Design And Synthesis Of Novel Bifunctional Diaryl Proline Ether - Thiourea Organic Catalysts And Asymmetric Michael Addition Reaction

In recent years, the development of chiral drugs receives much attention in many countries. The synthesis of chiral compounds transformed from the enzyme catalysis, metal complexes catalysis to organocatalyst, which manifests great developing prospect, achieving the goal of obtaining massive chiral compounds by chiral amplification and chiral value-added. And the organocatalyst has the advantages of low-cost, non-toxicity and it is relatively stable for water and air. Therefore, organocatalyst has attracted much attention and interesting. Furthermore, organocatalyst plays an indispensable part in the production of chiral drugs and food additives because of wide application range and no heavy mental residual.The proline or its derivatives that catalytic activated by enamine or iminium ion, and the thiourea that catalytic with a double hydrogen bond is developing rapidly in recent years.They have high efficiency in catalytic asymmetric reactions, and their merits are stability, high stereoselectivity, high activity, widely application and so on.Based on the characteristicsof proline or its derivatives and thiourea, we designed and synthesized a new type of difunctional organocatalyst of diarylprolinol silyl ether thiourea and tried to connect diarylprolinol silyl ether together with thiourea fragment to achieve highly reactive and selectiveinasymmetric reaction. This paper mainly focuses on the following aspects:1. Starting from commercially available trarns-4-hydroxy-L-proline, diarylprolinol silyl ether-thiourea catalysts OC-A and OC-B were prepared in 8 steps in 19% and 13% overall yield.2.With the organocatalysts OC-A and OC-B in hand, we optimized reaction conditions (such as solvent, concentration, additive, catalyst loading, catalyst, etc.). Then we studied the scope of the substrates and get 52-99% yield,52/48-99/1 of diastereoselectivity,86-99% of enantioselectivity. It is worthy to note that reaction yield of the Michael addition of valeraldehyde to 4-bromophenyl nitroalkene is quantitative, with extremely high diastereoselectivity (99/1) and enantioselectivity (99%), which is the best result so far.3. With the bifunctional organocatalysts OC-B and the optimized conditions in hand, the asymmetric Michael addition of (E)-tert-butyl-3-nitroacrylate and 2-(pentan-3-yloxy) acetaldehydethe to give adduct (intermediate of tamiflu) in moderate yield (73%), diastereoselectivity (70/30), enantioselectivity (73%).4. In order to further study the mechanism of the reaction, we designed three sets of control experiment:(1) Catalyzed by diarylprolinol silyl ether. (2) Catalyzed by diarylprolinol silyl ether and thiourea (1/1). (3) Catalyzed by diarylprolinol silyl ether thiourea OC-B. The experiments showed that in catalytic asymmetric Michael reaction, the selectivity of catalyst bifunctional organocatalysts OC-B is improved than that of diarylprolinol silyl ether, and diarylprolinol silyl ether and thiourea (1/1), not only the reactivity could retained but also the selectivity have greatly enhanced.