Theoretical Studies On Organocatalytic Asymmetric Synthesis

Asymmetric synthesis, also called chiral synthesis, is organic synthesis that introduces one or more new and desired elements of chirality into the final product. It is of great significance in the realm of organic synthesis, especially for the synthesis of chiral drugs, because the different enantiomers or diastereomers of a drug molecule often behavior different biological activity. At present, chiral organometallic asymmetic catalytic synthesis might be the most dominant one among the various asymmetric synthetic methods duo to its notable versatility and efficient stereoselectivities. However, recently organocatalytic asymmetric synthesis has been attracting more and more attention as in many cases it can be performed under safe and mild conditions, and compared with the chiral metal complexes-catalyzed asymmetric synthesis, this metal-free method is more economical and environmentally friendly, which makes it an attractive and rapidly developing asymmetric synthesis.Recently, N-Heterocyclic carbenes and Brφnsted acid have been experimentally proven to be efficient enantioselective catalysts for Staudinger reaction ([2+2] cycloaddition of a ketene with an imine) and transfer hydrogenation of quinolines, respectively. The final productsβ-lactams and 1,2,3,4-tetrahydroquinolines are of great synthetic importance in the pharmaceutical industry. The former have being used as the traditional antibiotics for several decades, and the latter are commonly present in alkaloids and are required in pharmaceutical and agrochemical synthesis. However, in contrast to the successful practical application, synchronous mechanistic investigations are quite insufficient. The catalytic mechanism and the origin of stereoselectivities are not readily apparent, which has prevented further improvement and development of the two systems from to some extent. To get an in-depth understanding of the chemical basis of catalytic mechanisms and divergent stereoselectivities, we carried out a series of theoretical investigations on these issues and obtained some valuable results, which were mainly summarized as follows:(1) Mechanical investigations toward N-Heterocyclic carbene-catalyzed Staudinger reaction:The catalytic mechanism of N-Heterocyclic carbene-catalyzed Staudinger reaction was investigated by emplying density functional theory (DFT) method. According to different experimental results, the "ketene-first" and "imine-first" mechanisms arguing which reactant should be initially activated by NHC catalyst have been proposed. Our calculations reveal that the catalytic mechanism of NHCs-catalyzed Staudinger reaction is exclusively the "ketene-first" mechanism (A), but the competitive reactions of NHC catalysts with ketenes or imines will lead to different experimental observations. Based on this conclusion, we found that the NHCs-catalyzed Staudinger reaction would exhibit different stereoselectivities by appropriate choice of the nitrogen substitute of imines. In addition, these results are supposed to be applicable for other nucleophile-catalyzed Staudinger reactions.(2) Computational predictions of stereoselectivity in N-heterocyclic carbene catalyzedβ-lactams synthesis:The stereoselectivities of NHCs-catalyzed Staudinger reaction has been theoretically explored by using ONIOM method. Calculations using a combination of B3LYP/6-31G(d) and PM3 levels of theory for transitions-state optimization and M06 2X/6-31+G(d,p) level for single point calculation make predictions of stereoselectivities in accordance with the experimental observations. The origins of divergent stereoselectivities related to different NHCs were further identified:the concomitant electrostatic and steric effects involved in the reaction of imines with NHC-ketene intermediates cooperate in controlling the stereoselectivities of N-Heterocyclic carbenes (NHCs) catalyzed Staudinger reaction, but the structural features including symmetrically-substituted or asymmetrically-substituted and the relative size of substitutes will affect the cooperation manner of the two effects, subsequently, leading to divergent stereoselectivites. Based on the calculations, some useful information for further improvement of NHCs-catalyzed Staudinger reaction was obtained. Firstly, the imines with electron-rich N substituents, such as the experimentally reported N-sulfonyl and N-carbonyl imines, are found necessary for the asymmetric NHCs-catalyzed Staudinger reaction. Secondly, the size of bulky substituent of the unsymmetrical disubstituted NHCs is crucial to the enantioselectivity. Finally, our calculations also suggest that if the electronically-preferential re face reaction of (Z)-INTN-k could be effectively shielded by the bulky substituent of the catalysts, the control of the divergent cis/trans stereoselectivites through the appropriate choice of N tosyl/triflyl imines is possible.(3) Mechanical investigations into Brφnsted acid catalyzed transfer hydrogenation of quinoline:Two possible catalytic mechanisms have been proposed for transfer hydrogenation of quinoline including "2C position first" or "4C position first", which differ in the position of the first hydride transfer to iminium ion derived from the initial protonation of quinoline. There is no relevant information from the experiments. The two possible mechanisms have been calculated by employing density functional theory (DFT). The calculated results show that the "three point interaction model" established by Brφnsted acid catalyst hydrogen-bonded with other two reactants facilitates the "4C position first" mechanism. But the result could not preclude the possibility of "2C position first" mechanism for other catalytic system in which the "three point interaction model" can not well-established.