基于烯丙基化反应构建手性杂环化合物

Heterocyclic compounds containing stereogenic centers usually have physiological activity, and are important subunits in pharmaceuticals and natural products. Asymmetric allylation reaction is a rising protocol used for environment-friendly and atom-economical preparation of new compounds in organic synthetic chemistry. However, efficient chiral ligands and catalysts are not yet rich and catalytic activity also remains to be improved at present. Even more, reported reaction routes for constructing chiral heterocyclic compounds and successful examples are very limited. Therefore, deep studies on construction of chiral heterocyclic compounds via asymmetric allylation reactions will be of important theoretical significance and extensive application value. In this project, chiral catalytic systems with characteristics will been developed in combination with the phosphane ligands invented previously by our group and other commercially available ligands. Several kinds of optically active heterocyclic compounds will been synthesized by means of elaborate substrates design and corresponding asymmetric allylic amination, etherification, dearomatization, stereodivergent allylic substitutions and allylic-allylic alkylations. The catalytic systems will been screened and further optimized. The substrate scope will been expanded in turn. Different structure-effect relationships will been investigated. Additionally, the reaction mechanism will also been explored. Successful implementation of the project will enrich our chiral phosphane ligand family with independent intellectual property rights and their applications. All of these studies will also provide theoretical support for the development of highly efficient chiral catalysts, new allylation reactions and novel strategies for green synthesis of chiral heterocyclic compounds.

手性杂环化合物通常具有重要的生理活性，也是一些药物和天然产物的重要结构单元。催化不对称烯丙基化反应是一种正在兴起的环保、原子经济性地构建新化合物的合成策略，但目前有效的手性配体和催化剂仍然较少，催化活性有待进一步提高，报道的用于构建手性杂环化合物的路径和成功实例更是非常有限，因此基于此反应构建手性杂环化合物的深入研究具有重要的理论意义和广泛的应用价值。本项目拟结合课题组开发的具有自主知识产权的膦配体和市售配体，发展具有特色的手性催化体系，通过底物的精心设计和相应的烯丙基胺化、醚化、去芳构化、立体多样性烯丙基取代反应、烯丙位-烯丙位烷基化反应等，高效构建几类新型手性杂环化合物。项目将优化催化体系，扩大底物适用范围，考察各种构效关系，深化对反应机理的认识。项目的成功实施，将丰富具有自主知识产权的膦配体体系及其应用，为发展高效手性催化剂、烯丙基化新反应和新型手性杂环绿色合成新策略提供理论支撑。

手性杂环化合物通常具有重要的生理活性，也是一些药物和天然产物的重要结构单元。催化不对称烯丙基化反应是一种正在兴起的环保、原子经济性地构建新化合物的合成策略，但目前有效的手性配体和催化剂仍然较少，催化活性有待进一步提高，报道的用于构建手性杂环化合物的路径和成功实例也比较有限，因此基于此反应构建手性杂环化合物的深入研究具有重要的理论意义和广泛的应用价值。本项目结合课题组开发的具有自主知识产权的手性桥连联苯基亚磷酰胺配体和市售配体，发展了具有特色的手性铱催化体系，发现在所研究的不对称催化反应中，使用手性桥连的联苯基亚磷酰胺配体所获催化结果优于使用经典的BINOL-衍生的亚磷酰胺对照物；通过底物的精心设计和相应的分子内烯丙基胺化、醚化反应等，高效构建了6类新型手性杂环化合物。项目优化了催化体系，考察了底物的适用范围及构效关系，深化了对反应机理的认识。项目的成功实施，丰富了具有自主知识产权的手性桥连亚磷酰胺配体体系及其应用，为发展高效手性催化剂、烯丙基化新反应和新型手性杂环绿色合成新策略提供了理论支撑，也为新型手性药物先导化合物的发掘提供了宝贵的资源。项目还对铱-亚磷酰胺催化的MBH乙酸酯与吲哚酮类化合物的烯丙基化反应进行了探索，发现铱催化的区域选择明显不同于钯催化的反应，直接、高效地合成了一类未见报道的具有新结构的3,3-二取代的吲哚酮类化合物。到目前为止，已在国内外学术刊物上发表论文4篇，申请专利2件，其中一件已获授权，还有部分专利申请和论文正在整理中。