Complexity-Driven Total Synthesis

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With the support of the Chemical Synthesis (SYN) program in the Chemistry Division of NSF, David Sarlah of the Department of Chemistry at the University of Illinois at Urbana-Champaign (UIUC) is studying innovative strategies for the construction of complex, naturally occurring molecules. The salient feature of the work is the identification of novel disconnections that lead to rapid and controlled preparation of desired molecular structures in as few chemical steps as possible. In pursuit of this goal, several underexplored chemical processes are being evaluated and developed into general methods to improve the ability to efficiently synthesize compounds with varying levels of structural complexity. The results of these studies will have a positive impact across many different fields of applied molecular sciences, including agrochemicals, pharmaceuticals, and materials science. Moreover, the project is conceptually interesting and has many potential applications, making it well suited for the education of scientists at all levels. This grant will also enable wide-ranging science, technology, engineering, and mathematics (STEM)-focused outreach activities. The broader impacts of this work include the research training of undergraduate and graduate students at the forefront of synthesis. Moreover, the Sarlah group has been leading an outreach program, Science in Action (SIA), that provides crucial hands-on science education in the greater Champaign, IL area. Through the SIA program, several research groups in the department, in collaboration with local teachers, are bringing science experiences to children and younger students.The intellectual merit of this proposal is the development of several strategies for the rapid and controlled construction of different types of complex natural products. By exploring transition metal-catalyzed cyclizations and cycloisomerizations, a range of terpenoid-based structures the Sarlah group is working to streamline access to these natural product core structures and do so in a highly stereodivergent manner. These intermediates will serve as late-stage templates for final elaboration to a diverse set of natural products, ranging from triterpenoids, merosesquiterpenes, and indolosesquiterpenes, many of which have notable biological properties. As part of these studies, the team is working to leverage an underutilized nickel-catalyzed annulation to access a structurally unique class of norcembranoids. Utilizing a convergent strategy, the cycloadduct can be rapidly converted towards structurally distinct scabrolides or ineleganolide. Finally, a series of strategies involving challenging macrocyclizations, sp3-sp2 etherifications, and stereoselective C-C bond constructions is planned to drive the development of noncanonical amino acid synthesis, as exemplified with the potent antibiotic darobactin.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.