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Noteworthy Chemistry

March 25, 2013

The Heck–Matsuda reaction goes green. The Heck–Matsuda reaction, unlike its parent, the Heck–Mizoroki reaction, has received limited attention since it was developed in 1977 despite its higher efficiency. R. M. SebastiÁn, C. NÁjera, and colleagues at the Autonomous University of Barcelona and the University of Alicante (both in Spain) revisited the Heck–Matsuda reaction and made it more practical and environmentally friendly.

The Heck–Matsuda reaction attaches aryl groups to olefins with arenediazonium salts instead of aryl halides that are used in the Heck–Mizoroki reaction. Dinitrogen is a better leaving group than chloride, and the aryl–nitrogen bond is more reactive toward Pd(0) than aryl–chlorine.

The authors first studied reactions between simple arenediazonium salts and olefins. For the reaction between 1a and 2a, the combination of 1 mol% palladacycle catalyst and a 3:1 MeOH–H2O solvent mixture at 60 °C gives styrene derivative 3a in 88% yield. In the reaction between 1b and 2a, product 3b is obtained in 93% yield with Pd(OAc)2 catalyst at room temperature in water. The result is similar (88% yield of 3c) for the reaction between 1c and 2b under the same conditions.


The authors expanded the scope of their method by using Pd(OAc)2 as catalyst and water solvent. In general, arenediazonium salts form styrene derivatives with alkyl acrylates, substituted styrenes, and other vinyl compounds in yields ranging from 10% to 95%. In most cases, yields are moderate-to-high (50%–95%). Sterically hindered diazonium salt 4 reacts with olefin 2b to give the corresponding styrene ester in 35% yield. (Tetrahedron 2013, 69, 2655–2659; Xin Su)

Controllable self-assembly of a drug conjugate may aid cancer therapy. H. Cui and co-workers at John Hopkins University (Baltimore) conjugated the hydrophobic drug camptothecin to a β-sheet-forming peptide sequence derived from the tau protein. They used supramolecular assembly to achieve high, quantitative drug loading and controlled drug release.

The drug and the peptide were conjugated via the disulfylbutyrate linker, which can be reduced by glutathione. Camptothecin loading ranges from 23% to 38%, depending on how many camptothecin molecules are attached to the lysine units in the peptide.

The authors observed fibrillar nanostructures with a core–shell arrangement in water. The fibers’ widths and lengths depend on camptothecin loading and related strong interactions induced by π-stacking. The hydrophobicity and π–π interactions introduced by camptothecin also enhance the stability and glutathione degradation of the nanostructured assemblies. The greatest stability occurs at the highest camptothecin loading.

The authors note that nanostructure formation is critical to controlling camptothecin release. In cancer cell line studies, the conjugate that contained 31% camptothecin was the most effective—possibly because of the balance between cellular uptake and cytotoxicity that is controlled by the conjugate’s hydrophilic/hydrophobic ratio. (J. Am. Chem. Soc. 2013, 135, 2907–2910; LaShanda Korley)

Tweaking a peptide chain terminus changes protein behavior. Understanding how terminal structure affects protein folding and aggregation is important in amyloid peptide research. The aggregation mechanisms induced by various terminal groups, however, are not well understood. Y.-M. Li and colleagues at Tsinghua University (Beijing) used the human amylin peptide as a model to study how altering the C-termini affects the aggregation and cytotoxicity of proteins.

The peptides used by the authors had the same chain sequence but different C-termini. They were natural amylin37-CONH2 and its variant amylin37-CO2H. The amide-terminated peptide aggregates much faster than the acid when both are incubated for 2 h. The faster aggregation of amylin37-CONH2 converts more oligomers into larger aggregates, which leads to lower cytotoxicity.

The authors believe that the stronger helix–helix interaction in amylin37-CONH2 causes it to aggregate faster. This work may be helpful for deciphering the peptide assembly mechanism and the developing cytotoxicity induced by terminus variation. (Chem. Commun. 2013, 49, 1799–1801; Ben Zhong Tang)

Skin secretions contribute to the effectiveness of insect repellents. Chemical repellents disrupt the behavior of blood-seeking mosquitoes and other insects by inhibiting olfactory coreceptors (e.g., OR83b in Anopheles gambiae and Drosophila melanogaster). The active ingredient in most commercially available repellents is N,N-dimethylbenzamide (DEET, 1) or N,N-diethyl-m-toluamide (DETA); but recently plant-based compounds such as terpenes have been found to have repellent properties.

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Repellents act in combination with skin secretions, notably L-(+)-lactic acid (2), one of the most abundant compounds in skin. J Song and coauthors at the University of Michigan—Flint, Jiangxi Agricultural University (Nanchang, China), East China Medical Biotechnology Research Institute (Nanjing), and Wellesley College (MA) developed quantitative structure–activity relationships (QSARs) for several terpene–lactic acid complexes.

The authors synthesized 20 compounds derived from the terpenes α- and β-pinene (3 and 4, respectively) and prepared lactic acid complexes from them. They used the corrected repellent ratio (CRR) of each complex as a measure of its repellency. CRR is the compound’s repellent activity compared with that of a control substance.

The QSAR model that best describes the complexes requires four descriptors: LUMO energy (an indication of electron-accepting power), minimum valence of an oxygen atom in the repellent, principal moment of inertia, and shadow area of the repellent over the xz plane. The results suggest that the structures of repellent–host compound complexes may be as important in repellency as the structures of the repellents alone. (Bioorg. Med. Chem. Lett. 2013, 23, 1245–1248; José C. Barros)

What’s the best reaction sequence for making a hydroxymethylpyridine? 2-Hydroxymethyl-6-cyclopropyl-4-(trifluoromethyl)pyridine is a key intermediate in the synthesis of a dual neurokinin 1–serotonin receptor antagonist. C. Risatti, K. J. Natalie, Jr., and co-workers at Bristol-Meyers Squibb (New Brunswick, NJ) used a Boekelheide rearrangement to access a precursor to the target molecule.

In the authors’ first route, commercially available 2-chloro-4-trifluoromethyl-6-methylpyridine was oxidized with m-chloroperbenzoic acid (m-CPBA) to the N-oxide, which was rearranged by treating it with (CF3CO)2O. The desired hydroxymethylpyridine was the major product, but ≈30% of the product was 2-trifluoroacetoxy-4-trifluoromethyl-6-methylpyridine N-oxide, which resulted from SNAr attack by CF3CO2. The impurity was removed by washing with base, and the synthesis was completed by a Suzuki coupling with cyclopropaneboronic acid.

Reordering the steps gives a cleaner synthesis and requires less m-CPBA. The cyclopropylpyridine N-oxide intermediate, however, is thermally unstable (105 °C decomposition onset temperature). To avoid isolating the N-oxide, the authors concentrated it and treated it directly with (CF3CO)2O. (Org. Process Res. Dev. 2013, 17, 257–264; Will Watson)

Produce chemicals from bio-oils without generating waste. Bio-derived oils are a promising source of renewable chemicals, but using biomass pyrolysis to produce them gives a complex mixture that includes water and oxygenated molecules. To avoid this problem and make bio-oils more accessible, H. Jiang and colleagues at the University of Science and Technology of China (Hefei) developed a bio-oil processing method that combines direct atmospheric distillation and copyrolysis.

The authors first distilled low-boiling fractions from bio-oil at 240 °C at atmospheric pressure with no additives. They recovered 51.86 wt% of distillate that contained a less complex mixture of separable organic components than the original oil. The recovery efficiency of important commodity chemicals such as HOAc and propanoic acid was >80 wt%.

The atmospheric distillation residue (ADR) was recycled for copyrolysis with rice husks at 450 °C under a nitrogen atmosphere. This process produces additional bio-oil and a bio-char, and it was integrated with the distillation step. ADR copyrolysis did not change the overall yield of bio-oil from biomass.

The major components of the bio-oils were identified as common carboxylic acids, furan derivatives, and phenolic compounds. They are decomposition products from the pyrolysis of cellulose, xylan, and lignin. Some ketones and esters may be formed from simple acids and levoglucosan during the distillation process. (Sci. Rep. [Online] 2013, 3, article 1120; Xin Su)

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