Selective Functionalization of Aliphatic Amines - Supplement to Support Mariah Ramos

Columbia Univ New York Morningside, New York NY

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Abstract

Principal Investigator: Rovis, Tomislav Abstract Recent years have brought about a greatly enhanced understanding of structure-activity relationships (SARs) of biologically relevant compounds. Accordingly, there is a greater need for streamlined, complementary syntheses to access practical drug scaffolds. Current methods focus on editing the periphery of drug compounds to install versatile functional handles. Alternatively, altering the core of target molecules would provide access to diverse drug scaffolds while leaving peripheral handles untouched. Direct core editing would significantly decrease the design-synthesis-test time, as most drug core alterations require an entirely new synthesis. This proposal describes an efficient synthetic route to access 1,2-diazepines from readily available pyridines through dearomative ring expansion. Aim 1 outlines using previously established methods to obtain the pyridinium ylide intermediate on multi-gram scale, the diazepine can be obtained through a 6π electrocyclic ring opening upon irradiation with 370nm light. 1,2-Diazepines are among the least common nitrogen heterocycles present in FDA approved drugs, likely due to the lack of synthetic pathways that enable access to these scaffolds rather than their biological properties. While pyridine expansions are generally multistep procedures, our work has shown promise for a one-pot route to this expansion product. Additionally, Aims 2 and 3 propose novel, alternate methods of obtaining these valuable products. A one-pot catalytic nitrene transfer with simultaneous irradiation could afford the 1,2 diazepine and variants. Taken together, this proposal provides access to synthetically difficult drug cores, while also introducing synthetic handles for further derivatization. 5