Modular Access to meta-Substituted Benzenes via Mo-Catalyzed Intermolecular Deoxygenative Benzene Formation.

The substituted benzene derivatives are essential to organic synthesis, medicinal chemistry, and material science. However, the 1,3-di- and 1,3,5-trisubstituted benzenes are far less prevalent in small-molecule drugs than other substitution patterns, likely due to the lack of robust, efficient, and convenient synthetic methods. Here, we report a Mo-catalyzed intermolecular deoxygenative benzene-forming reaction of readily available ynones and allylic amines. A wide range of unsymmetric and unfunctionalized 1,3-di- and 1,3,5-trisubstituted benzenes were obtained in up to 88% yield by using a commercially available molybdenum catalyst. The synthetic potential of the method was further illustrated by synthetic transformations, a scale-up synthesis, and derivatization of bioactive molecules. Preliminary mechanistic studies suggested that this benzene-forming process might proceed through a Mo-catalyzed aza-Michael addition/[1,5]-hydride shift/cyclization/aromatization cascade. This strategy not only provided a facile, robust, and modular approach to various meta-substituted benzene derivatives but also demonstrated the potential of molybdenum catalysis in the challenging intermolecular deoxygenative cross-coupling reactions.

Computational Design of Enhanced Enantioselectivity in Chiral Phosphoric Acid-Catalyzed Oxidative Desymmetrization of 1,3-Diol Acetals.

A general method for the highly enantioselective desymmetrization of 2-alkyl-substituted 1,3-diols is presented. A combination of computational and experimental studies has been utilized to understand the origin of the stereocontrol of oxidative desymmetrization of 1,3-diol benzylideneacetals. DFT calculations demonstrate that the acetal protecting group is highly influential for high enantioselectivity, and a simple but effective new protecting group has been designed. The desymmetrization reactions proceed with high enantioselectivity for a variety of substrates. Moreover, the reaction conditions are also shown to be effective for desymmetrization of 2,2-dialkyl-substituted 1,3-diols, which provides chiral products bearing acyclic all-carbon quaternary stereocenters. The method has been applied to the formal synthesis of indoline alkaloids.

Reliable method for the detection of horseradish peroxidase activity and enzyme kinetics.

Enzyme-catalyzed reactions are complicated and their kinetics depend on various chemical and physical factors. In a simple enzyme-catalyzed reaction, the enzyme kinetics often involve two or more substrates. However, this complexity is often ignored when studying enzyme kinetics or determining enzyme activity. Such an example is horseradish peroxidase (HRP), whose activity and kinetics in the reduction of H2O2 are usually detected and studied using spectroanalysis, with guaiacol (GA) as the hydrogen donor. In this process, the concentrations of two substrates, GA and H2O2, both change, which makes the practical detection, based on determination of the GA oxydate, GA(O), totally wrong. In this study, we introduce a new electrochemical method for detecting the specific activity (SA) and studying the enzyme kinetics of HRP. This electrochemical method was used to directly detect one substrate (H2O2) while the concentration of the other substrate (GA) was kept constant by adding ascorbic acid to the system to reduce GA(O) and regenerate GA. For the first time, this HRP-catalyzed reaction, including the mechanism and kinetics, was investigated precisely using a simple electrochemical method. The maximum SA and reaction rate constant k1 were reliably detected and calculated. The proposed method indicated that the SA of commercially available HRP (300 U mg-1 detected by spectroanalysis) was 1228.8 U mg-1 at a GA concentration of 4.5 mM, and up to 2049.9 U mg-1 as the GA concentration tended toward infinity. Our results suggest that reported methods for detecting enzyme activity and/or kinetics should be re-examined according to the catalytic mechanism of the enzyme.

Stereoselective intermolecular radical cascade reactions of tryptophans or ɤ-alkenyl-α-amino acids with acrylamides via photoredox catalysis.

The radical cascade reaction is considered as one of the most powerful methods to build molecular complexity. However, highly stereoselective intermolecular radical cascade reactions that can produce complex cyclic compounds bearing multiple stereocenters via visible-light-induced photocatalysis have been challenging yet desirable. Herein we report a facile and efficient synthesis of multi-substituted trans-fused hexahydrocarbazoles via a stereoselective intermolecular radical cascade reaction of readily available tryptophans and acrylamides enabled by visible-light-induced photoredox catalysis. The trans-fused hexahydrocarbazoles with up to five stereocenters including two quaternary ones can be accessed in up to 82% yield, >20/1 diastereoselectivity, and 96% ee. Interestingly, the tetrahydrocarbazoles are favorably formed when the reaction is performed under air. Moreover, by simply switching the starting material from tryptophans to ɤ-alkenyl substituted α-amino acids, this protocol can be further applied to the stereoselective syntheses of 1,3,5-trisubstituted cyclohexanes which are otherwise challenging to access. Preliminary mechanistic studies suggest that the reaction goes through radical addition cascade and radical-polar crossover processes.