Theoretical Studies On The Three Kinds Of Catalytic Reactions For The Construction Of 3,3-disubstituted Oxindoles

3,3-disubstituted oxindoles are a type of very important structural motif with chiral quaternary carbon atoms and widely occure in natural products and drugs. Screening efficient catalyst and developing efficient synthetic methods for preparation of 3,3-disubstituted oxindole skeleton will help to explore the structure-activity relationships, and to accelerate drug discovery, which has an important theoretical and practical significance. However, due to the steric effect and electrical property of reaction substrate, the construction of these skeletons are still one of the important challenges in organic catalysis. Moreover, the lack of clear understanding of the mechanism and the selectivity-controlled factors prevents the development of this field. With the development of computational chemistry, it plays an increasingly important role in understanding the mechanism and selectivity as well as designing more efficient catalyst, and has became an important tool in catalysis research. Understanding and grasping the characteristics and nature of the synthetic reactions of these structural motif from molecular level, will help to optimize the reaction conditions, design and develop new type high efficiency catalyst, and to further promote the development of the field.In this thesis, we focus on three kinds of important catalytic reactions for the construction of 3,3-disubstituted oxindoles:the Rh(II)-catalyzed cyclopropanation of diazooxindole and alkenes, the quinine-derivatives catalyzed aza-Henry reaction of isatin derived N-Boc ketimine, and the Sakurai-Hosomi reaction of the isatin and isatin derived ketimine. Density functional theory (DFT) was employed to study the mechanism, the activation mode and the stereoselectivity. Our studies have elucidated the mechanism, established reasonable stereochemical modes, and revealed the origin of the stereoselectivity. These results not only elucidated the experimentally observed phenomena and deepened the understanding of these reactions, but also provided new opinion on the catalytic mechanism and modes, which will be helpful in design and development of novel reaction and catalyst. Our results are summarized as follows:1. Theoretical study on the mechanism and stereoselectivity of the Rh(II)-catalyzed cyclopropanation of diazooxindoleThe mechanism and origin of stereoselectivity of Rhodium(II)-catalyzed cyclopropanation reactions with diazooxindole and styrene has been studied using DFT calculations. The catalyzed reactions by achiral Rh2(OAc)4 and chiral Rh2(S-PTTL)4 as well as the uncatalyzed model were comparatively studied. In the absence of the catalyst, the cyclopropanation between diazooxindole and styrene is a single concerted step with very high barrier and poor selectivity. The catalyzed reaction proceeds through a stepwise process including the formation of carbene species and a cyclopropanation step, and the cyclopropanation step is a single concerted but asynchronous process. The nitrogen extrusion step is found to be the rate-limiting step, whereas the cyclopropanation step is the stereoselectivity-determining step. The results show that styrene can approach to the carbenoid complex through the end-on or side-on trajectory, and the former is more favorable than the latter. A reasonable stereochemical model was established and the stereoselectivity was successfully predicted. The calculations revealed the origin of the excellent catalytic activation and the stereo-controlling ability of the Rh2(S-PTTL)4. It was found that the noncovalent interactions (NCIs) play an important role in increasing the reactivity and determining the stereoselectivity. The diastereomeric ratios (dr) and the enantiomeric excess (ee) values were successfully predicted. The high trans-diastereoselectivity might be governed by the ?-? interactions between the syn indole ring in carbenoid ligand and the phenyl group in styrene, whereas the good enantioselectivity can be ascribed to the aromatic interactions (?-? and CH-?) of the phenyl group in styrene and the phthalimido ligand with the indole ring in carbenoid. Additionally, the methodological study'using different functionals demonstrated the importance of considering the dispersion interactions in the current reaction systems. This theoretical study will help in understanding the mechanism of the asymmetric cyclopropanations of olefins through carbene-transfer reactions, and provides useful information for designing new catalysts and reactions.2. Theoretical study on the mechanism and enantioselectivity of the aza-Henry reaction catalyzed by quinine-derivativesDFT calculations were performed to elucidate the mechanism and the origin of high enantioselectivity of aza-Henry reaction of isatin derived N-Boc ketimine catalyzed by quinine-derived catalyst (QN). The results indicated that the catalytic cycle involves three steps:deprotonation of nitromethane, the subsequent C-C bond formation, and protonation of the product and the regeneration of the catalyst. The important role of C6'-0H group observed in experiment was confirmed and reasonably explained. The results reveal the dual role played by the catalyst QN, which is crucial for both reactivity and selectivity. Three possible activation modes for C-C bond formation involving different coordination patterns of catalyst and substrates were studied, and it was found that dual activation modes are prefered over the single activation mode. These results further confirmed the hypothesis that the bifunctional catalyst adopts a dual activation mode. A new Bronsted acid-hydrogen bonding activation mode was confirmed, which is different from the tranditional ion pair-hydrogen bonding mode as previously proposed. Moreover, both the two dual activation modes are viable with the the Br(?)nsted acid-hydrogen bonding mode slightly preferred. These results are different from the tranditional opinion, i.e., the ion pair-hydrogen bonding mode is more favorable. In both modes there is a remarkable preference for the S-enantiomer, in agreement with the experimental findings. Based on the proposed model, the enantiomeric excess (ee) favoring the S enantiomer and the solvent effects were successfully predicted, which further confirms the reasonability of the proposed stereochemical model. These results further deepen the understanding of hydrogen-bonding type catalytic mode and provide further support for the generality of the recently proposed Br(?)nsted acid-hydrogen bonding model for cinchona alkaloid catalysis. The multiple noncovalent interactions including classical H-bonding (N(O)-H…N(O)), non-classical H-bonding (C-H…N(O)) and anion…? interactions are found to cooperatively stabilize the stereocontrolled TSs and control the enantioselectivity. Our results also reveal the importance of dispersion interactions in stabilizing transition states and highlight the importance of inclusion of dispersion correction for the proper description of the enantioselectivity in current reaction. This study provides further evidence for the significance of attractive dispersion interactions in catalysis, even in the presence of hydrogen bonds or ion pairs. This study is expected to provide theoretical guide and new clue for the design and development of hydrogen-bonding mediated chiral catalyst based on cinchona alkaloids.3. Theoretical study on the mechanism of Hg(?) catalyzed allylation of isatin with allyltrimethylsilaneThe mechanism of the allylation reaction between isatin with allyltrimethylsilanecatalyzed by Hg(C104)2·3H20 has been investigated using the density functionaltheory (DFT) method. Thermodynamic analysis was firstly performed for investigating the reactive species involved in the reaction system, and it was found that the generation of the reactive species diallylmercury is likely, which is in agreement with the experimental observation. Based on the experimental results, five possible reaction pathways were suggested and investigated. The calculations found a relatively high activation barrier for the reaction in the absence of the Lewis acid (path ?). In the presence of Lewis acid diallylmercury, the catalyzed reaction can take place facilely with a significantly lower barrier height than that of path I. The reactions catalyzed by the allylmercury perchlorate or mercury perchlorate cation are kinetically unfavourable with higher barrier height than that of diallylmercury, although their free energy barrier height are significantly lower than that of path ?. Our study reveals a new activation mode in which the role of Hg(C104)2·3H20 is not to directly activate isatin but acts as an initiator for producing the actual active species TMSX and diallylmercury. Our theoretical results confirm the reactive species involved in the reaction system and give more insight into the mechanism of the reaction and the role of Hg(?) salt. The present study provides a new way to comprehensively understand the catalytic mechanisms of the important Sakurai-Hosomi allylation, which is expected to provide new clue for the development of new catalyst and reactions.