基于自由基型环醚碳氢(Cα)芳基化策略的芳基碳糖苷合成研究

Aryl C-glycosides with a broad spectrum of bioactivities and favorable metabolic stability and drugability have received considerable interest in medicinal chemistry and chemical biology. However, the lack of efficient synthetic methods facilely accessing aryl C-glycoside structures is the bottleneck of this field. The direct coupling of sugar with aryl/heteroaryl structures represents the most straightforward approach to construct this class of molecular architectures. However, the available methods generally employ hydroxyl-protected sugars as coupling partners and suffer from non-easily accessible staring materials, harsh reaction conditions, limited substrate scope, and poor stereocontrol. Furthermore, the extra protection and deprotection steps dramatically reduce the reaction efficiency. In this research program, we propose to develop efficient and practical synthetic technologies for the synthesis of diverse aryl C-glycoside structures by exploring Cα-arylation reaction of sugar based cyclic ethers, especially those without any hydroxyl-protecting groups. To achieve the formidably challenging goals, we plan to develop innovative strategies by exploring new more efficient hydrogen atom transfer (HAT) technology, as well as new visible light/Ni dual catalytic reaction system. These strategies are distinct from establishes catalytic systems. These newly developed methodologies will streamline the synthesis of aryl C-glycosides and its application in drug discovery. Therefore, we believe the proposed research is highly innovative and has broad impact on this important and exciting field.

广谱的生物活性和优良的代谢稳定性使芳基碳糖苷类分子在药物化学和化学生物学上得到了广泛的应用。但是缺乏简洁高效的合成方法成为制约相关新药研发和化学生物学研究的瓶颈。通过糖基和芳环的直接偶联形成碳糖苷键，是合成芳基碳糖苷最为简洁有效的方式。然而目前已报道的相关合成方法，普遍使用羟基保护糖为原料，存在反应原料制备困难，反应条件苛刻，底物范围窄，反应选择性差等缺点。额外的保护和脱保护反应，客观上增加了合成步骤，降低了反应效率。本研究以实验室前期报道的自由基型环醚碳氢(Cα)芳基化反应为基础，通过发展氢原子转移新技术，融合可见光/金属镍协同催化新体系，致力于开发绿色，温和，高选择性的碳糖苷键构建新技术。该技术将有助于实现羟基无保护糖类环醚与芳环的有效偶联和结构多样性芳基碳糖苷的高效合成。本项目将为芳基碳糖苷类分子合成提供新颖实用的新手段，从而加快相关新药的研发进程。

本研究围绕创新氢原子转移等异头位自由基生成方式，发展可见光催化的芳(杂)基碳糖苷合成新方法这一研究目标，开展了两部分研究：1、以三价碘(PIFA)为氧化剂，乙醇为添加剂，发展了一类可见光促进的环醚与芳杂环的交叉去氢偶联反应，实现了绿色温和条件下芳杂基碳糖苷的有效合成，并初步阐明了烷氧自由基介导氢原子转移的独特机制，实现了核心技术的有效拓展。2、以易于制备、性质稳定的异头酸为原料，利用可见光/镍协同催化的偶联反应，实现了一系列芳(杂)基碳糖苷的高效高选择性合成，并将该技术拓展至炔基碳糖苷的合成和烟酰胺碳核苷类似物快速构建中。相关研究成果共发表SCI论文13篇；申请中国专利6项，PCT专利1项，其中1项授权，3项公开；共培养博士研究生2人，硕士研究生7人。受益于该面上项目的资助，申请人得以持续推动自由基化学驱动的新药创制这一特色研究，为进一步开展更为原创和前沿的研究奠定了基础。