基团添加法导向的动力学拆分制备手性叔醇和α-取代酮

Chiral tertiary alcohols, α-alkyl ketones, and 1,3-diketones with quaternary carbon centers are important building blocks, and have been widely used in the synthesis of drug molecules and natural products. However, owing to the limitation of enantiodiscrimination and reactivity of substrates, a large amount of the above chiral molecules are hard to be obtained via direct asymmetric catalysis and kinetic resolution. Moreover, to some degree, this challenge cannot bo solved by developing new catalysts and ligands. To address this problem, we plan to develop group addition-directed kinetic resolution. In more details, we will introduce a hydroxy group into a racemic tertiary alcohol, add a nucleophilic group into a racemic α-alkyl ketone, and install a reactive group into a racemic 1,3-diketone, to intrigue further reactions and finally achieve the access to the above chiral molecules via kinetic resolution. This strategy is able to expand significantly the domain of current asymmetric catalysis system, and can be used in the synthesis of more chiral molecules, and therefore, to provide more concise and efficient methods to make drug molecules and natural products.

手性叔醇、α-烷基酮和含季碳中心的1，3-二酮是重要的手性砌块，广泛应用于手性药物和天然产物合成中。但由于底物活性和对映面选择性的限制，很多类型的上述三类分子难以通过直接的不对称催化和动力学拆分获得，并且这些限制在一定程度上是难以通过发展新的催化剂和配体来解决的。在本项目中，我们将开发基团添加导向的动力学拆分克服上述限制以实现这三类手性分子的制备。具体来说，我们分别在消旋叔醇中引入羟基，在消旋α-烷基酮中引入亲核基团，在消旋1，3-二酮中引入活性反应基团，通过进一步的催化转化实现上述三类手性分子的动力学拆分方法制备。这一策略能够有效扩展现有的不对称催化体系的作用范围，并且可以用于制备更多类型的手性分子，从而为天然产物和药物分子的快速高效合成提供新的途径。

在国家自然科学基金项目（21871260）的支持下，针对不对称合成中的难点比如含多个相似取代基的叔醇和季碳取代酮的不对称合成，我们系统性开发了基于基团添加-动力学拆分的新策略，实现了含多个立体中心的四氢萘酮分子的快速制备、alpha-官能团化酮的普适性拆分、季碳分子的通用型拆分方法开发、大位阻beta-酮酯的获取、alpha-羟基环氧的制备等。这一系列成果的获得解决了不对称合成领域的诸多难点，拓宽了传统不对称催化的作用范围，为不对称合成的进一步发展提供了新的思路。