Strategies for the Concise Syntheses of Complex Natural Products

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In this project funded by the Chemical Synthesis Program of the Chemistry Division, Professor Vanderwal of the Department of Chemistry at UC Irvine develop innovative designs for the assembly of structurally complex naturally occurring structures. The underlying theme of the work is the strategic use of inexpensive and readily available molecular building blocks to arrive at the complex architectures of the targeted natural products in as few chemical operations as possible. In so doing, existing synthetic methods are pushed to their limits by their use in very challenging contexts, and novel chemical reactivity is uncovered and utilized. The results of these studies positively impact any area of applied science that benefits from chemical synthesis, including pharmaceutical development, materials science, and more. This grant also supports outreach activities to middle school students from underserved communities to engage in scientific experiments on-campus, and simultaneously learn about the college experience. The intellectual merit of this proposal is the development of several strategies for the rapid buildup of the molecular architectures of four different types of complex natural products. The Himbert intramolecular arene/allene cycloaddition reaction and the resulting strain-driven rearrangement of the cycloadducts, transformations that have both previously been carefully investigated in these laboratories, are being leveraged in a concise synthesis of a small family of alkaloids. A combination of an arene-terminated cation-pi cyclization, a bioinspired A-ring cleavage, and a cycloaddition of a novel cumulene equivalent Diels-Alder dienophile set the stage for a rapid synthesis of a complex diterpenoid. An underutilized heterocycle annulation is leveraged to synthesize a structurally unique antibiotic alkaloid. Finally, either a concise and unusual but potentially biogenetically relevant route or a more conventional approach facilitate the first synthesis in an unusual family of complex alkaloids. The broader impacts of this work include the exceptional research training for undergraduate and graduate students. This grant also supports the UCI-LEAPS program that brings in local middle school students for day-long experiences in university chemistry and physics laboratories.