手性吡哆醛仿生催化氨基酸衍生物的不对称aldol反应和Mannich反应的研究

This project will focus on the development of chiral pyridoxal catalysts and also explore chiral pyridoxal catalyzed asymmetric biomimetic aldol and Mannich reactions of amino acid derivatives. As an important co-enzyme, Vitamin B6 family including pyridoxal (PL), pyridoxamine (PM), and their phosphate derivatives (PLP and PMP) have displayed highly powerful catalytic capabilities in biological systems. However, vitamin-B6-based catalytic systems as well as their applications in the field of asymmetric catalysis are waiting to be developed. Chiral β-hydroxy-α-amino acids and α,β-diamino acids both are significant compounds with high biological activities. Chiral pyridoxal catalyzed asymmetric biomimetic aldol and Mannich reactions of amino acid derivatives are straightforward and efficient ways to synthesize these two types of compounds. The significance of the proposed research includes the following three aspects. (1) The project will contribute new and novel chiral pyridoxal catalysts and also explore and expand the application of vitamin B6 in the field of asymmetric catalysis. (2) The proposed research will develop the first asymmetric biomimetic aldol reaction of amino acid derivatives and also contribute an environmentally friendly, direct, and efficient biomimetic method for the synthesis of biologically important chiral β-hydroxy--amino acid compounds. (3) The proposed research will develop the first asymmetric biomimetic Mannich reaction of amino acid derivatives and also contribute an environmentally friendly, direct, and efficient biomimetic method for the synthesis of biologically significant chiral ,β-diamino acid compounds.

本项目致力于手性吡哆醛催化体系的发展及其仿生催化氨基酸衍生物的不对称aldol反应和Mannich反应的研究。维生素B6，即吡哆醛/吡哆胺及其磷酸酯衍生物，在生物体内有强大催化功能，但基于维生素B6的催化体系及其在不对称催化中的应用都有待发展。手性β-羟基-α-氨基酸和α,β-二氨基酸都是非常重要的生物活性化合物，手性吡哆醛仿生催化氨基酸衍生物的不对称aldol反应和Mannich反应是合成这两类化合的好方法。本项目执行有三方面意义：1) 模拟生物酶发展手性吡哆醛催化体系，有利于发展和拓展维生素B6骨架在不对称催化中的应用；2) 第一次实现吡哆醛仿生催化氨基酸衍生物的不对称aldol反应，发展出手性β-羟基-a-氨基酸衍生物的高效、绿色的仿生合成新方法。3) 第一次实现吡哆醛仿生催化氨基酸衍生物的不对称Mannich反应，发展出手性a,β-二氨酸衍生物的高效、绿色的仿生合成新方法。

辅酶维生素B6催化功能非常强大，能催化很多生物转化，尤其是生物体内与胺的合成和代谢相关的转化，通过这些转化，为生命提供了具有生理活性的各种手性胺类化合物。我们基于维生素B6骨架结构发展了一系列新型的仿生手性吡哆醛和手性吡哆胺催化体系，并利用这些催化体系首次成功实现了甘氨酸酯的仿生不对称aldol反应、与α,β-不饱和酯的Michael加成-分子内酰胺化、与MBH醋酸酯的不对称烯丙基化、炔丙胺α-位对三氟甲基酮的不对称加成、苄胺α-位对芳基醛的不对称加成反应、α-酮酰胺的不对称转氨化等，为具有重要价值的手性 β-羟基-α-氨基酸衍生物、手性焦谷氨酸衍生物、手性多取代谷氨酸衍生物、手性多肽等的合成发展了新方法，克服了以往传统合成方法中需要对胺基进行保护、脱保护操作的多步过程，具有广泛的应用前景。项目研究拓展了羰基催化的应用范围，实现了无需对NH2保护条件下，伯胺α-位直接与亲电试剂进行反应的新转化，是仿生催化领域中的重要进展。