Chemoselective Hydrogenolysis of Urethanes to Formamides and Alcohols in the Presence of More Electrophilic Carbonyl Compounds.

The development of methods for the chemical recycling of polyurethanes is recognized as an urgent issue. Herein, we report the Ir-catalyzed hydrogenolysis of the urethane C-O bond to produce formamides and alcohols, where both formamides and ester and amide functionalities are tolerated. The chemoselectivity observed is counterintuitive to the generally accepted electrophilicity order of carbonyl compounds. Hydrogenolysis of urea and isocyanurate, potential byproducts in the polycondensation process of polyurethanes, is also achieved alongside the selective degradation of polyurethanes themselves, which affords diformamides and diols. The time-course of the hydrogenative polyurethane degradation reveals that the bond cleavage occurs not from the terminal, but from any part of the polymer chain. The present catalysis offers a novel method for the recycling of polyurethane-containing polymer waste.

Linear, Planar, Orbicular, and Macrocyclic Multinuclear Zinc (Meth)acrylate Complexes.

Zinc carboxylate complexes are widely utilized as artificial models of metalloenzymes and as secondary building units of PCPs/MOFs. However, the relationship between the structure of the monodentate carboxylato ligand and the molecular arrangement of multinuclear zinc carboxylate complexes is not fully understood because of the coordination flexibility of the Zn ion and carboxylato ligands. Herein, we report the structural analysis of a series of complexes derived from zinc (meth)acrylate which has a linear infinite chain structure. The molecular structure of µ4-oxido-bridged tetranuclear complexes [Zn4(µ4-O)(OCOR)6] revealed a distorted Zn4O core. Crystallization of zinc acrylate under aqueous conditions afforded a µ3-hydroxido-containing pentanuclear complex [Zn5(µ3-OH)2(OCOR)8] as the repeating unit of an infinite sheet-like structure in the solid state. It was also obtained by the hydrolysis of the µ4-oxido-bridged tetranuclear complex. In sharp contrast, the methacrylate analog retained the methacrylato ligands under aqueous crystallization conditions to form a macrocyclic dodecanuclear complex with methacrylato as the sole ligand.

Cross- and Multi-Coupling Reactions Using Monofluoroalkanes.

Carbon-fluorine bonds are stable and have demonstrated sluggishness against various chemical manipulations. However, selective transformations of C-F bonds can be achieved by developing appropriate conditions as useful synthetic methods in organic chemistry. This review focuses on C-C bond formation at monofluorinated sp3 -hybridized carbons via C-F bond cleavage, including cross-coupling and multi-component coupling reactions. The C-F bond cleavage mechanisms on the sp3 -hybridized carbon centers can be primarily categorized into three types: Lewis acids promoted F atom elimination to generate carbocation intermediates; nucleophilic substitution with metal or carbon nucleophiles supported by the activation of C-F bonds by coordination of Lewis acids; and the cleavage of C-F bonds via a single electron transfer. The characteristic features of alkyl fluorides, in comparison with other (pseudo)halides as promising electrophilic coupling counterparts, are also discussed.

Identification of novel benzimidazole derivatives as highly potent AMPK activators with anti-diabetic profiles.

Diabetes is a global healthcare problem that affects more than 400 million people worldwide. Treatment for type 1 and 2 diabetes is expected by targeting adenosine monophosphate activated protein kinase, AMPK, a well-known master regulator of glucose. Many pharmaceutical companies have tried to identify AMPK activators but few direct AMPK activators with high potency for the ß2-AMPK isoform, which is important for glucose homeostasis, have been found. In addition, their chemical structure is limited to benzimidazole or indole derivatives bearing an aromatic substituent at the C5 position of the core structure. We describe herein our efforts to identify novel benzimidazole derivatives that directly activate the ß2-AMPK isoform. Our newly designed activator 14d bearing a 1-amino indanyl moiety at the C5 position of the core exhibited high in vitro potency and good pharmacokinetic profiles. A single oral dosing of 14d showed dose-dependent activation of AMPK and blood-glucose-lowering effects was observed in a diabetic animal model. In addition, chronic AMPK activation with 14d led to dose-dependent reduction in HbA1c of the animal model.

Identification of novel indole derivatives as highly potent AMPK activators with anti-diabetic profiles.

AMP-activated protein kinase (AMPK) has been shown to play an important role in the beneficial effects of exercise on glucose and lipid metabolism in skeletal muscle and liver. Therefore, activation of AMPK has been proposed as an attractive strategy for the treatment of metabolic disorders, such as type 2 diabetes. Many of existing AMPK activators bearing diverse chemical structure were reported. However, there have been few reports of direct AMPK activator with high potency for ß2-AMPK isoform, which is thought to be important for glucose homeostasis, and their chemical structure is limited to benzimidazole core. We describe herein our efforts for identification of novel AMPK activator. Our newly designed 4-azaindole derivative 16g exhibited single-digit nM in vitro activity, and chronic treatment with 16g led to dose-dependent improvement in HbA1c as well as decrease in hepatic lipid accumulation in diabetic animal model.

Bio-inspired asymmetric aldehyde arylations catalyzed by rhodium-cyclodextrin self-inclusion complexes.

Transition-metal catalysts are powerful tools for carbon-carbon bond-forming reactions that are difficult to achieve using native enzymes. Enzymes that exhibit inherent selectivities and reactivities through host-guest interactions have inspired widespread interest in incorporating enzymatic behavior into transition-metal catalytic systems that highly efficiently produce enantiopure compounds. Nevertheless, bio-inspired transition-metal catalysts that are highly enantioselective and reactive have rarely been reported. In this study, we applied γ-cyclodextrin-imidazolium salts to the rhodium-catalyzed asymmetric arylations of aldehydes. The method exhibits wide substrate scope and the corresponding arylcarbinols are obtained in excellent yields under optimized conditions, with enantiomeric excesses of up to 96% observed. Kinetic and competition experiments revealed that self-inclusion of the Rh complex contributes to the high enantioselectivity and reactivity achieved by this catalytic system. Thus, this bio-inspired self-inclusion strategy is promising for the development of highly enantioselective and reactive transition-metal catalysts for asymmetric carbon-carbon bond formation.

Copper-Catalyzed Amination of C(sp3)-H bonds: From Anilides to Indolines.

Copper-catalyzed oxidative intramolecular cyclization of o-alkylated anilines via cleavage of C(sp3)-H and N-H bonds for the production of indolines is described. This approach provides a straightforward strategy for the synthesis of nitrogen-containing heterocyclic compounds through the functionalization of unactivated C(sp3)-H bonds with high site selectivity. The present catalytic system shows high preference for functionalization of unactivated C(sp3)-H bonds over C(sp2)-H bonds, leading to C-N bond formation.

Alternating Copolymerization of CO2 and Cyclohexene Oxide Catalyzed by Cobalt-Lanthanide Mixed Multinuclear Complexes.

Heteromultimetallic complexes consisting of three Co(II) ions and one lanthanide ion were synthesized and applied to the alternating copolymerization of CO2 and cyclohexene oxide. Unlike the conventional cobalt(III) salen complexes, the high thermal stability of the present catalyst allowed us to reach a turnover number of 13000, one of the highest values ever reported for multimetallic systems. The chain propagation was first-order to the catalyst, suggesting a cooperative behavior of the metal centers.

Molecular Packing and Solid-State Photophysical Properties of 1,3,6,8-Tetraalkylpyrenes.

The relationship between the photophysical properties and molecular orientation of 1,3,6,8-tetraalkylpyrenes in the solid state is described herein. The introduction of alkyl groups with different chain structures (in terms of length and branching) did not affect the photophysical properties in solution, but significantly shifted the emission wavelengths and fluorescence quantum yields in the solid state for some samples. Pyrenes bearing ethyl, isobutyl, or neopentyl groups at the 1-, 3-, 6-, and 8-positions showed similar emission profiles in both the solution and solid states. In contrast, pyrenes bearing other alkyl groups exhibited an excimer emission in the solid state, similar to that of the parent pyrene. On studying the photophysical properties in the solid state with respect to the obtained crystal structures, the observed solid-state photophysical properties were found to depend on the relative position of the pyrene chromophores. The solid-state photophysical properties can be controlled by the alkyl groups, which provide changing crystal packing. Among the pyrenes tested, 1,3,6,8-tetraethylpyrene showed the highest fluorescence quantum yield of 0.88 in the solid state.

Ni-Catalyzed Dimerization and Hydroperfluoroarylation of 1,3-Dienes.

A nickel-catalyzed three-component coupling reaction between perfluoroarenes and two molecules of a 1,3-diene in the presence of an alkyl Grignard reagent, which acted as a hydride source, provided 3-perfluoroarylated-1,7-octadienes via 1,3-diene dimerization and subsequent perfluoroarylation upon C-F bond cleavage. The reaction proceeded smoothly in a regioselective manner by simply combining NiCl2 and PPh3 as a catalyst and tolerated various functional groups on the perfluoroarenes. When substituted perfluoroarenes were employed, the reaction selectively occurred at the para-position. Mechanistic studies revealed that an anionic Ni complex, generated upon the reaction of Ni(0) with two molecules of a 1,3-diene and an alkyl Grignard reagent, played an important role in the C-C bond forming step with perfluoroarenes. The C-F bond cleavage was found to be a relatively fast step in the catalytic cycle.

Chronic hyperinsulinemia contributes to insulin resistance under dietary restriction in association with altered lipid metabolism in Zucker diabetic fatty rats.

Hyperinsulinemia is widely thought to be a compensatory response to insulin resistance, whereas its potentially causal role in the progression of insulin resistance remains to be established. Here, we aimed to examine whether hyperinsulinemia could affect the progression of insulin resistance in Zucker fatty diabetic (ZDF) rats. Male ZDF rats at 8 wk of age were fed a diet ad libitum (AL) or dietary restriction (DR) of either 15 or 30% from AL feeding over 6 wk. Insulin sensitivity was determined by hyperinsulinemic euglycemic clamp. ZDF rats in the AL group progressively developed hyperglycemia and hyperinsulinemia by 10 wk of age, and then plasma insulin rapidly declined to nearly normal levels by 12 wk of age. Compared with AL group, DR groups showed delayed onset of hyperglycemia and persistent hyperinsulinemia, leading to weight gain and raised plasma triglycerides and free fatty acids by 14 wk of age. Notably, insulin sensitivity was significantly reduced in the DR group rather than the AL group and inversely correlated with plasma levels of insulin and triglyceride but not glucose. Moreover, enhanced lipid deposition and upregulation of genes involved in lipogenesis were detected in liver, skeletal muscle, and adipose tissues of the DR group rather than the AL group. Alternatively, continuous hyperinsulinemia induced by insulin pellet implantation produced a decrease in insulin sensitivity in ZDF rats. These results suggest that chronic hyperinsulinemia may lead to the progression of insulin resistance under DR conditions in association with altered lipid metabolism in peripheral tissues in ZDF rats.

The role of acylated-ghrelin in the regulation of sucrose intake.

The octanoyl modification of ghrelin by ghrelin O-acyltransferase (GOAT) is essential for exerting its physiologic actions. Since exogenous acylated-ghrelin has shown to stimulate food intake in humans and rodents, GOAT has been regarded as a promising target for modulating appetite, thereby treating obesity and diabetes. However, GOAT-knockout (KO) mice have been reported to show no meaningful body weight reduction, when fed a high-fat diet. In this study, we sought to determine whether GOAT has a role in the regulation of body weight and food intake when fed a dietary sucrose. We found that GOAT KO mice showed significantly reduced food intake and marked resistance to obesity, when fed a high-fat + high-sucrose diet. In addition, GOAT KO mice fed a medium-chain triglyceride (MCT) + high-sucrose diet showed a marked resistance to obesity and reduced feed efficiency. These results suggest that blockade of acylated-ghrelin production offers therapeutic potential for obesity caused by overconsumption of palatable food.

Regioselective phosphorylation of myo-inositol with BINOL-derived phosphoramidites and its application for protozoan lysophosphatidylinositol.

A regioselective phosphorylation method for myo-inositol was developed by utilizing readily preparable BINOL-derived phosphoramidites. The method also facilitated the complete separation of the diastereomeric products by simple chromatography. Based on this phosphorylation and Ni-catalyzed alkyl-alkyl cross-coupling reaction for long fatty acids, we achieved the first synthesis of a lysophosphatidylinositol, EhPIa having long fatty acid C30:1, as a partial structure of glycosylphosphatidylinositol (GPI) anchor from the cell membrane of a protozoa, Entamoeba histolytica.

Nickel-Catalyzed Dimerization and Alkylarylation of 1,3-Dienes with Alkyl Fluorides and Aryl Grignard Reagents.

In the presence of a nickel catalyst, 1,3-butadiene undergoes selective dimerization and alkylarylation with alkyl fluorides and aryl Grignard reagents to give 1,6-octadienes with alkyl and aryl groups at the 3- and 8-positions, respectively, by the consecutive formation of three carbon-carbon bonds. The formation of an anionic nickel complex plays an important role in forming C-C bonds with alkyl fluorides.

Development of a novel immunoassay specific for mouse intact proinsulin.

The blood concentration of intact proinsulin, but not total proinsulin, has been suggested to be a diagnostic marker for type 2 diabetes mellitus (T2DM), but a sensitive assay specific for rodent intact proinsulin is lacking. Here, a novel enzyme-linked immunosorbent assay (ELISA) for mouse intact proinsulin was developed. The developed ELISA detected mouse intact proinsulin with the working range of 8.3 to 2700pg/ml. Cross-reactivity with mouse split-32,33 proinsulin was approximately 100times lower than the reactivity with mouse intact proinsulin, and no cross-reactivity with mouse insulin was detected. The developed ELISA was sufficiently sensitive to detect low levels of intact proinsulin in normal mouse plasma. The measurement by the developed ELISA revealed that intact proinsulin was elevated in the plasma of type 2 diabetic db/db mice as mice aged, and the ratio of intact proinsulin/insulin in plasma was correlated with levels of glycated hemoglobin A1c as seen in T2DM patients. These results suggest that the plasma level of intact proinsulin, but not total proinsulin, is a sensitive marker for pancreatic dysfunction and the ensuring diabetic disease progression of db/db mice. This ELISA could aid nonclinical evaluation of therapeutic interventions in T2DM.

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.

Nickel-catalyzed synthesis of diarylsulfides and sulfones via C-H bond functionalization of arylamides.

The direct sulfenylation and sulfonylation of (sp(2))C-H bonds of benzamide derivatives were achieved using a Ni catalyst with the aid of an 8-aminoquinoline moiety as a bidentate directing group. These protocols represent a convenient route for the formation of valuable diaryl sulfides and sulfones in moderate to excellent yields.

Copper-Catalyzed Regioselective Hydroalkylation of 1,3-Dienes with Alkyl Fluorides and Grignard Reagents.

Copper complexes generated in situ from CuCl2, alkyl Grignard reagents, and 1,3-dienes play important roles as catalytic active species for the 1,2-hydroalkylation of 1,3-dienes by alkyl fluorides through C-F bond cleavage. The alkyl group is introduced to an internal carbon atom of the 1,3-diene regioselectively, thus giving rise to the branched terminal alkene product.

cAMP-responsive element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) promotes glucagon clearance and hepatic amino acid catabolism to regulate glucose homeostasis.

cAMP-responsive element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) regulates transcription of gluconeogenic genes by specifying targets for the transcription factor CREB in response to glucagon. We used an antisense oligonucleotide directed against CRTC2 in both normal rodents and in rodent models of increased gluconeogenesis to better understand the role of CRTC2 in metabolic disease. In the context of severe hyperglycemia and elevated hepatic glucose production, CTRC2 knockdown (KD) improved glucose homeostasis by reducing endogenous glucose production. Interestingly, despite the known role of CRTC2 in coordinating gluconeogenic gene expression, CRTC2 KD in a rodent model of type 2 diabetes resulted in surprisingly little alteration of glucose production. However, CRTC2 KD animals had elevated circulating concentrations of glucagon and a ∼80% reduction in glucagon clearance. When this phenomenon was prevented with somatostatin or a glucagon-neutralizing antibody, endogenous glucose production was reduced by CRTC2 KD. Additionally, CRTC2 inhibition resulted in reduced expression of several glucagon-induced pyridoxal 5'-phosphate-dependent enzymes that convert amino acids to gluconeogenic intermediates, suggesting that it may control substrate availability as well as gluconeogenic gene expression. CRTC2 is an important regulator of gluconeogenesis with tremendous impact in models of elevated hepatic glucose production. Surprisingly, it is also part of a previously unidentified negative feedback loop that degrades glucagon and regulates amino acid metabolism to coordinately control glucose homeostasis in vivo.

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.