Design, Synthesis Of Bifunctional Amine-thioureas Based On The Strategy Of Multiple Hydrogen Bonds Synergic Activation And Their Applications In Asymmetric Organocatalysis

In the past decade, the importance of the small organic molecules as catalyst has been rediscovered, and the design and application of organocatalysts have received much attention due to asymmetric organocatalysis emerging as a powerful and environmentally friendly methodology for the catalytic production of the valuable synthetic building blocks. Impressive progress has been made in the development of chiral small molecules bearing hydrogen bonding donors for a diverse range of reactions with high enantioselectivities attributed to their strong activation of carbonyl or nitro groups through efficient hydrogen-bonding interactions. Of the developed organocatalysts, bifunctional amine-thioureas have been proved to be powerful and applied successfully in asymmetric Michael addition reactions. Considering the importance of the hydrogen bonding interactions between thiourea moiety and substrates in amine-thiourea catalyzed asymmetric reactions, we designed and synthesized a novel class of amine-thiourea catalysts through application of the strategy of multiple hydrogen bonds synergic activation for the first time. The characteristic features of the fine-tunable amine-thiourea catalysts were containing multiple hydrogen bonding donors and stereocenters, which significantly enhanced the adjustability of the electronic effect and steric hindrance effect of those organocatalysts.Firstly, we designed and synthesized a new kind of bifunctional amine-thiourea catalysts I containing sulfonamide. In the Michael addition of acetylacetone to nitroolefins, catalyst I-d showed high yields and excellent enantioselectivities for a broad spectrum of aryl nitroolefins (0.1-1 mol%catalyst loading,89-97%yield,95-99%ee,1-2 h) and alkyl nitroolefins (1-5mol%catalyst loading,80-85%yield,81-85%ee,16-36 h).Due to the good results of catalysts I in the Michael addition of acetylacetone to nitroolefins, catalysts I were used in the Michael addition ofα-substitutedβ-ketoesters to nitroolefins. However, low diastereoselectivities and high enantioselectivities were obtained. Based on the analysis of mechanism, we designed and synthesized the second generation of fine-tunable bifunctional amine-thiourea oganocatalystsⅡcontaining hydroxide radical. CatalystⅡ-d showed excellent yields (89-99%yield), diastereoselectivities (85:15-99:1 d.r.), enantioselectivities (90-99%ee) and structural scope in the asymmetric Michael addition of .α-substitutedβ-ketoesters to nitroolfins. This reaction provided an easy entry to access high functional compounds featuring adjacent quaternary and tertiary stereocenters in one step.In the successive research of the applications of bifunctional amine-thiourea catalysts bearing multiple hydrogen bonding donors. Catalyst I were used in the asymmetric amination of c(?)cβ-keto esters with dialkyl azodicarboxylates. Catalysts I-d showed good results for the transformation and provide optically active a-amino acid derivatives in up to 96%ee.The concept of multiple hydrogen bonds synergic activation was used for designing and synthesizing amine-thiourea catalysts successfully. Also, it was proved that multiple hydrogen bonding donors played a significant role in accelerating reactions, improving yields and stereoselectivities through these results above.