Exploring N-Alkynylazole Cyclizations in Synthesis

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With this Award, the Chemical Synthesis Program of the NSF Division of Chemistry is supporting the research of Professor Sean Kerwin of Texas State University. Dr. Kerwin works with undergraduate and graduate students and postdocs to streamline the process of preparing complex chemical compounds. Compounds with nitrogen-containing ring systems are very common in nature and often possess interesting biological activity. In this research, specific examples of these compounds are targeted for synthesis, and the prepared compounds will be made available to address important biological questions. The scientific approach employed for these syntheses focuses on the utilization of simpler starting materials to prepare structurally complex, biologically active natural products. The educational activities undertaken prepare students for careers in STEM through training in an interdisciplinary team employing laboratory automation. Outreach activities include the design and preparation of 3D printed materials to highlight the historical, structural, and medicinal impacts of chemistry for students and the broader public.The efficient synthesis of complex heterocyclic natural products and related biologically-interesting compounds has broad potential impact on pharmaceuticals, agrochemicals, materials, and other areas. Retrosynthetic analyses of heterocyclic compounds reveal simplifying disconnections leading to N-alkynylazole intermediates, in which an acetylene group is bonded to the nitrogen atom of a five-membered heteroaromatic ring. Professor Kerwin is developing cyclization reactions to enable these simplifying disconnections as well as other methods to access the requisite N-alkynylazoles. Multiple cyclization strategies are being pursued in the synthesis of analogs of pentostatin, morodin, and lycoposerrine natural products, including 5-endo-dig cyclization of homopropargylic systems, indolization of N-alknynylazoles, and thermal rearrangements of 1,x-dialkynylazoles. In addition to providing access to the targeted compounds as tools for biological research, the broader impact of this work derives from its wide potential applicability to diverse synthetic targets. Other broader impacts include the recruitment of underrepresented students to science, technology, engineering and mathematics (STEM) careers through research training experiences. These training experiences include the use of laboratory automation systems and the implementation of outreach activities for students and the public focused on the impact of natural products on society.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.