Noteworthy Chemistry

April 18, 2011

A promising small-molecule inhibitor for treating asthma. Nitric oxide and its major metabolite S-nitrosothiol (SNO) are produced by the body to regulate the cardiovascular, pulmonary, and gastrointestinal (GI) systems, among others. The enzyme S-nitrosoglutathione reductase (GSNOR) regulates SNO by reducing S-nitrosoglutathione (GSNO). SNO elicits many biological functions of NO and is a stable adduct for NO, which has a short biological half-life.

Reduced SNO concentrations are found in the lungs of asthma patients and are probably caused by the up-regulation of GSNOR activity. In certain GI disorders, reduced GSNO and NO levels are evident and may be a result of GSNOR activity up-regulation. These observations suggest that GSNOR inhibitors may be valuable for treating many diseases, including asthma.

X. Sun and coauthors at N30 Pharmaceuticals (Boulder, CO), Simpharma (Guilford, CT), and Emerald BioStructures (Bainbridge Island, WA) identified potent small-molecule GSNOR inhibitors based on a highly functionalized pyrrole scaffold. They developed two synthetic methods that lead to roughly equivalent yields of candidate inhibitor compounds, and they assessed appropriate structure–activity relationships over a range of substituent groups.

Their work led to optimized inhibitor structure 1, which has inhibitory concentrations in the nanomolar range (IC50 = 20 nM). Incorporating the imidazole moiety on the phenyl ring in 1 appears to produce the most significant enhancement of inhibitory properties.

Compound 1 shows excellent in vivo activity, as manifested by reduced bronchoconstriction and pulmonary inflammation in a mouse model of asthma. The authors note that 1 is selective and reversible; it is in clinical development as a treatment for acute asthma. (ACS Med. Chem. Lett. 2011, 2, Article ASAP DOI: 10.1021/ml200045s; W. Jerry Patterson)

Inclusion complexation gives a [3]pseudorotaxane. Easy access to rotaxanes is a prerequisite for making molecular machines. The usual ways to prepare rotaxanes include capping, clipping, and slipping, in which the molecular components are organized with the use of hydrogen bonding, metal coordination, hydrophobicity, coulombic interactions, and other interatomic forces. Y. Liu and co-workers at Nankai University (Tianjin, China) developed a “bottom-up” technique and guest-exchange process for synthesizing a “heterowheel” pseudorotaxane.

The researchers prepared a heterowheel [3]pseudorotaxane by integrating binary inclusion complexes of β-cyclodextrin (β-CD)–naphthalene-2,6-diol⋅(green and red in the figure) and cucurbit[8]uril–viologen-functionalized adamantine (blue and violet). The simultaneous molecular recognition of the adamantine moiety by β-CD and the charge transfer between the naphthalenediol and viologen units in the cucurbit[8]uril cavity are the main driving forces for forming the quaternary complex. (Org. Lett. 2011, 13, 856–859; Ben Zhong Tang)

How does a Pummerer byproduct form during Moffatt oxidations? When other oxidation methods for converting a 3-azacycloheptanol to the corresponding cycloheptanone proved unreliable, S. N. Goodman and co-workers at GlaxoSmithKline (King of Prussia, PA) optimized the original Moffatt oxidation with DMSO and Ac2O. The reaction is sensitive to water and requires high levels of DMSO. The workup also requires excessive amounts of water and EtOAc.

The authors carried out a design-of-experiments study that focused on the effect of concentration in DMSO, equivalents of Ac2O, equivalents of water, and temperature. Ac2O and water levels had the greatest effects on the relative yields of the Pummerer reaction byproduct, a methylthiomethyl ether, and the desired ketone.

The authors explained this result by examining the reaction mechanism: Ac2O and DMSO combine to form an acylated DMSO cationic intermediate that can react with the alcohol substrate to give the ketone, AcOH, and Me2S or eliminate AcOH to form CH2=SMe+, which leads to the Pummerer byproduct. Any water present hydrolyzes Ac2O to form AcOH, which, the authors believe, hinders the reaction of the acylated DMSO cationic intermediate with the substrate and favors formation of the Pummerer byproduct. (Org. Process Res. Dev. 2011, 15, 123–130; Will Watson)

Microfluidic technology produces coordination polymer nanofibers. D. Maspoch, P. S. Dittrich, and coauthors at ETH Zurich and Catalan Institute of Nanotechnology (Bellaterra, Spain) produced aligned 1-D nanofibers of coordination polymers by using interfacial reactions within a microfluidic device. They demonstrated the technology’s applicability in a variety of systems, including Cu(II)-aspartate, Ag(I)-cysteine, and others that cannot be synthesized in bulk; assembly times were measured in microseconds.

The microreactor consists of two flow streams containing the reactant solutions and two containing auxiliary aqueous streams (see figure). Spatial control of nanofiber formation within the microreactor is achieved by regulating flow rate. For example, the coordination polymer nanofiber was synthesized in the middle of the channel under equivalent flow conditions, but it can also be directed to the channel walls by reducing two flow rates.

The ≈50–200 nm diam nanofibers formed from Cu(II)-Asp are collected as bundles regardless of precursor concentration <1 M. The researchers also demonstrated the capability of parallel reaction technology to generate gel coordination materials, scale up nanofiber production, and produce templated 4–9 nm diam nanoparticles in a chainlike microstructure. (J. Am. Chem. Soc. 2011, 133, 4216–4219; LaShanda Korley)

Carbon dioxide induces micellization in polymer solutions. CO2 is soluble in many organic solvents and can change solvent and solute properties considerably. Compressed CO2 can stabilize micelles, precipitate particles, and change particle morphology in emulsion systems.

J. Zhang, B. Han, and co-workers at the Chinese Academy of Sciences (Beijing) discovered a new CO2 phenomenon: The compressed gas stimulates micelle formation from a series of triblock poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO-b-PPO-b-PEO) copolymers in an aqueous medium.

At 15 °C, PEO-b-PPO-b-PEO dissolves evenly in water. Applying moderate CO2 pressure exaggerates the hydrophobicity of the PPO fraction and triggers phase separation. This action forms amphoteric micelles with PPO as the core and hydrophilic PEO that protects the micelle structure. With increasing gas pressure, some PEO segments are forced into the core to make it amphiphilic, and the particles swell significantly because the core also absorbs water and CO2. The micelles collapse, and a homogeneous system re-forms when the pressure is released. (Chem.—Eur. J. 2011, 17, 4266–4272; Sally Peng Li)

Careful optimization simplifies click reactions. The copper-catalyzed [3 + 2] cycloaddition of alkynes and azides to form 1,2,3-triazoles is the basis for now-familiar click chemistry. This efficient transformation is typically mediated by large amounts of [CuBr(PPh3)3] catalyst and a reducing agent such as sodium ascorbate. Yet no true click system has been reported for this complex. (Click conditions specify that the reaction is insensitive to water and oxygen, proceeds under mild conditions neat or in benign solvents, and allows product recovery without chromatographic purification.)

S. Lal and S. DÍez-GonzÁlez* at Imperial College London studied the model reaction of phenylacetylene with benzyl azide to form 1,4-disubstituted 1,2,3-triazole 1 in an effort to optimize the reaction conditions. They carried out the reaction at room temperature with no solvent and used 0.5 mol% catalyst without any other additive. A reaction time of 3 h gave a 99% yield of 1 without a chromatographic purification step. At this catalyst loading, turnover numbers (TONs) approaching 20,000 were achieved. The use of only 0.1 mol% catalyst and longer reaction time gave a >95% yield of 1.

Aryl, benzyl, and alkyl azides react well under these conditions. The process tolerates several reactive functional groups, including alcohol, ester, amine, pyridine, nitrile, halogen, nitro, and trimethylsilyl.

The authors challenged their optimized process by preparing difficult glycosides such as 2, which formed in 97% yield with somewhat higher catalyst loading. They note that the highly efficient catalyst complex is commercially available or can be prepared in a few minutes from CuBr2 and PPh3. (J. Org. Chem. 2011, 76, 2367–2373; W. Jerry Patterson)

“Smart” gels respond reversibly to multiple stimuli. Researchers have prepared various forms of gels, including hydrogels, organogels, aerogels, and xerogels. Despite much research to develop functional gels, “intelligent” gels that respond simultaneously to multiple stimuli are rare. J. Y. Zhang, Y. Wang, and coauthors at Jilin University (Changchun, China) and the Chinese People’s Armed Police Force Academy (Langfang) report a synthesis of multiply responsive gels.

The authors prepared a series of cholesteryl-functionalized quinacridone derivatives such as 1. Organogels were readily formed when a solution (sol) of 1 was irradiated by ultrasound. Ultrasonication also changed the color of the compound from green to orange. Heating the gel induced a reverse gel-to-sol transition and color change.

Xerogels of 1 changed emission color from yellow to orange when heated, and grinding converted the orange emission back to yellow. Gelator 1 is thus truly “smart”: its organogels and xerogels show reversible sono-, thermo-, and piezochromic effects in response to ultrasonic, thermal, and mechanical stimuli, respectively. (Sci. Chin. Chem. 2011, 54, 641–650; Ben Zhong Tang)

What do you think of Noteworthy Chemistry? Let us know.