Michael Addition Catalyzed By Chiral Bifunctional Thiourea Organocatalysts Bearing Multiple Hydrogen-bonding Donors

Chiral catalysis is currently the most cost-effective route for preparation of chiral compounds. Currently, organocatalysis has been emerged as an increasingly active area in organic synthesis. Michael addition is an important organic transformation which leads to the formation of new C-C bonds and thus being regarded as an important method to synthesis of many chiral drugs and medicinal intermediates.Chiral thiourea, of which preparation method is quite simple, has been gaining increasing interests. Recently, the tertiary amine thiourea catalysts bears particular bifuntional group, which has been successfully applied in many transformations. On one hand, the two NH of thiourea can form intermolecular hydrogen bonds with electophiles, thus activating the electophiles. On the other hand, the tertiary amine can form intermolecular hydrogen bonds with carbonyl compounds and activate the nuclearphiles. So the bifuntional effect could be realized due to the multiple hydrogen bonds between the catalyst and the reactants.In this thesis, a novel type of bifunctional chiral thiourea organocatalysts bearing multiple hydrogen-bonding donors was developed, which was succefully applied to the asymmetric Michael addition of acetylacetone to nitroolefins. The research consists mainly of two parts:1. A series of new bifunctional chiral thiourea organiccatalyst bearing multiple hydrogen-bonding donors were synthesized from inexpensive natural amino acids and cinchona alkaloids as raw material. It was found that these bifunctional chiral thiourea compounds are effective organocatalysts for the asymmetric Michael addition of acetylacetone to nitroalkenes. Especially the compound 67e exhibited good catalytic activity. Under the optimum reaction conditions, the reaction ran smoothly to afford the corresponding adducts in good to excellent yields (up to 92%) and with good enantioselectivities (up to 91% ee).2. Two other bifunctional chiral thiourea organocatalysts bearing multiple hydrogen-bonding donors were synthesized from commercial availableβ-amino alcohols and cinchona alkaloids as raw material. In optimal conditions, organocatalyst 82 showed high efficient and excellent enantioselectivity, affording the desired products with enantioselectivity of up to 98% ee. And a broad range of substrates was also achieved. A probable catalytic mechanism was presented,by which the significant role of hydrogen-bonding action can be interpreted.To sum up, it was found that these bifunctional chiral thiourea organocatalysts bearing multiple hydrogen-bonding donors are effective organocatalysts for the asymmetric Michael addition of acetylacetone to nitroalkenes. This new catalyst system for the asymmetric Michael addition is valuable due to its high effience, excellent enantioselectivity, mild conditions and low cost. It's promising to develop a practical method to synthesis theα-substituted-β-amino acids in large scale.