新型P-手性氮膦配体的设计合成及其在手性炔丙胺制备中的应用

P,N-lignads were widely applied in a broad range of transition metal-catalyzed enantioselective transformations. The development of chiral P,N-ligands with novel structural motif and high efficiency is of great interest to synthetic chemists. This project will focus on the design of new P-chiral ligand, which provide highly tunable chiral environment. Such ligands containing [2.2.1] bicyclic P-chiral framework and biaryl backbone could be easily prepared from readily available L-hydroxyproline. Modification of its electronic and steric properties can be accomplished by simple variations of the protecting group and substituents on the phenyl ring. The chiral environment could also be further modified by the introduction of other chiral elements. We believe the application of these ligands will solve the problem of low reactivity and limited substrate scope in asymmetric A3-coupling reactions. Under the optimal conditions, optically active propargylamines would be achieved in excellent yields and ee values. Manipulations of the product would offer new opportunities to the enantioselevtive synthesis of (S)-(+)-coniine and Conessine. Based on the X-ray structure of the optimal ligand and DFT calculations, we will propose a stereochemical model to explain relationship between the structure of the catalyst and the result of the reaction. These investigations will provide a green and practical methodology for the efficient synthesis of drug-like structure and nature products. The high tunability of these P-chiral ligands holds promise to be applicable to a variety of asymmetric catalytic reactions. Moreover, research in this project will promote the development of enantioselective synthesis.

氮膦配体广泛应用于过渡金属催化的不对称反应，发展新型、高效的手性氮膦配体一直是有机合成化学研究的热点和难点。本项目将针对A3偶联反应活性低、底物适应性差等问题，设计合成可调节性强的P-手性氮膦配体。我们从廉价易得的氨基酸出发，合成P-手性桥环[2.2.1]骨架，同时构筑联芳基结构。通过对配体取代基、保护基的改变和其他手性元素的引入，调节催化剂的电子效应、立体效应和空间效应，提高催化剂的活性和选择性，解决A3偶联反应的底物适应性差等问题。高效、高选择性合成一系列手性炔丙胺化合物，并将其应用于毒芹碱和天然产物Conessine的不对称合成中。结合单晶衍射和理论计算，研究反应机理，提出可能的催化模型，揭示催化剂和反应结果之间的构效关系。这一研究将为复杂天然产物和药物的高效合成提供实用、绿色的催化反应方法学。这一可调节性强的P-手性配体有望适用于多种不对称催化反应，并推动手性合成领域的发展。

有机膦试剂在有机化学研究中十分重要，其介导的脱氧取代反应，广泛应用于羧酸和醇类化合物的转化。通过可见光催化的单电子氧化反应，可以实现三价膦的极性反转。本项目基于膦的连续单电子氧化过程，发展了一种活化羧酸，直接形成季鏻盐中间体的催化方法。高效制备了一系列结构多样、多官能化的酰胺类化合物。结合流动化学、固相合成等方法，为多肽的规模化制备提供了新的方法和思路。利用三苯基膦阳离子自由基促进了羟胺的脱氧反应，为酰胺、亚胺自由基的产生提供了一种温和高效的方法，应用于氮杂叶立德和吡咯啉类化合物的合成。以氮杂环卡宾为催化剂，实现了烯烃的非对映选择性氨酰化反应。该催化模式通过基态单电子转移，产生两个自由基中间体，然后发生非对映选择性的交叉偶联，从而生成吡咯及恶唑烷酮等重要杂环化合物。通过一系列电化学研究，证明了Breslow中间体的还原能力，从热力学上阐明了这一基态单电子转移过程的可行性。详细的理论计算表明自由基之间的交叉偶联是反应过程中的决速步骤，并解释了反应的非对映选择性是通过自由基中间体的π-π相互作用控制的。项目执行期间共发表论文3篇，申请中国发明专利1件。