Intramolecular Guanine C8-Amination for the Synthesis of Guanosine Cyclonucleosides

第1年：一般技能培训和实验室轮换第2-4年：这项工作旨在以已建立的分子间平台为基础，提供分子内鸟嘌呤C8胺化反应的概念证明，作为机械探测器，并获得以前难以合成的具有潜在生物学意义的环核苷化学空间。为此，我们提出了两种截然不同且具有潜在互补性的策略来实现鸟苷核苷的环化。最直接的环化转化将以分子内C8-胺化反应为特征，并在糖基序上具有侧胺功能。它不仅在几何上(限制可进入的反应路径)、动力学上(锻造高度应变的多环结构)和电子上(在单个分子中包含胺和碱基反应伙伴)挑战反应多种多样，而且它将为探索这一化学作为一种工具来约束合成多胺模板周围的寡核苷酸奠定基础，其中一个或多个步骤必须是分子内的。

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.