Intramolecular Guanine C8-Amination for the Synthesis of Guanosine Cyclonucleosides

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Year 1: General skills training and lab rotationsYears 2-4: This work aims to deliver a proof of concept of an intramolecular guanine C8-amination reaction based on the established intermolecular platform to serve as a mechanistic probe as well as to gain access to previously synthetically intractable cyclonucleoside chemical space with potential biological interest. To this end, we propose two distinct and potentially complementary strategies to achieve cyclisation of the guanosine nucleoside.The most direct cyclising transformation would feature an intramolecular C8-amination reaction with a pendant amine functionality on the sugar motif. Not only would it challenge the reaction manifold geometrically (limiting accessible reaction pathways), kinetically (forging highly strained polycyclic structures), and electronically (containing the amine and nucleobase reaction partners in a single molecule), but it would set the stage for exploring this chemistry as a tool for constraining oligonucleotides around synthetic polyamine templates, in which one or more steps would be obligately intramolecular.