Reaction Design for the Synthesis of Neuroactive Agents

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DESCRIPTION (provided by applicant): This proposal is guided by an overarching interest in the chemistry of nitrogen-containing compounds that display selective activity as neurochemicals. The guanidinum toxins, tetrodotoxin and saxitoxin, represent two such targets, each having a unique molecular architecture and remarkable potency to block ion passage through voltage-gated Na+ channels. Accordingly, both compounds have been invaluable tools in neurophysiology and ion channel research. Efforts to interrogate the structure and mechanism of these large (260-280 kDa) and complex transmembrane channel proteins would be advanced greatly with access to labeled and analogue structures of the natural products. Synthesis of either toxin, or variants thereof, is made particularly challenging, however, because of the elaborate and dense positioning of functional groups within these molecules. Thus, new chemical strategies have been devised to help reduce the difficulties associated with synthesizing structures of this type. Methodology for the selective conversion of saturated C-H bonds to carbinolamine centers through metal-catalyzed C-H insertion underlies our approach. The prevalence of amine functional groups in natural products and pharmaceuticals makes this chemistry broadly applicable to problems encountered in both academic and industrial research. The amination reaction can be performed with any number of starting materials possessing secondary, tertiary, allylic, benzylic C-H bonds, and may be used to construct 1,2-amino alcohols or 1,3-difunctionalized amine derivatives from simple alcohol precursors. In addition, the process is stereospecific, thereby enabling the assembly of enantiopure tetrasubstituted amine groups from substrates possessing optically defined tertiary centers. Insertion products can be manipulated through selective nucleophilic addition reactions to myriad amine derivatives. For our purposes, these types of reactions will expedite the preparation of tetrodotoxin and saxitoxin as well as select toxin analogues. Such compounds will be used to examine the molecular workings of the Na+ channel with a focus on understanding the ion selectivity region of the channel pore. Collectively, these studies are stimulated by the essential role of ion channel proteins for electrical signaling in cells and their widely recognized importance as targets for treating central nervous system-related disorders.