Studies On Asymmetric Reactions Catalyzed By Chiral Bifunctional Thiourea-tertiary Amine Organocatalysts

Over the past years organocatalysts bearing hydrogen bonding activating group are the subjects of intensive research. The double hydrogen-bonding interaction of N-H of urea (or thiourea) and reactant has been generally realized to have a specific role in the efficient catalysis and high enantiocontrol. Since the pioneering work by Jacobsen in 1998, a number of urea (thiourea) derivatives connected to suitable amino acids have catalyzed several types of asymmetric reactions with excellent enantioselectivity. However, the substrates used in these reactions are somewhat restricted to aldimines and ketoimines. This limitation was overcome by the development of bifunctional urea and thiourea catalysts from Takemoto in 2003. From then on, a number of thiourea-based organocatalysts have been designed and widely applied in various enantioselective transformations.This dissertation includes six parts. The first part reviewed the studies on asymmetric reactions catalyzed by chiral urea/thiourea organocatalysts. In the second part, a series of chiral bifunctional thiourea-tertiary amine organocatalysts were designed and synthesized using chiral DPEN, DACH and natural Cinchona alkaloids as starting materials. The asymmetric reactions catalyzed by chiral bifunctional thiourea-tertiary amine organocatalysts were reported respectively in the next three parts. The third part was the research on enantioselective Michael addition of α-substituted cyanoacetates to vinyl sulfones and vinyl ketones. In the fourth part, we developed the first direct asymmetric vinylogous Mannich (AVM) reaction ofα,α-dicyanoolefins and N-Boc aldimines. The fifth part focused on the organocatalytic asymmetric Friedel-Crafts alkylation/cascade reactions of naphthols and nitroolefins. The last part was a summary of each chapter in this dissertation.In the first part of the dissertation, the recent progress on urea- and thiourea-catalyzed stereoselective reactions has been summarized.In the second part, a series of chiral bifunctional thiourea-tertiary amine organocatalysts were designed and synthesized starting from chiral DPEN, DACH and natural Cinchona alkaloids. We hoped to find excellent catalysts with potent catalytic efficiency and high enantiocontrol through tuning the chiral amine backbones or the electronic effect of the aryl group on thiourea moiety.In the third part of the article, we described a highly efficient organocatalytic method for the asymmetric Michael addition ofα-substituted cyanoacetates to vinyl sulfones. This reaction was synergistically promoted by available bifunctional thiourea-tertiary amine organocatalysts and constructed an all-carbon-substituted quaternary stereocenter. In addition, the reaction scope was substantial sinceα-aryl or alkyl cyanoacetates could be successfully applied, and excellent enantioselect-ivities (up to 96% ee) were achieved. To the best of our knowledge, this is the first enantioselective catalytic reaction which might involve a double-hydrogen bonding interaction between the N-H of thiourea and a sulfonyl group. Moreover, the biologically importantβ^2,2-amino acids could be smoothly prepared from the addition products.In the following study, we presented a highly enantioselective Michael addition ofα-substituted cyanoacetates to vinyl ketones synergistically promoted by simple bifunctional thiourea-tertiary amine organocatalysts. A variety ofα-aryl or alkylcyanoacetates could be utilized to give multifunctional compounds—each of themhad an all-carbon-substituted quaternary stereocenter and exhibited excellent enantioselectivity (up to 97% ee). Furthermore, the usefulβ^2,2-amino acid esters with diverse structural types could be efficiently derived from the optically pure adducts. In addition, based on the absolute configuration of the conjugate adduct and computational studies, an interesting reaction model involving multiple hydrogen-bonding interactions amongst the thiourea/tertiary amine catalyst and the reactants has been proposed.In the fourth part of the dissertation, we developed the first direct asymmetric vinylogous Mannich reaction promoted by a simple bifunctional thiourea-tertiary amine organocatalyst. The reaction was highly regio-, stereoselective and practical for a broad range of substrates (generally >99% de, 96 to >99.5% ee) at room temperature, and the catalyst loading could be decreased to 0.1 mol% without ruining the excellent enantiocontrol. Moreover,δ-amino acid derivatives with multiple chiral centers could be generated from the adducts. In this study, we developed a superior approach to the synthesis of optically pureδ-amino acid derivative.In the fifth part we reported the novel asymmetric Michael-type Friedel-Crafts reaction of naphthols and nitroolefins, employing readily available thiourea-tertiary amine organocatalysts derived from cinchona alkaloids. Both 2- or 1-naphthols, and aryl- or alkyl-substituted nitroolefins could be successfully applied, furnishing good to excellent enantioselectivities (80-95% ee). Moreover, the unexpected intricate domino reactions could take place to generate enantiopure dimeric l,2-dihydro-naphtho[2,1-b]furany1-2-hydroxylamine derivatives through kinetic resolution by the same catalytic system. The absolute configurations of both the Friedel-Crafts alkylation product and the following cyclization product have been confirmed, and a plausible mechanism of the cyclization reaction has been proposed.The last part was a summary of each chapter in this dissertation.