Takanori Iwasaki

Enzyme-like chemoselective acylation of alcohols in the presence of amines catalyzed by a tetranuclear zinc cluster.

Acylation of alcohols and amines is one of the most fundamental reactions. Due to the greater nucleophilicity of the amino group compared to the hydroxyl group, complete N-acylation occurs. Only an enzymatic reaction can promote a highly selective O-acylation reaction, and there are no examples using an artificial catalyst. Here we report that the tetranuclear zinc cluster Zn4(OCOCF3)6O efficiently catalyzes highly chemoselective O-acylation in the presence of primary and secondary alkyl amines. Our results suggest the high potential of the zinc cluster as the core structure of an artificial enzyme to realize further enzyme-like chemoselective reactions.

Rhodium-catalyzed intermolecular oxidative cross-coupling of (hetero)arenes with chalcogenophenes.

A straightforward and efficient method for the rhodium-catalyzed intermolecular oxidative cross-coupling of arenes and heteroarenes with thio- and selenophene derivatives (chalcogenophenes) via double C-H bond cleavage has been developed by using Cu(OAc)2/AgSbF6 as an oxidant. The reaction is applicable to a wide range of (hetero)arenes carrying a directing group and chalcogenophenes to yield substituted biaryl heterocyclic derivatives and oligothiophene derivatives in moderate to high yields.

Transesterification of Various Methyl Esters Under Mild Conditions Catalyzed by Tetranuclear Zinc Cluster

A new catalytic transesterification promoted by a tetranuclear zinc cluster was developed. The mild reaction conditions enabled the reactions of various functionalized substrates to proceed in good to high yield. A large-scale reaction under solvent-free conditions proceeded with a low E-factor value (0.66), indicating the high environmental and economical advantage of the present catalysis.

The Palladium-Catalyzed Intermolecular C–H Chalcogenation of Arenes

Palladium catalyzes the intermolecular chalcogenation of carbazole, 2-phenylpyridine, benzo[h]quinolone, and indole derivatives with disulfides and diselenides via selective C-H bond cleavage, providing a convenient route to thio and selenoethers.

Co-catalyzed cross-coupling of alkyl halides with tertiary alkyl Grignard reagents using a 1,3-butadiene additive.

The cobalt-catalyzed cross-coupling of alkyl (pseudo)halides with alkyl Grignard reagents in the presence of 1,3-butadiene as a ligand precursor and LiI is described. Sterically congested quaternary carbon centers could be constructed by using tertiary alkyl Grignard reagents. This reaction proceeds via an ionic mechanism with inversion of stereochemistry at the reacting site of the alkyl halide and is compatible with various functional groups. The use of both 1,3-butadiene and LiI was essential for achieving high yields and high selectivities.

Chemoenzymatic Synthesis of Glycosylated Glucagon-like Peptide 1: Effect of Glycosylation on Proteolytic Resistance and in Vivo Blood Glucose-Lowering Activity

Glucagon-like peptide 1 (7-36) amide (GLP-1) has been attracting considerable attention as a therapeutic agent for the treatment of type 2 diabetes. In this study, we applied a glycoengineering strategy to GLP-1 to improve its proteolytic stability and in vivo blood glucose-lowering activity. Glycosylated analogues with N-acetylglucosamine (GlcNAc), N-acetyllactosamine (LacNAc), and alpha2,6-sialyl N-acetyllactosamine (sialyl LacNAc) were prepared by chemoenzymatic approaches. We assessed the receptor binding affinity and cAMP production activity in vitro, the proteolytic resistance against dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase (NEP) 24.11, and the blood glucose-lowering activity in diabetic db/db mice. Addition of sialyl LacNAc to GLP-1 greatly improved stability against DPP-IV and NEP 24.11 as compared to the native type. Also, the sialyl LacNAc moiety extended the blood glucose-lowering activity in vivo. Kinetic analysis of the degradation reactions suggested that the sialic acid component played an important role in decreasing the affinity of peptide to DPP-IV. In addition, the stability of GLP-1 against both DPP-IV and NEP24.11 incrementally improved with an increase in the content of sialyl LacNAc in the peptide. The di- and triglycosylated analogues with sialyl LacNAc showed greatly prolonged blood glucose-lowering activity of up to 5 h after administration (100 nmol/kg), although native GLP-1 showed only a brief duration. This study is the first attempt to thoroughly examine the effect of glycosylation on proteolytic resistance by using synthetic glycopeptides having homogeneous glycoforms. This information should be useful for the design of glycosylated analogues of other bioactive peptides as desirable pharmaceuticals.

Diarylrhodates as Promising Active Catalysts for the Arylation of Vinyl Ethers with Grignard Reagents

Anionic diarylrhodium complexes, generated by reacting [RhCl(cod)]2 with 2 equiv of aryl Grignard reagents, were found to be effective active catalysts in cross-coupling reactions of vinyl ethers with aryl Grignard reagents, giving rise to the production of vinyl arenes. In this catalytic system, vinyl-O bonds were preferably cleaved over Ar-O or Ar-Br bonds. A lithium rhodate complex was isolated, and its crystal structure was determined by X-ray crystallography.

Endothelin generating pathway through endothelin1-31 in human cultured bronchial smooth muscle cells.

The effects of endothelin (ET)‐11–31 and ET‐21–31, human chymase products of the corresponding big ETs, on the intracellular free Ca2+ concentration ([Ca2+]i) and [125I]‐ET‐1 binding were investigated using human cultured bronchial smooth muscle cells (BSMC). ET‐11–31 (10−8 M – 3×10−7 M) and ET‐21–31 (3×10−8 M–3×10−6 M) caused an increase in [Ca2+]i in a concentration‐dependent manner. Big ET‐1 (3×10−8 M – 10−6 M) also caused this increase, but not big ET‐2 at concentrations up to 10−6 M. The [Ca2+]i increase induced by ET‐1 was inhibited by both BQ123, an ETA‐receptor antagonist, and BQ788, an ETB‐receptor antagonist, whereas that induced by ET‐3 was inhibited by BQ788 but not by BQ123. Increases in [Ca2+]i caused by ET‐11–31, big ET‐1 and ET‐21–31 were completely inhibited by 10−4 M phosphoramidon, a dual neutral endopeptidase (NEP)/endothelin‐converting enzyme (ECE) inhibitor, and 10−5 M thiorphan, a NEP inhibitor. Scatchard plot analyses of the saturation curves of [125I]‐ET‐1 and [125I]‐ET‐3 showed that both ETA‐ and ETB‐ receptors at the ratio of 4 : 1 were expressed on BSMC. ET‐11–31, big ET‐1 and ET‐21–31 inhibited [125I]‐ET‐1 binding in a concentration‐dependent manner, and these effects were attenuated by treatment with thiorphan. On the other hand, big ET‐2 slightly inhibited the binding at a high concentration and this was not affected by thiorphan. These results suggest that ET‐11–31, big ET‐1 and ET‐21–31 cause an increase in [Ca2+]i by being converted into the corresponding ET‐1 and ET‐2 by NEP, but this did not occur with big ET‐2 in human BSMC. ET‐21–31 produced by human chymase from big ET‐2 might be important for the generation of ET‐2 in human bronchial tissue.

A tetranuclear-zinc-cluster-catalyzed practical and versatile deprotection of acetates and benzoates

A new catalytic deacylation of acetates and benzoates through transesterification with methanol was developed (see scheme). Reactions with various acid- and nucleophile-sensitive functional groups proceeded efficiently in the presence of a catalytic amount of the tetranuclear zinc cluster. The present catalysis is applicable to less-reactive tertiary acetates, the deacylation of which is difficult to achieve by transesterification with other catalysts.

Copper-catalyzed coupling reaction of unactivated secondary alkyl iodides with alkyl Grignard reagents in the presence of 1,3-butadiene as an effective additive

Cu-catalyzed cross-coupling of unactivated secondary alkyl iodides with alkyl Grignard reagents in the presence of 1,3-butadiene as a ligand precursor was developed. The use of 1,3-butadiene resulted in improved yields of alkyl-alkyl products with improved selectivities.