铜催化的不对称去对称化Ullmann类偶联反应研究

One of the most efficient methods for the formation of Carbon-Hetero atom bonds is the copper-catalyzed Ullmann-type coupling reactions, which have been extensively studied in the academia and widely applied in the industry. However, few studies are concerned with the construction of chiral centers using this reaction. Thus, it is remained as a significant challenge to achieve enantioselectivity using this reaction, although there is indeed one such example in the long history of Ullmann-type coupling reactions. Organocatalytic or transition metal-catalyzed asymmetric desymmetrization reactions have offered effective methods for the enantioselective synthesis of chiral molecules. In this proposal, we intend to achieve some important progress in the enantioselective Ullmann-type coupling reaction via an asymmetric desymmetrization strategy. We have successfully developed an intramolecular asymmetric Ullmann type of C-N coupling reaction via the desymmetrization strategy. The enantiomeric excess of the product is up to 85%, and is increased to above 95% after one crystallization. We have aslo found that the absolute configuration of the prodcut may be reversed after addition of certain types of achiral coordinating additives. Based on these results, we wish to further explore the asymmetric Ullmann-type coupling reactions through the desymmetrization process. The success of this project will significantly increase the scope of the Ullmann-type of coupling reactions and will promote its further application in organic synthesis and drug discovery.

铜催化的Ullmann类偶联反应是构建碳杂键最有效的方法之一，在学术界和工业界得到了广泛的应用。但光学选择性Ullmann类偶联反应仅有一例报道，是一个极具挑战性的新领域。过渡金属或者有机催化的不对称去对称化反应，为合成光学活性的各类化合物提供了新的方法，对推动有机及药物化学的发展具有重要意义。本项目希望通过不对称去对称化的方法，在发展光学选择性的Ullmann类偶联反应方面取得突破。我们前期的研究，通过铜/手性配体催化的分子内不对称去对称化Ullmann C-N偶联反应已经取得成功，产物的ee值最高达到85%，经过一次重结晶可以达到95%左右。同时我们发现非手性添加剂能有效的使反应产物构型发生翻转。本项目将在此基础上，进一步深入研究不对称去对称化Ullmann类偶联反应。本项目的成功将进一步推动Ullmann类偶联反应在有机合成以及药物研发领域的发展和应用。

铜催化的Ullmann类偶联反应是构建碳杂键最有效的方法之一，在学术界和工业界得到了广泛的应用。但光学选择性Ullmann类偶联反应仅有一例报道，是一个极具挑战性的新领域。过渡金属或者有机催化的不对称去对称化反应，为合成光学活性的各类化合物提供了新的方法，对推动有机及药物化学的发展具有重要意义。本项目通过不对称去对称化和动力学拆分的方法，在发展不对称Ullmann类偶联反应方面取得突破。在本项目支持下，相关研究在Angew.Chem.Int.Ed., Org. Lett., Synlett等期刊共发表研究论文十余篇，申请专利两项。本项目的成功将进一步推动Ullmann类偶联反应在有机合成以及药物研发领域的发展和应用。