Asymmetric Reactions Catalyzed By Chiral Tertiary Amine-squaramides

The importance of enantioselective organocatalysis has beenrediscovered in the past few years, and it has become a powerfulsynthetic paradigm that is complementary to metal complex and enzymecatalysis. As a subfield of organocatalysis, hydrogen-bond-mediatedcatalysis has emerged as an important tool for enantioselective synthesis,especially since Takemoto’s pioneering work on the development ofbifunctional tertiary amine-thiourea organocatalysts in2003. Recently,the squaramide core has been explored as a novel hydrogen bondingcatalaphore by Rawal’s group, and several chiral aminosquaramidederivatives have been developed as chiral bifunctional organocatalysts forthe asymmetric catalyzed reactions after their work.This dissertation includes four parts as follows：Firstly, advances in the hydrogen-bond-mediated catalysis and the applications of bifunctional tertiary amine-thiourea catalysts inasymmetric catalysis were briefly summarized. Based on this, the recentdevelopment of squaramides as powerful hydrogen-bonding catalysts inasymmetric organocatalysis was reviewed extensively, which is veryrelevant to my Ph.D. study.Secondly, an efficient, organocatalytic enantioselective addition ofcyclic diketones with β,γ-unsaturated α-keto esters using the tertiaryamine-squaramide catalysts has been developed, thereby affording theproducts in high yields (up to95%) and excellent enantioselectivities (upto>99%ee) under mild conditions with low catalyst loading (2.5mol%).The unsaturated α-keto esters are effectively coordinated and activated byhydrogen bonds of squaramides and proved to be excellent hydrogen-bondacceptors in this asymmetric organocatalysis. This catalytic asymmetricreaction provides a valuable and easy access to this kind of chiral Michaeladducts which are substructures found in skeletons of important biologicaland pharmaceutical molecules.In the third part, a highly efficient enantioselective Michael addition of1,3-dicarbonyl compounds to nitroolefins using the chiral squaramidederivatives as hydrogen bonding catalyst under solvent-free condition in aplanetary ball mill was developed. High yields, high enantioselectivities andshort reaction times were achieved with low catalyst loading. The intensemixing of the reactants in the ball mill accelerates the reaction efficiently, while the diastereo-and enantioselectivities don’t decrease compared withhomogeneous catalysis. The results suggest that hydrogen-bondinginteractions which are enhanced in the absence of solvents are crucial for thecourse of the reaction. Simplicity of the reaction, solvent-free condition, fastreaction times, high yields and selectivities lead us to conclude that the ballmill procedure is a significant version of the described reaction.In the fourth part, an enantioselective domino Micheal-S_N2reaction of1,3-dicarbonyl compounds with α-bromonitroolefins synergisticallypromoted by bifunctional tertiary amine-squaramide organocatalysts waspresented. The reaction proceeds extraordinary well in a biphasic catalysissystem, for successful exclusion of the acid from the organic phase, which isgenerated during the reaction process. This novel methodology should be ofgreat importance for the asymmetric synthesis of2,3-dihydrofuran, which isa ubiquitous motif present in natural products and medicinally importantagents. Furthermore, it may provide some critical ideas for the asymmetricreactions having similar mechanism.