Noteworthy Chemistry

July 30, 2012

Here is a stable compound with a boron–boron triple bond. Except for carbon and nitrogen, stable homonuclear triple bonds occur rarely in main group elements. OCB≡BCO, which was isolated in an argon matrix at 8 K (Zhou, M., et al. J. Am. Chem. Soc. 2002, 124, 12936–12937), inspired numerous theoretical predictions for stable LB≡BL compounds, but none has been prepared until now. H. Braunschweig and colleagues at Julius Maximilians University WÜrzburg (Germany) isolated a compound (4) that has a verifiable B≡B bond at room temperature.

Assuming that reducing a preformed B−B bond can lead to the formation of an LB≡BL compound, the authors started from tetrabromodiborane (1). They first prepared N-heterocyclic carbene (NHC)–stabilized diborane 2. (Dip is 2,6-diisoproylphenyl.) Treating 2 with 2 and 4 equiv of sodium naphthalenide in THF at –78 °C yielded 3 (48%) and 4 (57%), respectively. Both products were isolated by removing naphthalene and then extracting them from solution.

As might be expected, the comproportionation of equimolar amounts of 2 and 4 in benzene-d6 at room temperature fully converts both compounds to 3. Triple-bonded structure 4 is stable at room temperature in the absence of air and moisture, and it does not decompose until it is heated to >234 °C.

11B NMR spectra of compounds 24 showed increasing chemical shifts from –4.8 to +39 ppm, consistent with a decrease in boron coordination number. The crystal structure of 3 revealed a B−B distance of 1.546 Å, in line with reported values for diborenes and theoretical predictions. The B−B distance decreased to 1.449 Å in 4; this result fits well with calculated values and measurements of other diborynes. The authors attribute the green color of 3 and 4 to their UV–vis absorptions in the blue and red regions, which is also consistent with calculated energy levels. (Science 2012, 336, 1420−1422; Xin Su)

Use copper to cleave glycol ether bonds. Despite widespread interest among chemists, there are only few reports of catalytic aerobic cleavage of ether C(sp3)–C(sp3) bonds. Z.-Q. Liu and coauthors at Lanzhou University (Lanzhou Gansu) and Gannan Normal University (Jiangxi, both in China) report an unexpected copper-catalyzed oxidative cleavage of C–C bonds in glycol ethers.

The authors first exposed p-anisic acid and 1,4-dioxane to copper and iron catalysts in the presence of an oxidant, Ag2CO3. One C–C dioxane bond was cleaved to form an α-acyloxy diester aldehyde. The best results were obtained with 1 mol% Cu2O.

The authors also discovered that Ag2CO3 could be replaced by less expensive K2CO3 (1 mol%) and molecular oxygen (1 atm) or even air (1 atm) as the oxidant (see figure). Several substituted aromatic, heteroaromatic, and benzylic acids worked as well as anisic acid, as did aldehydes if CuBr was substituted for Cu2O. When aromatic aldehydes that contain hydroxyl substituents (e.g., vanillin) were used, the reaction led to acylation and hydroxyl protection.

To demonstrate the method’s robustness and scale-up potential, the authors tested it on a 10-g sample of p-anisic acid. The method is atom-efficient, and it may contribute to the synthesis of α-acyloxy ethers that are the core of biologically active compounds such as artemisinin. The method can also be used to degrade glycol-based polymers. (Org. Lett. 2012, 14, 3218–3221; JosÉ C. Barros)

A sensitive fluorescent bioprobe “sees” low-abundance proteins. Protein analysis is important for proteomics researchers, who study biological processes at the protein level. A variety of bioprobes for protein assays have been developed, but many of them lack sensitivity and accuracy and require time-consuming procedures. A research team led by J. Ouyang at Beijing Normal University developed a sensitive fluorescence “switch-on” probe for visualizing proteins.

The probe is a readily accessible, environmentally stable fluorogen (1). When 1 is used for protein staining after polyacrylamide gel electrophoresis, its detection limit for ferritin in gel is 0.78 ng/μL. It easily detects several low-abundance proteins in serum. The fluorogen is an excellent bioprobe with these features:

  • It can visualize complete proteins in serum in a short time.
  • Its sensitivity is comparable with silver staining.
  • It is soluble and stable in aqueous media and therefore a “safe” stain.

(Chem. Commun. 2012, 48, 7395–7397; Ben Zhong Tang)

What is the best method for reducing a carbonyl group? The answer is, of course, “It depends,” because there are many variables to consider. The type of carbonyl group and other functionalities present in the molecule are two examples.

J. Magano* and J. R. Dunetz* at Pfizer Worldwide Research and Development (Groton, CT) review large-scale (>100 mmol) carbonyl group reductions that are used in the pharmaceutical industry, including hydride reductions and catalytic hydrogenations. They cover reduction reactions of aldehydes, ketones (symmetric and asymmetric), carboxylic acids, esters, amides, imides, and acid chlorides. Ester reductions are common whereas, surprisingly, aldehyde reductions are relatively rare. (Org. Process Res. Dev. 2012, 16, 1156–1184; Will Watson)

Coming soon: Oral, glucose-dependent type 2 diabetes drugs. Type 2 diabetes mellitus (T2DM) is a metabolism disorder characterized by high blood glucose levels (hyperglycemia) that occur when the pancreas cannot produce enough insulin or the body cannot properly use insulin. More than 90% of all diabetes patients have T2DM.

Current treatments successfully lower the blood glucose level, but these agents stimulate the pancreas to secrete insulin continuously regardless of prevailing glucose levels and can cause hypoglycemia. Oral agents that can induce glucose-dependent insulin secretion (GDIS) would be ideal for T2DM treatment.

S. He and 42 co-workers at Merck Research Laboratories (Rahway, NJ) found that agonists of somatostatin receptor SSTR3 may act as GDIS drugs for treating T2DM. They previously discovered that imidazolyl-β-carboline 1 is a potent, selective SSTR3 antagonist (Pasternak, A. et al. ACS Med. Chem. Lett 2012, 3, 289–293). But because 1 has potentially serious cardiovascular side effects, its structure had to be optimized.

When the authors optimized the structure–activity relationships of analogues of 1, they identified compounds 2 and 3 as candidates with better potency than 1 and much lower risks of adverse side effects. They then decided to combine the substituents N-methylpyrazole in 2 and 1,2,3-oxadiazole in 3 to create a series of disubstituted isomers such as compound 4, which is a highly potent STTR3 antagonist. In a mouse model, 4 also effectively lowered the blood glucose level in the oral glucose tolerance test in a dose-dependent manner without inducing hypoglycemia.

With these results in hand, the authors selected compound 4 for further development as a T2DM treatment. (ACS Med. Chem. Lett. 2012, 3, 484–489; Chaya Pooput)

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