Novel Methods for the Synthesis of Nitrogen Heterocycles

With the support of the Chemical Synthesis Program in the Division of Chemistry, Joshua G. Pierce of North Carolina State University at Raleigh is studying new methods for the preparation of an important class of natural product scaffolds featuring nitrogen heterocycles. Specifically, the targets of interest contain five-membered nitrogen-containing rings and the varied range of methods being developed to access them all share a common theme of constructing the ring by adding a two-atom component to a three-atom component.

Beyond the fundamental advances to the field of organic synthesis that the research promises, it will also provide new ways to access complex molecules of value to medicine, agriculture, and materials science. The broader impacts of the funded project will extend to the benefits accrued to society as the Pierce research team engages in various public outreach activities, including events for adults at the Natural Sciences Museum in Raleigh, NC, and for children at a local elementary school.

These activities, in addition to immersive laboratory experiences that will be offered via the agency of Project SEED, will promote STEM (science, technology, engineering and mathematics) education in the community while also helping to broaden the participation of individuals from underrepresented groups in science.

This research project aims to leverage formal [3+2]-cycloaddition logic to prepare densely functionalized heterocyclic scaffolds in a stereoselective fashion and to expand the substrate scope and mechanistic understanding of processes conforming to this paradigm. Three areas of focus are under investigation: (1) an allene (or alkene) / 1,3-dipolar cycloaddition with novel dipoles to construct spirocyclic pyrrolidines and/or lactams; (2) a photoredox-enabled synthesis of 3-azabicyclo[3.2.1]octane derivatives; and, (3) enantioselective approaches to pyrrol-2-one scaffolds via a three component, formal [3+2]-cycloaddition process and their subsequent conversion to value added products.

The subprojects being pursued are united by a retrosynthetic disconnection that envisions the relevant heterocyclic target emerging from a three- and a two-atom synthon and each is enabled by a unique reactivity strategy. All three of the approaches being pursued are designed to overcome an existing limitation in the synthesis of azacycles and it is anticipated that this work with lead to an improved understanding of fundamental reactivity and to findings that are more broadly applicable to the elaboration of other types of heterocycles.

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.