Transition Metal-Catalyzed Reaction Development Toward the Synthesis of Alkaloids

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With the support of the Chemical Synthesis Program in the Division of Chemistry, Professor Brian Stoltz of the California Institute of Technology is studying new methods designed to facilitate the preparation of marine-derived chemical substances with anticancer properties. The methods of interest leverage the reactivity of transition metal catalysts to enable rapid construction of the challenging molecular frameworks found within the targeted products and related bioactive substances. It is anticipated that the developed synthetic tools will improve access to a range of molecules that could serve as a platform for the discovery of novel therapeutics against a variety of cancer types. The broader impacts of the funded project extend to the benefits accrued to society as Professor Stoltz and his team engage in an extensive assortment of educational and outreach activities intended to promote interest in STEM (science, technology, engineering and mathematics) among K-12 students and to widen participation in scientific disciplines by students belonging to groups that have been historically underrepresented. The award will also help to support the ongoing efforts of Professor Stoltz to improve upon the diversity, equity, and inclusion landscape of the Division of Chemistry and Chemical Engineering at Caltech.Pyrroloiminoquinone natural products have been of longstanding interest to organic chemists because of their structural complexity, which provides a driving force for the development of synthetic methods and strategies, and also due to the broad range of biological activities associated with this alkaloid class. Notwithstanding the recognized value of pyrroloiminoquinone alkaloids, a sufficiently rapid and general approach to these polycyclic molecules that may enable analogue development and the synthesis of new congeners is as yet unrealized. The funded project focuses on the development of two palladium-catalyzed methods that are designed to address this deficiency while also improving access to other important target molecules, namely: (1) a Larock/Buchwald–Hartwig cascade process that facilitates biannulations and rapid increases in structural complexity from simple precursors, and (2) a transition metal-catalyzed spirocyclization reaction. The total synthesis of representative pyrroloiminoquinones, including makaluvamines A and F and sanguinone B, as well as other indole alkaloids, such as indolactam V, will be pursued to demonstrate the utility of the developed methods and to evaluate their scope. In addition, the second method will be studied more generally for the synthesis of novel heteroatom-containing spirocycles and enantioselective variants of this technology will be investigated. It is anticipated that the funded project will lead to fundamental advances in the practice of transition metal-based organic synthesis while improving access to a class of alkaloids that are a potentially rich source of lead compounds for the development of new clinical candidates. Finally, it is noted that the research supported by the award provides valuable training opportunities for graduate students to enable their pursuit of future careers in the chemical sciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.