叠氮和炔基1,3-偶极环加成反应及其偶联应用的研究

Click chemistry is a chemical strategy introduced by Nobel Laureate K. Barry Sharpless to describe chemistry tailored to generate substances quickly and reliably by joining small units together. The reactions in click chemistry have many advantages: modular, selective, wide in scope and easy to perform. The concept became one of the most noticeable synthetic trends in recent years, and publications citing click chemistry has seen explosive growth with widespread applications, especially in life sciences and materials science.. The copper catalyzed azide-alkyne cycloaddition (CuAAC) reaction has become emblematic reaction of the click chemistry. This reaction has wide applications as selective and efficient conjugation methods, but it also has limitations. The high concentration of copper catalyst is cellular toxic, which precludes applications wherein cells must remain viable. In materials science, the remained tiny copper salt always has unfavorable influence to the properties of materials. Thus, it is essential to improve and explore more click chemistry reactions as efficient and reliable conjugation methods, and apply them to solve some difficulties in different applications.. This project plan to develop more efficient, reliable and compatible azide-alkyne 1,3-dipole cycloadditions for better conjugation methods, and investigate their applications in the field of glycoconjugated biomolecule labellings and nanoparticle modifications. The methods of exploring more efficient 1,3-dipole cycloadditions include: (1) to develop copper catalyzed azide-alkyne cycloadditions　(CuAAC) by investigating new copper catalysts, new ligands, and new fluorogenic click reagents; (2) to develop catalyst-free strain-promoted azide-alkyne cycloadditions (SPAAC) by investigating new cyclooctyne derivatives.. This project will explore new click chemistry reactions as powerful and efficient chemical tools, and apply these conjugation tools in life sciences and materials science. The research results will be important for future applications in different fields.

点击化学作为一类新型的偶联方法，是当前研究的前沿和热点，已经在有机合成、生物学和功能材料等领域有着十分广泛的应用。但是由于原有点击化学反应的缺点和实际应用中的更高要求，目前仍然需要开发更高效和更安全的点击化学偶联方法，并用其解决实际应用中的问题。本项目拟重点研究叠氮和炔基1,3-偶极环加成反应，将其发展为反应速率高、对生物和材料相容性优异的点击化学偶联反应，并探索其在糖生物分子标记和纳米颗粒材料修饰领域的应用。对于发展高效偶联反应，其主要内容包括：（1）开发铜催化叠氮-端炔环加成反应，合成并研究全新的铜催化剂、铜配位体和荧光开启偶联试剂；（2）开发无催化剂环张力促进叠氮-炔基环加成反应，合成并研究新型环辛炔类化合物。本项目着重研究点击化学偶联反应的新特点和新策略，将其发展为高效和多能的偶联化学工具，并研究其在生物和材料领域中的应用，为进一步理解和应用点击化学提供一定的理论指导和实验依据。

本项目的主要研究内容：发展以点击化学为代表的高效、高选择性偶联反应，并应用于生物有机合成、生物医学和功能材料等领域。..本项目有关研究内容的重要结果有：.1.发展新的高效、高选择性偶联反应.（1）首次将Mo(W)/S/Cu系列的原子簇合物作为催化剂应用于铜催化叠氮-端炔环加成反应（CuAAC）；.（2）研究比较了各种氧酯、硫酯和硒酯等活泼酯的胺解偶联反应的反应速率，开发新的高效生物偶联反应；.（3）开发了一种新型可见光催化的高效、高选择性脱硫反应。通过自然连接化学法合成多肽和蛋白质需要巯基作为辅助基团参与偶联反应，该反应用于在后期要将辅助巯基选择性去掉。.2.新型偶联反应的应用.（1）将原子簇合物作为催化剂的点击反应用于生物分子和高分子的偶联修饰；.（2）利用活泼酯偶联反应和收敛法策略高效合成均一结构的N-连接糖肽；.（3）利用自然连接化学法和开发的光化学脱硫反应合成糖肽和环肽；.（4）利用活泼酯偶联反应高效修饰蛋白质，以及全合成抗肿瘤糖疫苗。..科学意义：发展和开发了新的高效、高选择性偶联反应的化学工具，并将其用于有机合成和生物医学等领域，合成得到了具有重要功能的分子和材料，为其它相关研究提供了化学工具和应用实例。