discovery 120 years ago, carbon-centered free radicals have captivated the attention of organic chemists worldwide. As the thermodynamic and kinetic properties of radical reactions have been studied, it has been recognized that open-shell intermediates offer complementary and orthogonal modes of reactivity when compared to traditional polar mechanisms. Persistent radicals, which by definition have higher kinetic barriers for reactivity, serve to increase the selectivity with which radical reactions occur through the persistent radical effect – a phenomenon that has recently begun to be leveraged for synthesis. The work described herein seeks to advance the field of radical chemistry in the context of employing persistent radicals for synthesis through synergistic combination of physical organic chemistry and chemical synthesis. In particular, these efforts target chemical synthesis of oligomers from the resveratrol class of natural products – an extensive and structurally diverse set of polyphenols to which a broad range of biological activities has been ascribed – with the goal of better understanding the mechanism(s) by which these compounds are biologically active. Chapter 1 summarizes the state of the field of radical chemistry in the context of natural product synthesis, concluding with a discussion of how persistent radicals have begun to be employed. The inspiration for the synthetic approach described in the subsequent chapters derives from the final example in which, during the course of a natural product total synthesis campaign, a key equilibrium between persistent phenoxyl radicals and their dimeric adducts was discovered and leveraged to access C8–C8′ resveratrol dimers and tetramers. Chapter 2 details how a mild, sustainable, and scalable approach for the generation of these persistent radicals was developed by relying upon electrochemical oxidation. This new method enabled the synthesis of a set of natural product analogs for initial structure-activity relationship (SAR) analysis of the compounds as radical trapping antioxidants (RTAs). Surprisingly, it was determined during the course of this study that the persistent radicals are more potent RTAs than any of the polyphenols evaluated, calling into question the exact cellular role these compounds fulfill in nature. Finally, Chapter 3 describes how thermodynamic study of the equilibrium between the persistent phenoxyl radicals and the corresponding C8–C8′ dimers resulted in the discovery of a C8–C8′ to C3–C8′ homolytic bond migration. This reaction was subsequently leveraged as the key step for the synthesis of the resveratrol tetramers vitisin A and vitisin D – two members of a subset of resveratrol oligomers to which perhaps the most interesting biological activity has been attributed. This chapter concludes with a discussion of where this project is headed in terms of the use of these persistent radicals for intermolecular C8–C10′ bond-forming reactions to access resveratrol trimers. In total, the strategy developed herein for resveratrol oligomer synthesis mimics the proposed manner in which Nature constructs these complex molecules, offering a direct route for the evaluation of their pharmacological potential.PhDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/155104/1/kevjrom_1.pd