Strategy-Guided Syntheses of Complex Natural Products

With the support of the Chemical Synthesis (SYN) Program in the Chemistry Division of NSF, Professor Christopher D. Vanderwal of the Department of Chemistry at UC Irvine (UCI) is developing innovative approaches for the assembly of structurally complex naturally occurring molecules. The underlying theme of the work is the strategic use of 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 chemical methods will be pushed to their limits by their use in very challenging contexts, and new strategies for rapidly building complicated molecular architectures are expected to be uncovered. The results of these studies will positively impact the many areas of applied science that benefit from chemical synthesis, including pharmaceutical development and materials science.

This grant will also permit outreach activities to middle school students from underserved communities to engage in scientific experiments on-campus, and simultaneously learn about the college experience. The Vanderwal group will further engage in the mentorship of local community college students and enable them to have their first laboratory research experiences.

The core of these research studies lie in the development of several strategies for the rapid assembly of the complex molecular architectures of several interesting natural products. First, the complex polycyclic alkaloid arcutinidine, which has been synthesized via lengthy sequences by other chemists, will be targeted via a concise and highly convergent design that seeks to unite two equally complex pieces via a short multiple-bond-forming sequence.

Second, the dihydro-beta-agarofurans—a group of over 500 stereochemically complex, highly oxygenated terpenoids with many interesting biological properties—will be assembled in an efficient manner starting from a highly oxidized B-ring, which itself will be accessed via novel applications of either stereoselective benzene reductions or asymmetric Diels–Alder chemistry. Finally, the potent and selective anti-pancreatic-tumor agent aleutianamine will be synthesized by a novel intramolecular cycloaddition reaction, which will also drive the development of new reactivity.

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, and the UC-SCC program that supports the internship of local community college students in chemistry labs at UCI.

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.