Dearomative Alkaloid Synthesis

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With the support of the Chemical Synthesis program (SYN) in the Division of Chemistry (CHE), Joel M. Smith of Florida State University (FSU) will study more efficient ways to prepare complex biologically active natural products. The structural complexity of the target molecules still poses a significant challenge for molecular construction. This provides an opportunity for inventing and implementing novel synthetic strategies and tactics to assemble these important molecular scaffolds. To this end, we will use feedstock starting materials as cheap and malleable building blocks to quickly build some of nature’s more challenging molecular architectures. The chemistry developed under this grant will not only benefit our scientific goals, but will provide a novel technological platform for other practitioners to exploit when building important nitrogenous molecules. Additionally, the impact of chemistry will be emphasized both in the curriculum at FSU and in the broader Tallahassee area. A new course will be made available to both graduates and undergraduates that will incorporate talks from practitioners in the chemical and pharmaceutical industries. Furthermore, laboratory demonstrations and activities for primary and secondary students will highlight the role chemistry has on everyday life (e.g. indigo in denim clothing). These research and educational endeavors aim to inspire both interest in the art of molecular construction and provide a foundational platform for the promotion of science in young students. The piperidine ring is the most prevalent heterocycle in marketed pharmaceutical ingredients and is a common substructure in many biologically active alkaloids. Joel Smith and his FSU team are interested in the controlled synthesis of a variety of complex fused piperidines from pyridines, their aromatic congeners. The controlled functionalization of pyridines is endowed with as many advantages for redox economy as much as it is fraught with challenges with imbuing precise regiochemical and stereochemical outcomes. The Smith Lab has developed a malleable dearomatization reactivity platform with which to access various alkaloids including those from the aspidosperma, tangutorine, strychnos, and manzamine families. Many of these synthetic targets have never been accessed previously. Having a unified approach to this level of molecular diversity is distinguishing feature of this approach. Surmounting these synthetic challenges will provide for new avenues in chemical reactivity, and advance the area of pyridinium-system-based strategic approaches to architecturally novel and complex natural product scaffolds. If successful, the proposed regio- and stereocontrolled entries into these alkaloid natural products will permit the further study of their biological activity and allow for the inclusion of a collection of interesting fragments in diversity-oriented synthesis (DOS) endeavors in the community.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.