Theoretical Study Of Several Organic Asymmetric Catalytic Reactions

Asymmetric catalysis represents one of the major challenges in modern organic chemistry. It plays a key role in drug discovery and pharmaceuticals. In the last decade, more attention has been paid to transition metal catalysis, and the success in this field led to the Nobel Prize in Chemistry in2001. However, in recent years, many chemists are getting acquainted with the advantages of organic catalysts, and organocatalysis has received considerable attention. Great progress in organocatalysis has been made theoretically and experimentally. Organocatalysis as a new concept emerged at the21st century has been developing within organic chemistry into its own subdiscipline, and its Golden Age has already dawned.The term "organocatalysis" describes the acceleration of chemical reactions through the addition of a substoichiometric quantity of an organic compound. The interest in this field has increased spectacularly in the last few years as result of both the novelty of the concept and, more importantly, the fact that the efficiency and selectivity of many organocatalytic reactions meet the standards of established organic reactions. Organocatalytic reactions are becoming powerful tools in the construction of complex molecular skeletons.The advantages of organocatalysts include their lack of sensitivity to moisture and oxygen, and their ready availability, low cost, and low toxicity, which confers a huge direct benefit in the production of pharmaceutical intermediates when compared with transition metal catalysts. Moreover, the design and use of synergic systems and bifunctional organocatalysts, which have two distinct functionalities (e.g. a Lewis base and a Br(?)nsted acid) within the same molecule, is becoming more and more common.As realization grows that organic molecules not only are green and easy to manipulate but also can be very efficient and remarkably enantioselective catalysts, asymmetric organocatalysis gradually catch up with the spectacular advancements of transition metal catalysis. Despite thorough experimental investigations and possible catalytic mechanism proposal, relative little is understood about the intricacies of organocatalysis, a situation that needs to be addressed to enable catalyst design to advance on a rational basis. Therefore, further thorough investigations on organocatalysis will be of important theoretical and practical values.Theoretical studies of reaction mechanism by computational methods have been greatly facilitated by innovation of computer technology and development of the methods. Recently, B3LYP methods have been applied for non-metal small molecular catalytic reaction and have achieved the considerable results.In this dissertation, we studied the bifunctional amine catalysis with density functional theory (DFT) calculations. Our purposes are to (1)shed light on the mechanistic details of the bifunctional nitrogen-containing catalysis and hence obtain a better interplay between theory and experiment,(2) understand the roles of bifunctional group of the catalyst and the origin of enantioselectivity for the catalyzed reaction, and (3) provide a general profile of the catalytic reaction by nitrogen-containing catalysts. Our results provide detailed information on the transition states of nitrogen-containing catalyzed organic reaction and should be helpful for the designing the new efficient catalyst examples.The valuable results in this dissertation can be summarized as follows:1. The research history and current state on organocatalysis have been briefly reviewed. A number of asymmetric organocatalytic reactions have recently been developed, and new asymmetric reactions are constantly being reported.. Moreover, the general mechanisms of organocatalysis have been illustrated:covalent bonded interactions and non-covalent bonded interactions.2. The asymmetric direct aldol reactions of aliphatic ketones (acetone, butanone and cyclohexanone) with4-nitrobenzaldehyde catalyzed by a chiral primary-tertiary diamine catalyst (trans-N,N-dimethyl diaminocyclohexane) have been investigated by performing density functional theory calculations to rationalize the experimentally observed stereoselectivities. Focused on the crucial C-C bond-forming steps, we located several low-lying transition states and predicted their relative stabilities. The calculated results demonstrate that the catalytic direct aldol reactions of aliphatic ketones favor the (S)-enantiomer. It is also shown that butanone prefers the branched syn-selective product, while cyclohexanone yields predominantly the opposite anti-selective product. The theoretical results are in good agreement with the experimental findings and provide a reasonable explanation for the high enantioselectivity, high diastereoselectivity, as well as high regioselectivity of the aldol reactions under consideration.3. The Michael reaction of nitro-compounds catalyzed by a amine-urea chiral bifunctional organocatalyst is investigated using density functional theory (DFT) calculations. The predicted mechanism involves first nucleophile activation via protonation of the amino group and electrophile activation through substrate binding to urea; then C-C bond formation between these two activated components; and finally, the proton transfer from the protonated amino group to adduct, followed by the dissociation of the H-bonded complex to give amination product along with the catalyst. The structures of the catalyst and two substrates as well as the catalyst-substrate complexes have been discussed in detail. Four reaction channels have been shown for the C-C bond-forming. The origin of enantioselectivity'for the investigated reaction is also discussed. Our calculated results confirm the urea moiety of the catalyst has a significant effect on the title reaction. The present DFT study well explains the experimental findings and provides the details of the mechanisms. The enantioselectivity and diastereoselectivity for the investigated reaction is originated from the different coordination modes of nitro-compounds to catalyst. The calculated results show that the reaction prefers syn-products, which is consistent with the experimental results.4. The nitro-Mannich reaction of nitro-compounds and imide catalyzed by a amine-urea chiral bifunctional organocatalyst is investigated using density functional theory (DFT) calculations. The computational results support the proposed mechanism, which involves:(i) The conjugate hydrogen bonding interactions of nitro-compounds and catalyst.(ii) A plausible transition state in which imide derivatives and the imides to the thiourea moiety and the tertiary amine group, respectively. The rate determining step is nucleophilic carbon of the anion of tautomer attacking imides. The origin of the high diastereoselectivity is explained. The calculated results show that the reaction prefers anti-configurational products, which is consistent with the experimental results.5. Based on density functional calculations, we have studied the reaction of nitrostyrene with a typical sulfur ylid catalyzed by1-(2-Chlorophenyl)-2-thiourea to understand the Michael addition mechanism. Transition state structures for the C-C bond-forming step controlling the stereoselectivity of the reaction have been located and their relative stabilities have been evaluated, and the role of the catalyst played in the reaction has been illustrated. The calculated results show that the formation of the anti-product is energetically more favorable than that of the syn-product, and that the catalyst (proton donor) promotes the reaction by forming the double H-bond complex with nitrostyrene (proton acceptor), where the charge transfer between the donor and acceptor increases the eletrophilicity of β-C atom of the nitrostyrene, favoring the nucleophilic attack of the sulfur ylides.Although substrate dependence remains an important issue in many of the reactions discussed, more and more transformations now meet the standards of established asymmetric reactions. Despite the considerable progress that has been made in the elucidation of transition states, we are only beginning to understand the basic factors that control reactivity and selectivity in these reactions, and the rational design of catalysts remains in most cases a dream. The number of organocatalytic (non-asymmetric) reactions is steadily increasing, which provides a solid basis for the development of novel enantioselective reactions. New asymmetric reactions are constantly being reported. Although creativity and persistence will certainly remain the major factors in the success of this research, the increasing use of automatization and computational techniques may facilitate both the discovery of novel catalyst structures and the screening of reactions for catalysts of the next generations.In this dissertation, the valuable results have provided reliable verification and theoretical guide for further studying of bifunctional amine catalysis even for the development of organocatalysis.