CAREER: Synthetic Strategy for Polycyclic Meroterpenoids and Sulfur-Containing Macrolatam Natural Products.

With the support of the Chemical Synthesis Program in the Chemistry Section, Dr. Martin Tomanik of New York University is developing new approaches to build complex natural products, or secondary metabolites made by plants, fungi, and microorganisms. Such small molecules provide the basis for many important medicines, agrochemicals, and materials, but many of these compounds are difficult to prepare or modify using existing chemical techniques. As a result, the potential utility of many natural products is hindered by inefficient and laborious synthetic routes. A central tenet of this work is to implement modern chemical methods that have found limited application in the synthesis of complex molecules as key strategic elements. The resulting approaches developed for natural products in this program serve as a platform to identify new bond construction tactics and expand our understanding of reactivity in complex settings. The researchers involved in this program receive rigorous synthetic training, preparing them to drive innovation across a range of chemical industries. The project also provides educational benefits by introducing high school students in the New York City area to chemistry research through outreach programs, designing lessons that integrate modern chemical methods into teaching laboratories, and supporting undergraduate success in organic chemistry through peer-to-peer learning environments. The award will support research on the development of modular synthetic platforms for the total synthesis of two architecturally complex natural products, including the talaromyolide meroterpenoids and sulfur-containing macrolactams. One major objective is the synthesis and structural reassignment of talaromyolide D and related family members using C–H functionalization and stereoretentive electrochemical sp2–sp3 cross-coupling transformations. These studies will confirm the correct molecular structure, provide access to previously unavailable congeners, and evaluate the generality of the key complexity-generating reactions across diverse terpenoid scaffolds. A second objective focuses on the synthesis of macrocyclic sulfur-containing natural products and fully synthetic analogs bearing redox-active sulfur motifs, enabling studies of their chemical activation and reactivity in complex molecular settings. Collectively, the project will establish broadly useful strategies for constructing and modifying complex molecular architectures and improve access to natural products that are otherwise difficult to obtain. 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.