Efficient asymmetric synthesis of novel gastrin receptor antagonist AG-041R via highly stereoselective alkylation of oxindole enolates

An efficient method for asymmetric synthesis of the potent Gastrin/CCK-B receptor antagonist AG-041R was developed. Core oxindole stereochemistry was established by asymmetric alkylation of oxindole enolates with bromoacetic acid esters, using l-menthol as a chiral auxiliary. The key alkylation reaction of the oxindole enolates generated tetrasubstituted chiral intermediates with high diastereoselectivity. The stereoselective alkylation reactions are described in detail.     

General method of obtaining deuterium-labeled heterocyclic compounds using neutral D2O with heterogeneous Pd/C

A protocol of a versatile H-D exchange reaction of heterocyclic compounds catalyzed by heterogeneous Pd/C in D₂O is described. The reaction of various nitrogen-containing heterocycles with 10% Pd/C (10 wt % of the substrate) under hydrogen atmosphere in D₂O as a deuterium source at 110-180 °C for 24 h afforded the corresponding deuterated compounds with satisfactory efficiency of deuteration in moderate to excellent isolated yields. Furthermore, the Pd/C-H₂-D₂O system can be extended to the direct deuteration of biologically active compounds such as sulfamethazine, which is used as a synthetic antibacterial drug for fat stocks and would be applied as a general method for the preparation of the standard materials for the analysis of residual chemicals in foods and so on.     

Bacterial hydrolytic dehalogenases and related enzymes: occurrences, reaction mechanisms, and applications

Dehalogenases catalyze the cleavage of the carbon-halogen bond of organohalogen compounds. They have been attracting a great deal of attention partly because of their potential applications in the chemical industry and bioremediation. In this personal account, we describe occurrences, reaction mechanisms, and applications of bacterial hydrolytic dehalogenases and related enzymes, particularly L-2-haloacid dehalogenase, DL-2-haloacid dehalogenase, fluoroacetate dehalogenase, and 2-haloacrylate reductase. L-2-Haloacid dehalogenase is a representative enzyme of the haloacid dehalogenase (HAD) superfamily, which includes the P-type ATPases and other hydrolases. Structural and mechanistic analyses of this enzyme have yielded important insights into the mode of action of the HAD superfamily proteins. Fluoroacetate dehalogenase is unique in that it catalyzes the cleavage of the highly stable C--F bond of a fluorinated aliphatic compound. In the reactions of L-2-haloacid dehalogenase and fluoroacetate dehalogenase, the carboxylate group of Asp performs a nucleophilic attack on the alpha-carbon atom of the substrate, displacing the halogen atom. This mechanism is common to haloalkane dehalogenase and 4-chlorobenzoyl-CoA dehalogenase. DL-2-Haloacid dehalogenase is unique in that a water molecule directly attacks the substrate, displacing the halogen atom. The occurrence of 2-haloacrylate reductase was recently reported, revealing a new pathway for the degradation of unsaturated aliphatic organohalogen compounds.     

Facile and convenient method of deuterium gas generation using a Pd/C-catalyzed H2-D2 exchange reaction and its application to synthesis of deuterium-labeled compounds

The Pd/C-catalyzed H(2)-D(2) exchange reaction using a H(2)-D(2)O combination provided a general, efficient and environmentally friendly route for the preparation of deuterium gas (D(2)). H(2) sealed in a reaction flask was converted into nearly pure D(2), which could be used for the Pd/C-catalyzed one-pot reductive deuteration of various reducible functionalities and the chemoselective one-pot deuterogenation of olefin and acetylene. Additionally, we established the capturing method of the generated D(2) in a balloon, which was successfully applied to the Pd/C-catalyzed reductive mono-N-alkylation of a primary amine using nitrile as the alkylating reagent.     

The Catalytic Mechanism of Fluoroacetate Dehalogenase: A Computational Exploration of Biological Dehalogenation

The biological dehalogenation of fluoroacetate carried out by fluoroacetate dehalogenase is discussed by using quantum mechanical/molecular mechanical (QM/MM) calculations for a whole‐enzyme model of 10 800 atoms. Substrate fluoroacetate is anchored by a hydrogen‐bonding network with water molecules and the surrounding amino acid residues of Arg105, Arg108, His149, Trp150, and Tyr212 in the active site in a similar way to haloalkane dehalogenase. Asp104 is likely to act as a nucleophile to attack the α‐carbon of fluoroacetate, resulting in the formation of an ester intermediate, which is subsequently hydrolyzed by the nucleophilic attack of a water molecule to the carbonyl carbon atom. The cleavage of the strong C? F bond is greatly facilitated by the hydrogen‐bonding interactions between the leaving fluorine atom and the three amino acid residues of His149, Trp150, and Tyr212. The hydrolysis of the ester intermediate is initiated by a proton transfer from the water molecule to His271 and by the simultaneous nucleophilic attack of the water molecule. The transition state and produced tetrahedral intermediate are stabilized by Asp128 and the oxyanion hole composed of Phe34 and Arg105.     

Optical absorption of In1−xGaxAsGaSb1−yAsy superlattices

The formation of subbands in In_1?xGa_xAsGaSb_1?yAs_y superlattices has resulted in entirely different absorption characteristics from those of the host semiconductors. The measured absorption edges agree with the calculated energy gaps of the superlattices of various configurations, establishing that the conduction bandedge of InAs lies approximately 0.15eV below the valence bandedge of GaSb.     

Synthesis of adamantane derivatives—43: 1,3-Dipolar cycloaddition reactivity of methyleneadamantane derivatives with substituted benzonitrile oxides

The 1,3-dipolar cycloaddition reactivity and regioselectivity of methyleneadamantane 1, ethyl adamantylideneacetate 7a, adamantylideneacetonitrile 7b and ω-methoxymethyleneadamantane 7c with substituted benzonitrile oxides 3a-i were calculated by CNDO/2 method using the perturbation equation derived by Klopman and Salem. The calculation predicted an exclusive formation of adamantan - 2 - spiro - 5' - 3' - aryl - Δ²' - isooxazoline 4a-i in the reactions of 1, 7a and 7b with 3a-i, and a formation of 67–69:33-31 mixture of 4a-i and isomeric 5a-i in the reaction of 7c with 3a-i. The predicted exclusive formation of 4a-i were experimentally observed in the reactions of 1,7a and 7b with 3a-i generated from 2a-i with Et₃N or thermally, but the reaction of 7c with 3a did not afford the corresponding adducts. A considerably higher reactivity of CN triple bond than CC double bond was observed in the reaction of 7b with 3a and 1,2,4-oxadiazole derivative 11 was obtained as the major product.     

Two-dimensional electronic structure in InAs-GaSb superlattices

We have achieved by molecular-beam-epitaxy the new type of superlattice of InAs and GaSb whose energy gaps do not overlap. The observed Shubnikov-de Haas oscillations manifest the two-dimensional electronic subband structure, corroborating theoretical calculations. The deduced electron mass is enhanced primarily as a result of the strong nonparabolicity in the conduction-band of InAs.