具有大位阻基团新型手性伯胺催化剂的设计、应用及催化机理研究

The development and application of the new reagents and catalysts is one of the core contents in asymmetric synthesis. In this project, a bulky group was introduced by design into a diamine catalyst and a series of robust and tunable bulky chiral primary amine catalysts were developed, and could be applied in asymmtric transformations of new types of heterocyclic nucleophiles, such as oxazolone, 3(2H)-furanone, rhodanine, thiazolone, imidazolone and so on. High efficient and stereoseletive synthesis of chiral heterocyclic compounds, could provide chial building blocks for chiral drugs and lead compounds in drug discovery. Meanwhile, the approach could provide concise, efficient and flexible strategies for total synthesis of heterocyclic natural products，which has potential clinical significance. Through this project, a novel chiral primary amine organocatalyst with high efficiency and stereoselectivity is expected to be developed, and the steric effect of this catalyst on enantioselectivity and diastereoselectivity could be discovered, giving some new insight for catalysts design and application of the new reagents and reactions.

新试剂、新催化剂的发展及应用是不对称合成的核心研究内容之一。本项目将大位阻基团引入二胺催化剂结构中，自主设计并合成一类基于大位阻效应的稳定可调的手性伯胺类催化剂，并将其应用于噁唑酮、3（2H）-呋喃酮、罗丹宁、噻唑酮和咪唑酮等新型杂环类亲核试剂的不对称催化反应中。手性杂环化合物的高效高选择性合成，可为手性药物、药物发现中的先导物提供手性砌块，也为杂环类天然产物的全合成提供更简单多样化的合成策略。通过本项目的研究将有望开发出一类新颖、高效、高选择性的手性有机催化体系，揭示这类催化剂中大位阻效应在催化过程中的手性诱导规律，为手性伯胺催化剂的开发和反应的发展提供启示作用。

手性催化体系的催化效率和反应立体选择性是目前不对称催化领域最为关键的科学问题。本项目对新型手性伯胺催化剂进行精巧设计，通过精细的结构和构象分析研究，利用价廉易得的手性氨基酸原料，设计合成一类具有大位阻取代基团的新型伯胺催化剂(Figure 1)，实现了基于亚胺、二烯胺机理，及串联反应等策略一系列不对称催化反应。取得了一系列创新性的研究成果，共发表标注该项目资助的论文17篇，其中Nat. Comm. 1篇, Angew. Chem. Int. Ed. 3篇，Chem. Commun. 2篇，Org. Lett. 4 篇，Chem. Eur. J. 2篇，ACS Cata. 1篇，RSC Adv. 1篇，Org. Bio.Chem. 1 篇, Tetrahedron 1 篇, Tetrahedron Letters 1 篇。.同时在此项目的支持下，我们发现了一类可实现非对映选择性调控的催化剂及不对称反应，获得了另一个自然科学基金的资助（21572056，非对映发散的催化不对称共轭加成反应及机理研究），目前正在进行中。