Intramolecular Guanine C8-Amination for the Synthesis of Guanosine Cyclonucleosides

第一年：一般技能培训和实验室轮换2-4年：这项工作的目的是提供一个概念的证明分子内鸟嘌呤C8-胺化反应的基础上建立的分子间平台，作为一个机械探针，以及获得以前合成难处理的环己基糖苷化学空间与潜在的生物学利益。为此，我们提出了两种不同的和潜在的互补策略，以实现环化的鸟苷nucleosides.The最直接的环化转化将具有分子内C8-胺化反应与糖基序上的悬垂胺功能。它不仅在几何学上（限制可及的反应途径）、动力学上（形成高度紧张的多环结构）和电子学上（在单个分子中包含胺和核碱基反应伴侣）挑战反应歧管，而且它将为探索这种化学作为将寡核苷酸限制在合成多胺模板周围的工具奠定基础，其中一个或多个步骤将是绝对分子内的。

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.