Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China.
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
J Am Chem Soc. 2020 Nov 11;142(45):19226-19238. doi: 10.1021/jacs.0c09075. Epub 2020 Oct 29.
A novel concept that conversion of chiral 2-substituted DMAP into its DMAP--oxide could significantly enhance the catalytic activity and still be used as an acyl transfer catalyst is presented. A new type of chiral 2-substituted DMAP--oxides, derived from l-prolinamides, has been rationally designed, facilely synthesized, and applied in the dynamic kinetic resolution of azlactones. Using simple MeOH as the nucleophile, various l-amino acid derivatives were produced in high yields (up to 98% yield) and enantioselectivities (up to 96% ee). Furthermore, α-deuterium labeled l-phenylalanine derivative was also obtained. Experiments and DFT calculations revealed that in 2-substituted DMAP--oxide, the oxygen atom acted as the nucleophilic site and the N-H bond functioned as the H-bond donor. High enantioselectivity of the reaction was governed by steric factors, and the addition of benzoic acid reduced the activation energy by participating in the construction of a H-bond bridge. The theoretical chemical study indicated that only when attack directions of the chiral catalyst were fully considered could the correct calculation results be obtained. This work paves the way for the utilization of the C2 position of the pyridine ring and the development of chiral 2-substituted DMAP--oxides as efficient acyl transfer catalysts.
提出了将手性 2-取代的 DMAP 转化为其 DMAP-氧化物可以显著提高催化活性并仍然可用作酰基转移催化剂的新概念。本文合理设计、简便合成了一类新型手性 2-取代 DMAP-氧化物，其来源于脯氨酰胺，并将其应用于氮杂环丙烷酮的动态动力学拆分中。使用简单的甲醇作为亲核试剂，可以高产率（高达 98%的产率）和对映选择性（高达 96%的 ee）得到各种 l-氨基酸衍生物。此外，还得到了α-氘标记的 l-苯丙氨酸衍生物。实验和 DFT 计算表明，在 2-取代的 DMAP-氧化物中，氧原子充当亲核位点，N-H 键充当氢键供体。反应的高对映选择性受立体因素控制，添加苯甲酸通过参与氢键桥的构建来降低活化能。理论化学研究表明，只有充分考虑手性催化剂的攻击方向，才能得到正确的计算结果。这项工作为利用吡啶环的 C2 位以及开发高效酰基转移催化剂的手性 2-取代 DMAP-氧化物铺平了道路。
