A Unified Approach to Resveratrol-Derived Natural Products: Harnessing the Reactivity of Persistent Radical and Quinone Methide Intermediates for Complex Molecule Synthesis.

Abstract

Numerous reports of therapeutically relevant biological activities of resveratrol (3,4ʹ,5-trihydroxy-trans-stilbene) and oligomers derived therefrom have stimulated widespread interest in these natural products. In spite of this, their chemical synthesis has only recently been targeted. This is largely a symptom of the historically enigmatic mechanisms of action of polyphenols, which has precluded their clinical development. If the therapeutic potential of polyphenolic natural products such as the resveratrol oligomers is to be realized, synthetic advances must be made in order to confirm/refute the biological activities ascribed to oligomers obtained from isolates, to determine which scaffolds hold promise as small molecule chemopreventives and/or chemotherapeutics, and to enable structural modification for both structure-activity relationship (SAR) studies and the development of more potent congeners. The work described herein seeks to address the above issues through collaborative research, combining novel methods for chemical synthesis, physical chemistry and chemical biology in an effort to elucidate the mechanism(s) of biological activity of resveratrol and its derivatives and shed light on potential of plant-derived antioxidants in pathophysiology wherein oxidative stress has been implicated. Chapter 1 summarizes the biosynthesis and biological activities of resveratrol derived natural products in order to contextualize our biomimetic synthetic strategy and provide justification for our research objectives. Chapter 2 describes the development of a highly efficient and scalable oxidative dimerization of tert-butylated resveratrol derivatives, which for the first time has rendered biomimetic synthesis a viable approach for the controlled preparation of useful quantities of resveratrol oligomers. This method was showcased in the synthesis of dimeric natural products pallidol (6 steps/26% yield) and quadrangularin A (5 steps/54% yield), each representing the most efficient synthesis (either biomimetic or de novo) to date. Recently, the concise biomimetic total synthesis of resveratrol tetramers nepalensinol B, vateriaphenol C, and hopeaphenol was accomplished, representing just the second reported total synthesis of tetrameric resveratrol oligomers, and the first to these specific targets. The details of these efforts are provided in Chapter 3. The final chapter delineates our preliminary and ongoing efforts toward the application of this biomimetic strategy to the synthesis of resveratrol trimers.