Research Of Synthesis Of Dihydropyrimidines Via Asymmetric Biginelli Reactions Synergistically Catalyzed By Small Organic Molecules

Asymmetric organic synthesis is one of the most active areas in modern organic synthesis, drug synthesis. Asymmetric synthesis, with characterization of highly stereoselectivity, high atom economy and ease of industrialization, etc., play an important role in organic chemistry, pharmaceutical chemistry and material sciences. To date, no doubt, natural enzymes are the best choice of asymmetric synthesis. However, because of the harsh reaction conditions for the enzyme so that it is difficult to promote application. Developing chemical catalysts as effective as enzymatic system has been a challenge to organic chemists. In the process of evolving asymmetric synthesis, some small organic molecular catalyst was a breakthrough development. Proline, owning both an amino and a carboxyl groups in the molecule structure, is a chiral bidentate ligand, either as an acid but also can used as a base. In asymmetric catalysis, proline, as the first organic small molecule asymmetric catalyst, was discovered. After 10 years of research, it has become an important one in the field of small organic molecule catalyzed. Quinine alkaloids as organic catalyst have unique advantages of the structure, containing more chiral centers and polycyclic molecules; and the rigid three-dimensional structure is propitious to chiral induction; In addition, Quinine alkaloids, with inexpensive, readily available, stable and ease of structural modification, etc., also play an important role in asymmetric synthesis.3,4-dihydropyrimidine compounds (DHPMs) are very important drugs (such as statins, especially rosuvastatin calcium) intermediates. Further, since the inherent C4 atom in the pyrimidine ring of 3,4-dihydropyrimidine compounds is a central carbon atom, and it plays a controlling role in their pharmacological activity. Therefore, how to efficiently, to obtain a high selectivity of these compounds is a very worthy of study. On the basis of our research on asymmetric catalytic synthesis and analysis of the existing literature, we were designed and synthesized the trans-4,5-methano-L-proline (5) and quinine thiourea (6) catalyst, and inspired by combinatorial chemistry, we will use trans-4,5-methano-L-proline (5) and quinine thiourea (6) as a combination catalyst for catalytic synthesis of optically active 6-isopropyl-3,4-dihydropyrimidines by asymmetric Biginelli reaction.Research work of this thesis mainly includes the following two aspects:(1) On the basis of our preliminary work and the related research at home and abroad, first of all, we have synthesized the trans-4,5-methano-L-proline (5) using the S-pyroglutamic acid as raw materials. Then we also have synthesized quinine thiourea (6a) using the quinine alkaloid as raw materials. The asymmetric Biginelli reaction of 4-fluorobenzaldehyde with thiourea and isobutyryl methyl acetate were adopted as the model reaction for investigating the catalytic activity when the trans-4,5-methano-L-proline (5) and quinine thiourea (6a) alone as the catalyst. In addition, inspired by combinatorial chemistry, we examined the catalytic activity in asymmetric Biginelli model reaction when the trans-4,5-methano-L-proline (5) and quinine thiourea (6a) as a combinative catalyst. To our delight, we found that the catalytic activity was very excellent as a combinative catalyst.(2) After obtaining a catalyst with the excellent catalytic activity, by investigating the impact of the content of the catalyst, temperature, reaction time and feed ratio, we immediately obtain the optimum reaction conditions. Next, we examined the response of universality, we expand the substrate by changing the structure of the aromatic aldehyde and isobutyryl acetate, and synthesis of the 21 kinds of important new pharmaceutical intermediates. Finally, we discuss and speculate the mechanism of Biginelli reactions catalyzed by the combinative catalyst.The results showed that:we have designed and synthesized two types of small organic molecules catalyst. They have excellent synergy in catalytic asymmetric Biginelli reactions as a composite catalyst, and obtaining a higher yield and excellent enantioselectivity. We also preliminary explore the influence of the spatial structure of a chiral composite catalyst for catalytic activity from the reaction mechanism. This subject has some reference value for further research of asymmetric Biginelli synthesis and the development of new uses for the traditional catalysts.