Application In Asymmetric Reduction Research Articles

Dissecting the Mechanism of (R)-3-Hydroxybutyrate Dehydrogenase by Kinetic Isotope Effects, Protein Crystallography, and Computational Chemistry.

The enzyme (R)-3-hydroxybutyrate dehydrogenase (HBDH) catalyzes the enantioselective reduction of 3-oxocarboxylates to (R)-3-hydroxycarboxylates, the monomeric precursors of biodegradable polyesters. Despite its application in asymmetric reduction, which prompted several engineering attempts of this enzyme, the order of chemical events in the active site, their contributions to limit the reaction rate, and interactions between the enzyme and non-native 3-oxocarboxylates have not been explored. Here, a combination of kinetic isotope effects, protein crystallography, and quantum mechanics/molecular mechanics (QM/MM) calculations were employed to dissect the HBDH mechanism. Initial velocity patterns and primary deuterium kinetic isotope effects establish a steady-state ordered kinetic mechanism for acetoacetate reduction by a psychrophilic and a mesophilic HBDH, where hydride transfer is not rate limiting. Primary deuterium kinetic isotope effects on the reduction of 3-oxovalerate indicate that hydride transfer becomes more rate limiting with this non-native substrate. Solvent and multiple deuterium kinetic isotope effects suggest hydride and proton transfers occur in the same transition state. Crystal structures were solved for both enzymes complexed to NAD+:acetoacetate and NAD+:3-oxovalerate, illustrating the structural basis for the stereochemistry of the 3-hydroxycarboxylate products. QM/MM calculations using the crystal structures as a starting point predicted a higher activation energy for 3-oxovalerate reduction catalyzed by the mesophilic HBDH, in agreement with the higher reaction rate observed experimentally for the psychrophilic orthologue. Both transition states show concerted, albeit not synchronous, proton and hydride transfers to 3-oxovalerate. Setting the MM partial charges to zero results in identical reaction activation energies with both orthologues, suggesting the difference in activation energy between the reactions catalyzed by cold- and warm-adapted HBDHs arises from differential electrostatic stabilization of the transition state. Mutagenesis and phylogenetic analysis reveal the catalytic importance of His150 and Asn145 in the respective orthologues.

ChemInform Abstract: Synthesis of a P‐Stereogenic PNPtBu,Ph Ruthenium Pincer Complex and Its Application in Asymmetric Reduction of Ketones.

AbstractA wide range of aromatic ketones can be hydrogenated with high conversion and generally good to excellent enantioselectivity in the presence of the title ligand.

ChemInform Abstract: Synthesis of Novel Carbohydrate‐Based Valine‐Derived Formamide Organocatalysts by CuAAC Click Chemistry and Their Application in Asymmetric Reduction of Imines with Trichlorosilane.

AbstractThe applied catalyst can be recycled and reused at least five times.

Synthesis of novel carbohydrate-based valine-derived formamide organocatalysts by CuAAC click chemistry and their application in asymmetric reduction of imines with trichlorosilane

Novel organocatalysts combining carbohydrate and N-formyl-l-valine derivatives were prepared by CuII-catalyzed diazo transfer and CuI-catalyzed azide–alkyne 1,3-dipolar cycloaddition CuAAC click chemistry. It was found that the carbohydrate-based valine-derived formamide organocatalyst had high catalytic activity for the asymmetric reduction of imines with trichlorosilane. The reduction can proceed at room temperature in toluene in high yield (up to 98%) and with excellent enantioselectivity (up to 94%). ‘CuAAC’ click chemistry is a bridge to link N-formyl-l-valine derived organocatalysts with carbohydrates.

Synthesis of chiral polymers and its application in asymmetric reduction

Two new cinchona alkaloids copolymers (PMA-BQTP and PMA-QN) have been synthesized by copolymerization and their complexes (PMA-BQTP-PdCl2 and PMA-QN-PdCl2) have been prepared. Their structures were characterized by FTIR, GPC, and element analysis. The catalytic activity of PMA-QN-PdCl2 in the heterogeneous catalytic asymmetric reduction of aromatic ketone by sodium borohydride was studied. The results showed that the polymer complex catalyzed the reduction of aromatic ketone to get alcohol in high optical yield, but their catalytic efficiency was largely dependent on the aromatic ketone and solvent system, which relate to the accessibility of the catalytic active site. And the PdCl2/polymeric alkaloid complex can be simply recovered at the end of the reaction by centrifugation and then reused without serious losing of activity or enantioselectivity. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 148–152, 2007