Finding
The desired tandem reactions did not proceed with either N-arylimine or N-alkylimine, and only the 1,4-conjugate addition products were obtained.
Paper
Diastereo- and enantioselective catalytic tandem Michael addition/Mannich reaction: access to chiral isoindolinones and azetidines with multiple stereocenters.
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Semantic ScholarAbstract
Construction of multiple contiguous stereogenic centers in acyclic compounds by asymmetric catalysis represents a particularly difficult challenge. For the success of such a catalytic process, carbon–carbon bond-forming tandem reactions using well-known reactions as key transformation steps that give high diastereoand enantiocontrol are a prerequisite. The asymmetric Mannich-type reaction is a popular method for preparing optically active b-aminocarbonyl frameworks, which are interesting structures found in many useful biologically active compounds. This type of reaction has been frequently used as a fundamental step for establishing tandem protocols, and in those processes, the catalytic generation of chiral enolates is crucial for achieving high activity and selectivity. It is widely appreciated that copper-catalyzed conjugate addition of R2Zn to a,b-unsaturated carbonyl compounds is one of the most attractive way for constructing a carbon– carbon bond, in which the chiral zinc enolate is generated in situ. In the case when an appropriate electrophile is added to the reaction system, the tandem conjugate addition/ electrophilic trapping reaction might be realized. Based on this concept, various electrophiles such as aldehydes, ketones, esters, nitriles, oxocarbenium ions, carboxylates, alkyl halides, nitrosos, and tosylates have been used in the intermolecular or intramolecular conjugate addition/electrophilic trapping reactions for the construction of complex molecular frameworks through tandem processes. As with the carbon electrophile, imines might be another attractive substrate for the conjugate addition/electrophilic trapping reaction. However, to the best of our knowledge, the use of this type of synthetically versatile aldimine as the terminal electrophile for this kind of reaction remains unexplored—presumably owing to their relatively lower electrophilicity in comparison with aldehydes and other carbonyl-containing electrophiles. Moreover, most of the stereoselective tandem reactions of this kind install the stereogenic centers on cyclic compounds. This limitation is probably due to difficulty in the stereoselective construction of contiguous stereogenic centers in acyclic compounds as compared to cyclic systems. Herein we report a highly diastereoand enantioselective construction of three contiguous acyclic stereogenic centers through a copper-catalyzed tandem conjugate addition/Mannich reaction of organozinc reagents and acyclic a,b-unsaturated ketones in the presence of imines to afford b-aminocarbonyl derivatives (Scheme 1). Thus, allowing the asymmetric synthesis of chiral azetidines in high enantioselectivity. Notably, in a one-pot manipulation, chiral isoindolinones can also be obtained with high levels of relative and absolute stereochemical control by using this method. First, we investigated the reactivity of several types of imines as electrophiles toward the chalcone 1 and Et2Zn in the presence of Cu(CH3CN)4BF4 (1 mol%) and with (S,S)-L1 (1.2 mol%) as a chiral ligand in toluene at 10 8C for 12 hours—these are the same reaction conditions that previously led to good results for the copper-catalyzed conjugate Michael addition protocol. The desired tandem reactions did not proceed with either N-arylimine or N-alkylimine, and only the 1,4-conjugate addition products were obtained. However, the use of N-tosyl aldimine 2a as an electrophile under the same reaction conditions gave the desired tandem adduct in 72% yield with good enantioselectivity (76% ee) for the major diastereomer (Table 1, entry 1). Also, only two of the four possible diastereomers were detected. This exceptionally high reactivity may be attributed to the higher electrophilicity of the N-tosyl aldimine or the strong coordination of the copper ion to the N-tosyl aldimine through a 1,3binding mode of the nitrogen atom of the imine moiety and the oxygen atom of the sulfonyl group. We then focused our attention on this type of imine as the electrophilic tapping reagent and examined several catalytic systems. We used chalcone 1a, N-tosyl aldimine 2a, and Et2Zn as the reactants, and the reaction was performed at 10 8C in toluene for 12 hours. With L1 as a ligand, we screened a variety of copper sources including copper(I) and copper(II) species, and found the stereoselectivity was significantly affected by the nature of the counterion of the copper salts (Table 1, entries 1–8). The more coordinating counterions proved to be more suitable, and among those tested, CuBr led to the best results with respect to reactivity and stereoselectivity (Table 1, entry 3). Among the solvents [*] S. Guo, Y. Xie, Prof. Dr. X. Hu, Prof. Dr. C. Xia, Prof. Dr. H. Huang State Key Laboratory for Oxo Synthesis and Selective Oxidation Lanzhou Institute of Chemical Physics Chinese Academy of Sciences, Lanzhou, 730000 (China) Fax: (+ 86)931-496-8129 E-mail: hmhuang@licp.cas.cn
Authors
Shengmei Guo, Yinjun Xie, Xinquan Hu
Journal
Angewandte Chemie