醚和胺的氧化动力学拆分和循环去外消旋化研究

非酶催化的氧化动力学拆分和去外消旋化是获得光学纯化合物的两种重要策略，但目前其适用范围主要局限于仲醇。据我们所知，到目前还没有对外消旋的醚或酰胺的氧化动力学拆分或去外消旋化的研究报道。手性α-单取代、含有四级碳的α,α-二取代、顺式或反式α,α’-二取代环醚和环胺以及α-取代的开链醚或胺这四类结构是多种药物分子和天然产物的核心骨架，但是现有的不对称合成方法在反应普适性、选择性和经济性等方面仍不理想。为此，本项目拟发展一个手性氮氧试剂催化的不对称碳氢氧化体系，分别通过“氧化动力学拆分”和“循环去外消旋化”两种策略，实现上述四类骨架的不对称合成。然后通过直接对相关药物分子和天然产物高级中间体进行动力学拆分和去外消旋化，验证其在真实合成中的应用潜能，为含上述四类骨架的复杂分子的合成提供新的思路和策略。拟研究内容在不对称碳氢官能团化、动力学拆分及去外消旋化三大领域均具有重大的科学意义和创新性。

Nonenzymatic oxidative kinetic resolution and redox deracemization represent two of the most important strategies to afford chiral compounds. However, both techniques are overwhelmingly limited to secondary alcohols. To the best of our knowledge, nonenzymatic oxidative kinetic resolution and deracemization of either ethers or amides have never been established to date. On the other hand, chiral α-monosubstituted, α,α-disubstituted, and α,α’-disubstituted cyclic ethers and amines together with α-substituted acyclic ethers and amines are four types of core skeletons in numerous pharmaceuticals and bioactive natural products. However, current asymmetric synthetic methods are still not ideal in terms of substrate scope, enantioselectivity, and atom or step economy. Therefore, in this proposal, a chiral TEMPO variant catalyzed enantioselective C-H oxidation system will be designed, which would allow us to access the above four types of chiral skeletons through the direct “oxidative kinetic resolution” and “redox cyclic deracemization”. Subsequently, both strategies will be applied to the direct kinetic resolution and deracemization of four representative racemic pharmaceuticals and natural products. These studies would demonstrate the synthetic applications of the methods in real syntheses, and will provide a new synthetic planning for related molecules. We envision that this proposal has significant scientific sense and novelty in three research fields of “enantioselective C-H oxidation”, “kinetic resolution”, and “deracemization”.