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Compounds with multiple bonds between elements of the second and fifth periods are extremely unstable, and systematic investigations into their properties remain elusive. Herein, we report a tellurium-centered heteroallene that contains multiple bonds between carbon and tellurium. This compound is the first example of bis(methylene)-λ 4 -tellane, which was synthesized and fully characterized using multinuclear NMR spectroscopy and X-ray crystallography. In the solid state, this λ 4 -tellane exhibits a bent allene structure for the C═Te═C moiety and unsaturated Te-C bonds. Interestingly, the allene-type structure is retained in the solution, which is reflected in an absorption band due to the π-π* transition at 610 nm. This λ 4 -tellane also exhibits unique reactivity toward dihalogermylenes, which yielded rare cyclic telluragermetanes.

Azide-oligo(ethylene glycol)-terminated self-assembled monolayers (N 3 -OEG-SAMs) are promising interfacial structures for surface functionalization. Its many potential applications include chemical/bio-sensing and construction of surface models owing to its cross-coupling activity that originates from the azide group and oligo(ethylene glycol) (OEG) units for non-specific adsorption resistance. However, there are only a few studies and limited information, particularly on the molecular-scale structures and local cross-coupling activities of N 3 -OEG-SAMs, which are vital to understanding its surface properties and interfacial molecular design. In this study, molecular-scale surface structures and cross-coupling activity of azide-hexa(ethylene glycol)-terminated SAMs (N 3 -EG 6 -SAMs) were investigated using frequency modulation atomic force microscopy (FM-AFM) in liquid. The N 3 -EG 6 -SAMs were prepared on Au(111) substrates through the self-assembly of 11-azido-hexa(ethylene glycol)-undecane-1-thiol (N 3 -EG 6 -C 11 -HS) molecules obtained from a liquid phase. Subnanometer-resolution surface structures were visualized in an aqueous solution using a laboratory-built FM-AFM instrument. The results show a well-ordered molecular arrangement in the N 3 -EG 6 -SAM and its clean surfaces originating from the adsorption resistance property of the terminal EG 6 units. Surface functionalization by the cross-coupling reaction of copper(I)-catalyzed azide-alkyne cycloaddition was observed, indicating a structural change in the form of fluctuating structures and island-shaped structures depending on the concentration of the alkyne molecules. The FM-AFM imaging enabled to provide information on the relationship between the surface structures and cross-coupling activity. These findings provide molecular-scale information on the functionalization of the N 3 -EG 6 -SAMs, which is helpful for the interfacial molecular design based on alkanethiol SAMs in many applications.

Sophoraflavanone H ( 1 ) is a polyphenol with a hybrid-type structure containing 2,3-diaryl-2,3-dihydrobenzofuran and flavanone ring moieties. This compound and related analogues are promising leads for antimicrobial and antitumor drug development. Here we describe a total synthesis of 1 and its diastereomer. The dihydrobenzofuran and flavanone rings were constructed by a Rh-catalyzed asymmetric C-H insertion reaction and selective oxy-Michael reaction. The absolute configuration of 1 was established by X-ray crystallographic analysis and CD spectral investigation of synthetic derivatives.

The first total synthesis of (7″ R ,8″ R )-, (7″ S ,8″ S )-isomers of princepin ( 1 ) and (7″ R ,8″ R )-, (7″ S ,8″ S )-isomers of isoprincepin ( 2 ) was accomplished in a highly stereoselective manner via para quinomethide-mediated construction of the furofuran and 1,4-benzodioxane rings. Structural confirmation methods of 1 and 2 were established by CD and HPLC analysis of each diastereomers with natural products.

The metabolism of imidazole-4-carboxamide (ICA) in plants has been unknown. Two metabolites ( 1 and 2 ) were isolated from ICA-treated rice, and their structures were determined by spectroscopic analysis including the single-crystal X-ray diffraction technique and synthesis. The ribotide of ICA ( 3 ), whose existence was predicted, was also synthesized and detected from the treated rice by LC-MS/MS. These results indicated that rice might interconvert ICA, 1 , and 3 to regulate the biological activity.

Plant growth stimulators, 2-azahypoxanthine (AHX) and 2-aza-8-oxohypoxanthine (AOH), were isolated from the fairy-ring-forming fungus, Lepista sordida, and AHX-treated rice, respectively. Further metabolites of AHX were detected in AHX-treated rice by HPLC, and the metabolites 1-4 were isolated from the rice. The structures of 1-4 were determined by spectroscopic analysis and synthesis. Compounds 1-4 exhibited no significant activity against rice, indicating that rice regulates the activity of AHX and AOH by converting them into their glucosides.

Neuromedin U (NMU) is a neuropeptide that mediates a variety of physiological functions via its receptors, NMUR1 and NMUR2. Recently, there has been an increased focus on NMU as a promising treatment option for diabetes and obesity. A short form of NMU (NMU-8) has potent agonist activity for both receptors but is metabolically unstable. Therefore, we designed and synthesized NMU-8 analogues modified by polyethylene glycol (PEG; molecular weight, 20 kDa; PEG20k) via a linker. 3-(2-Naphthyl)alanine substitution at position 19 increased NMUR2 selectivity of NMU-8 analogues with retention of high agonist activity. Compound 37, an NMUR2-selective PEG20k analogue containing piperazin-1-ylacetyl linker, exhibited a potent body weight-lowering effect with concomitant inhibition of food intake in a dose-dependent manner (body weight loss of 12.4% at 30 nmol/kg) by once-daily repeated dosing for 2 weeks in mice with diet-induced obesity.

An efficient total synthesis of TAN1251C was accomplished by employing a Ugi four-component accumulation reaction and a Dieckmann condensation to construct the spiro-fused cyclohexanone and γ-lactam ring. Diastereoselective reduction by side-chain-controlled hydrogenation of enamide 15 or Zn reduction of oxime 23 enabled construction of the amino group with the desired stereochemistry.

The cyclopentane core framework 23 of pactamycin (1) was synthesized in 14 steps from symmetric cyclohexadiene 11. Our synthetic strategy features Rh-mediated catalytic desymmetrization of 10 via aziridination and then regioselective ring-opening reaction of sulfonylaziridine 9 with NaN 3 , ring-contraction of cyclohexene 14 by ozonolysis followed by intramolecular aldol reaction, and stereoselective construction of the sequential tetrasubstituted carbons by dihydroxylation and methylation reaction. Stereospecific incorporation of amine on tetrasubstituted carbon was achieved by Curtius rearrangement and subsequent carbamide formation.

The total synthesis of hedyotol A (1), a natural product isolated from Hedyotis lawsoniae (DC.) Wight et Arn. (Rubiaceae), was accomplished in a highly stereocontrolled manner. Key steps include an L-proline-catalyzed cross-aldol reaction and the biomimetic construction of a furofuran lignan skeleton through a quinomethide intermediate.

Practical total syntheses of acromelic acids A (1) and B (2), which have potent neuro-excitatory activity, were accomplished in 13 (36% total yield) and 17 steps (6.9% total yield), respectively, from 2,6-dichloropyridine (8). Regioselective transformation of symmetric 8 provided nitroalkenes 15 and 16. The pyrrolidine ring was efficiently constructed by Ni-catalyzed asymmetric conjugate addition followed by intramolecular reductive amination.

Total synthesis of SB-203207 (1) was achieved, beginning with a desymmetrical C-H insertion reaction of a diazoester bearing our recently developed chiral auxiliary. Utilizing the optically active bicyclo[3.3.0]octane ring, four stereogenic centers were efficiently constructed in sequence. Finally, mild oxidation of 27 to carboxylic acid via a cyanohydrin intermediate and hydrolysis of cyanide to carboxyamide in the presence of the labile enamide group completed an efficient total synthesis of 1.

A practical total synthesis of kainoid MFPA (5) was achieved in only six steps, via a novel Ni-catalyst-mediated asymmetric conjugate addition reaction. Furthermore, a fluorescein-based fluorescent ionotropic glutamate receptor probe 28 was efficiently synthesized from a precursor derived from a synthetic intermediate of 5.

Chemoselective hydrogenation of unsaturated compounds bearing an o-nitrobenzenesulfonyl (Ns)-amide moiety, affording the corresponding saturated compounds, was accomplished efficiently without loss of the nitro group by using the Pd/MS3A catalyst and a H2 balloon. Partial hydrogenation of alkynes bearing an Ns group to corresponding cis alkenes was achieved with the combination of the Pd/BN catalyst and an additive (diethylenetriamine or acetic acid).

Asymmetric bromolactonization of prochiral cyclohexadiene derivatives with N-bromosuccimide proceeded in the presence of (DHQD)(2)PHAL as a chiral catalyst to afford the corresponding bromolactones with up to 93% ee. This reaction was also applicable to the kinetic resolution of a racemic cyclic ene-carboxylic acid, where the starting material was recovered with high enantioselectivity.

In our previous work, we found that synephrine has six conformers in the gas phase, while adrenaline, which is a catecholamine and has the same side chain as synephrine, has been reported to have only two conformers. To determine the conformational geometries of synephrine, we measured resonance enhanced multiphoton ionization, ultraviolet-ultraviolet hole burning, and infrared dip spectra by utilizing the laser desorption supersonic jet technique. By comparing the observed infrared spectra with theoretical ones, we assigned geometries except for the orientations of the phenolic OH group. Comparison between the determined structures of synephrine and those of 2-methylaminno-1-phenylethanol, which has the same side chain as synephrine but no phenol OH group, leads to the conclusion that the phenolic OH group in synephrine does not affect the conformational flexibility of the side chain. In the case of adrenaline, which is expected to have 12 conformers if there are no interactions between the catecholic OH groups and the side chain, some interactions possibly exist between them because only two conformations are observed. By estimation of the dipole-dipole interaction energy between partial dipole moments of the catecholic OH groups and the side chain, it was concluded that the dipole-dipole interaction stabilizes specific conformers which are actually observed., (© 2011 American Chemical Society)

An efficient total synthesis of aperidine was accomplished using a Rh-catalyzed C-H insertion of a cis-dihydrobenzofuran ring. To circumvent the facile epimerization of the cis-dihydrobenzofuran ring, we designed and prepared the C-H insertion precursor diazoamide by Raines' protocol. Finally, the efficient incorporation of a guanidine group and mild deprotection conditions yielded this labile natural product.

The efficient total syntheses of (+)-methoxyphenylkainic acid (3) and (+)-phenylkainic acid (4) were achieved using a rhodium carbenoid-mediated intermolecular C-H insertion reaction. Complete stereoselective construction of the kainoid skeleton was accomplished by utilizing the stereochemistry at the C-4 position as a pivotal stereogenic center.

Inhibition of dipeptidyl peptidase IV (DPP-4) is an exciting new approach for the treatment of diabetes. To date there has been no DPP-4 chemotype possessing a carboxy group that has progressed into clinical trials. Originating from the discovery of the structurally novel quinoline derivative 1, we designed novel pyridine derivatives containing a carboxy group. In our design, the carboxy group interacted with the targeted amino acid residues around the catalytic region and thereby increased the inhibitory activity. After further optimization, we identified a hydrate of [5-(aminomethyl)-6-(2,2-dimethylpropyl)-2-ethyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid (30c) as a potent and selective DPP-4 inhibitor. The desired interactions with the critical active-site residues, such as a salt-bridge interaction with Arg125, were confirmed by X-ray cocrystal structure analysis. In addition, compound 30c showed a desired preclinical safety profile, and it was encoded as TAK-100.

The stereoselective synthesis of the key intermediate for altemicidin has been accomplished. The synthesis commenced with a bicyclo[3.3.0] framework, which was readily obtained via an intramolecular C-H insertion reaction. A Curtius rearrangement was employed as a key step to stereoselectively construct the beta-hydroxyl alpha-disubstituted-alpha-amino acid structure. Synthesis of vinylogous urea was achieved using hydrolysis of nitrile intermediate.

Small angle neutron scattering measurements have been performed on three systems (HFDeP-d5-C (N-1(1,1,2,2-tetrahydroperfluorodecanoyl)pyridinium-d5 chloride)/C16PC in 63 mM NaCl; HFDeP-d5-C/C12PC in 200 mM NaCl, and as an example of an ideally mixed system, SDS/SDS-d25 in 200 mM NaCl) containing micelles formed in a binary mixture of surfactants, in order to investigate the composition distribution of the mixed micelles. The experimental data were collected varying the contrast between the average scattering length density of micelles and aqueous solvent by changing the H2O/D2O ratio. Analysis of data includes a model-independent approach--the indirect Fourier transformation method and direct modeling-simultaneous fit at all contrasts by the scattering from micelles of equal size and shape with composition distribution and an effective interaction. It has earlier been shown (Almgren, M.; Garamus, V. M. J. Phys. Chem. B 2005, 109, 11348) that for micelles of equal size, independent of the composition, and with negligible intermicellar interactions, the scattered intensity at zero angle varies quadratically with the contrast, with the minimum intensity at the nominal match point proportional to sigma2, the variance of the micelle composition distribution. Within the regular solution framework, the composition distribution and its variance are uniquely defined by the value of the interaction parameter and the micelle aggregation number. At 25 degrees C, the first system gave sigma = 0.37, corresponding to a broad, bimodal composition distribution, the second sigma = 0.22, a broad distribution with a shallow minimum at the midpoint. For SDS/SDS-d25, we found sigma = 0.006 +/- 0.030, which is a smaller value than that of the binominal composition distribution expected for an ideally mixed system.

Alogliptin is a potent, selective inhibitor of the serine protease dipeptidyl peptidase IV (DPP-4). Herein, we describe the structure-based design and optimization of alogliptin and related quinazolinone-based DPP-4 inhibitors. Following an oral dose, these noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and a lowering of blood glucose in animal models of diabetes. Alogliptin is currently undergoing phase III trials in patients with type 2 diabetes.

An aggregation behavior of potassium N-acyl phenylalaninate in dilute aqueous solution was investigated. It was found that this surfactant formed large aggregates at lower concentrations, which were then transformed to micelles at higher concentrations. Fluorescence intensity measurements using a probe were used to examine the effects of alkali concentration, acyl chain length, and solvent isotope on the aggregation behavior. The influence of the alkali concentration suggested that formation of an acid-soap dimer brought about the construction of the large particles at very dilute concentrations. Increases in both the acyl chain length and replacement of H(2)O with D(2)O resulted in stronger hydrophobic interactions; consequently, the large aggregate formation was enhanced. This aggregation behavior has not been observed when racemic modification of N-acyl phenylalaninate has taken place. By using cryo-transmission electron microscopy (TEM) with a Zernike differential contrast phase plate, it was found that the large aggregates were tubes with bilayer structures, which were then transformed into spherical micelles via threadlike micelles with increasing concentration due to a drastic increase in the concentration of ionic species in the aggregate.

New gemini surfactants having two fluorocarbon chains were prepared by refluxing partially fluorinated alkyl bromide with N,N,N',N'-tetramethyl-1,6-diaminohexane in acetonitrile. The partially fluorinated gemini surfactants containing a six-methylene spacer chain are easily soluble in water. The critical micelle concentrations (cmc's) were determined by various fluorescent probe methods. The hydrophobicity of a CF2 group was estimated to be 1.5 times that of a CH2 group according to the cmc values. The micelle micropolarity of a fluorocarbon gemini sensed by pyrene fluorescence was unusually high, suggesting an apparent iceberg-like environment in the location of pyrene. The significantly small micelle aggregation numbers of fluorinated gemini surfactants were ascertained by the pyrene fluorescence quenching method. The micelle ionization degree estimated by fluorescence quenching of 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ) gave tendencies similar to those of the corresponding hydrocarbon geminis.

The surface-deformation characteristics of uniaxially drawn poly(ethylene terephthalate) (PET) film were successfully evaluated with multiline scratch tests using scanning probe microscopy (SPM) on a nanometer scale. The PET film was prepared by compression molding from the melt, followed by quenching in ice water. The obtained amorphous film was drawn uniaxially below its glass-transition temperature, and the resultant surface roughness could be reduced to within 5 nm. A multiline scratch with the Si(3)N(4) tip of an SPM on the oriented PET surface was made parallel and perpendicular to the drawing axis under applied loads of 5-30 nN. The perpendicular scratching generated a characteristic periodic pattern on the film surface, but the parallel scratching induced a tearing of the surface. These results suggest that surface-deformation mechanisms were dominated by molecular anisotropy. The surface-deformation properties, as evaluated from scratch-angle dependences on morphological changes on a nanometer scale, were similar to the mechanical properties of the bulk.

The degree of micelle ionization of gemini surfactants has been investigated by using halide-sensitive fluorescence probes (e.g., 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ)). The fluorescence is quenched by the free bromide ions dissociated from surfactants. The degree of micelle ionization increased with increasing spacer chain length, but it decreased with increasing surfactant concentration. The Stern-Volmer plot gave two inflection points (i.e., not only at the cmc but also far above the cmc). The second inflection point suggested spherocylindrical micellar growth with decreases in the degree of micelle ionization. The spherocylindrical micellar growth was depressed with increasing spacer chain length, whereas it was enhanced with increasing tail chain length. The degree of micelle ionization of spherocylindrical micelles depended on the concentration and chain length of gemini surfactants. The change in SPQ fluorescence spectra upon hydrogenation was utilized to evaluate the solubilization site in micelle solutions. The dissolved SPQ in water was instantly reduced by the addition of NaBH4, resulting in abrupt changes in fluorescence intensity and spectral shift. All of the SPQ in micelle solution was also instantly reduced by NaBH4, indicating the existence of SPQ in the water bulk phase, but its fluorescence intensity increased upon the solubilization of hydrogenated SPQ into micelles.

A halide-sensitive fluorescence probe was utilized to evaluate the miscibility of fluorocarbon and hydrocarbon surfactants in aqueous micellar systems. The fluorescence of 6-methoxy-N-1,1,2,2-tetrahydroheptadecafluorodecylquinolinium chloride, FC10MQ, was quenched by halide ions dissociated from the surfactant. The fluorescence in micellar solutions showed an initially rapid decay. This suggests that halide ions effectively quench FC10MQ fluorescence at the micellar surface. The subsequent slow decay corresponds to the quenching of FC10MQ fluorescence in the aqueous bulk phase by the free counterions. The Stern-Volmer plots for fluorescence quenching gave a distinct break at the critical micelle concentration of the cationic surfactants. The abrupt increase in fluorescence quenching is attributed to the solubilization of the probe in the micelles. The fluorescence quenching behavior provides direct information about the immiscibility of fluorocarbon and hydrocarbon species in micelles, and the results indicate that almost pure fluorocarbon micelles appear in surfactants mixtures.

The association behaviors of three 1-octanols (1-octanol:  C8OH; 1,1,2,2-tetrahydrotridecafluorooctanol:  TFC8OH; and 1,1-dihydropentadecafluorooctanol:  DFC8OH) in two hydrocarbon solvents (n-hexane and benzene) were examined by vibration spectroscopy from 288.15 to 318.15 K. From the analysis of results with a mass action model, it was found that dimers and tetramers of 1-octanols coexisted with monomers in the n-hexane solution. These aggregates were formed by hydrogen bonding between the OH groups of 1-octanols. In the n-hexane solutions, an increase in the fluorination number of the 1-octanol molecule enhanced the intermolecular hydrogen bonding between the OH groups, but reduced the amounts of polymeric species. Conversely, in the benzene solution, the NIR experiment suggested that the OH groups of 1-octanols did not interact with other OH groups, but with the benzene molecules instead. It was found from (19)F NMR chemical shift measurements that the fluorooctanols in the benzene solution aggregated by interaction between the fluorocarbon chains instead of by hydrogen bonding.