The Design And Synthesis Of Chiral Guanidines With Camphor Skeleton And Their Application To The Catalytic Asymmetric Amination Of β-Keto Esters

Organocatalysis, especially the use of small organic molecules to catalyse organic transformations, is a relatively new and popular field within the domain of chiral molecule synthesis. Chiral guanidines is one of the main branches of organocatalyst (the other branches being L-proline, cinchona base, chiral phosphoric acid, chiral thiourea and so on), and those who are involved in the synthesis of chiral molecules consider organocatalyst to be a fundamental tool in their catalysis toolbox. Therefore, synthesis of new chiral guanidines and application of them in enantioselective catalysis have received much attention in recent years.Optically pure a-amino acids are widely used in pharmaceutical and pesticide, and the fundamental building blocks for various valuable biological molecules. At present, the main ways to obtain optically pure a-amino acids are separation from the natural products and asymmetric synthesis. Due to the limited source and number of natural α-amino acid in single configuration (L), the efficient catalytic synthesis of optically pure α-amino acids and their derivatives has always been one of the hot areas that organic catalystis researchers focused on.In this dissertation we focus on the design and synthesis of novel chiral guanidine catalyst. Based on the cheap natural camphor skeleton, after the simple seven-step reactions, we synthesized two new chiral guanidine catalysts (c-1and c-2). Their application in the asymmetric electrophilic amination reaction of azo-biscarboxylate and (3-keto esters to enantioselective synthesis of a-amino acid derivatives was also studied. For comparison, we synthesized bicyclic chiral guanidines (c-3and c-4) of Tan group and bifunctional chiral guanidines (c-5and c-6) of Feng group. Reaction conditions, such as solvent, temperature, concentration, catalyst loading, and azo-biscarboxylate, were optimized. The results show that camphor-derived chiral guanidine catalyst c-2works best. With the optimal reaction conditions in hand, twenty examples of catalytic enantioselective electrophilic amination reaction are presented. The reaction does not need protection from air and moisture. Almost all the reactions can be conducted quickly at-78℃, yield for all the products can reach99%and enantioselective ratio up to90%.