钯/手性胺共催化环酮不对称芳基化反应研究

Transition-metal-catalyzed cross-coupling of α-C-H bonds of ketones with aryl halides represents one of the most important approaches for ketone α-arylation reaction. Therefore, the development of catalytic asymmetric reactions toward ketone α-arylation has been a topic of focus in asymmetric catalysis. So far, a few examples have appeared with excellent results by utilizing palladium- or nickel-based chiral complexes as catalysts. However, chiral ligands involved in the reactions are normally expensive and unavailable; the strong base employed in these transformations makes the generated tertiary stereocenters racemized and might result in side reactions, such as bis-arylation and aldol addition of ketones. To address these issues, a new strategy based on palladium/chiral amine cooperative catalysis is proposed in this project for the enantioselective α-arylation of cyclic ketones. Ketone is activated by chiral amine catalyst via enamine intermediate formation and aryl halide is activated by achiral palladium complex. On the basis of desymmetrization, kinetic resolution, and dynamic kinetic resolution approaches, the enantioselective Heck arylation of enamine intermediate leads to a series of α-arylated cyclic ketones bearing bridged-ring, spiro carbon center, or benzofused ring systems that contain tertiary or quaternary carbon centers. Further, the enantioselective γ-arylation of cyclic ketones will be studied through the reaction of dienamine intermediates. Detailed study in the project will gain insight on the mechanism of palladium/chiral amine cooperative catalysis and understand the role of chiral amines for enantiocontrol in the arylation reactions. The success will be a good contribution to enantioselective arylation of carbonyl compounds and helps to extend further application of this cooperatvie catalysis to this field.

卤代芳烃与羰基α-碳氢键交叉偶联是酮类化合物α-芳基化反应的重要方法，其催化不对称反应研究是有机化学的热点。在手性配体控制下可实现过渡金属催化的对映选择性反应，但手性配体通常昂贵不易得，且反应所需的强碱条件易引起副反应、造成叔碳手性中心外消旋化，使其构建成为挑战。针对这些现状，项目利用钯/手性胺共催化新策略，在催化剂活化卤代芳烃及酮羰基的基础上，利用去对称化、动力学拆分及动态动力学拆分等手段，基于手性烯胺中间体的Heck反应，实现环状酮类化合物的不对称α-芳基化反应，发展合成含环酮结构的手性桥环、螺环及并环骨架结构的新反应和新方法，并构建羰基α-芳基叔碳、季碳手性中心。进一步基于手性二烯胺中间体实现环己酮不对称γ-芳基化反应。项目将深化对钯络合物及手性胺协同催化作用机制的理解，揭示手性胺分子在芳基化反应中的手性诱导和对映选择性控制规律，在此基础上推动共催化策略在芳基化反应中的应用。

α-芳基取代环酮骨架普遍存在于医药、农药分子中，发展α-芳基取代手性环酮化合物的高效不对称合成方法是有机化学的热点之一，具有重要的研究价值和科学意义。过渡金属催化的卤代芳烃与羰基α-碳氢键的不对称交叉偶联反应是酮类化合物α-芳基化反应的重要方法，但手性配体通常昂贵不易得，且强碱条件易引起副反应、造成叔碳手性中心外消旋化，使其构建成为挑战。针对这些现状，项目基于原位生成烯胺发展Heck反应的思路，利用钯/手性胺共催化新策略，通过手性胺与环酮现场缩合形成烯胺中间体，在钯催化下与芳基卤代烃发生不对称偶联反应，实现羰基α-位不对称芳基化反应，合成手性环酮衍生物并建立叔碳手性中心。项目围绕环酮不对称 α-、γ-芳基化反应研究目标，通过手性烯胺或二烯胺中间体的不对称芳基化反应，利用去对称化、动力学及动态动力学拆分等手段，探索和研究了对称性环酮的去对称化不对称芳基化反应、3-取代环酮的分子内动力学拆分不对称芳基化反应、以及N-邻卤芳基侧链取代吲哚并环己酮的分子内不对称γ-芳基化反应，合成一系列手性桥环、螺环及并环化合物。此外，项目还研究并实现了稳定多取代烯胺的分子内不对称芳基化反应，在手性钯或铜催化下高对映选择性地合成一系列手性吲哚、假吲哚类化合物。项目探索和理解了钯/手性胺协同催化作用机制及其在芳基化反应中的应用范畴、手性诱导控制规律。在项目资助下，还开展了具有烯胺结构单元的吲哚、吡咯芳香体系的不对称去芳构化Heck类型反应，并进一步拓展至其他五元芳杂环、萘环及缺电性六元含氮芳杂环体系。项目执行期间，在国内外期刊上发表标注基金的 SCI论文 19篇，其中J. Am. Chem. Soc. 2篇、Angew. Chem. Int. Ed. 1篇、Nat. Commun. 1篇、ACS Catal. 2篇、Chem. Sci. 1篇等，并毕业18名硕博研究生。