Noteworthy Chemistry

April 4, 2011

A novel sensor is derived from DNA-nanotube interactions. Y. Weizmann, D. M. Chenoweth, and T. M. Swager* at MIT (Cambridge, MA) developed a sensor technology that uses DNA–single-wall carbon nanotube (SWCNT) nanowires. This conduction-based detection system relies on an analyte recognition scheme for single-stranded DNA–bridged SWCNTs and a functionalized enzymatic probe (see figure). HRP is the horseradish peroxidase enzyme.

The sensor has detection limits of ≈10 fM; relative conductance decreases as a function of decreasing concentration. When the sensor is exposed to various base pair mismatches in the analyte oligonucleotide sequence, the sensitivity decreases with increasing degree of mismatch.

Sensitivity increases slightly with increasing temperature (25–32 °C) because of oligonucleotide hybridization kinetics. An examination of the sensing junction showed the presence of silver deposits after development in the presence of the analyte as a result of enzyme probe metallization. (J. Am. Chem. Soc. 2011, 133, 3238–3241; LaShanda Korley)

A self-cleaning membrane purifies industrial wastewater. Membrane technology has been used in water treatment for decades. Membrane separation efficiency, however, is inhibited by the deposition of permeable or impermeable materials throughout the membrane’s porous structure or on its surface. Water-insoluble matter, microorganisms, and organic compounds are typical foulants. Managing membrane fouling is critical, and few ways solve the problem completely.

J. Li, T. Wang, and coauthors at Tianjin Polytechnic University (China), Dalian University of Technology (China), and the University of Technology (Sydney, Australia) propose a novel anode membrane design that they claim is effective for industrially purifying wastewater.

The anode is graphitic carbon with TiO2 (anatase) particles deposited on it. When a voltage is applied, excitation of the TiO2 causes it to dissociate water into hydrogen and oxygen gases, helping to clear blockages. Reactive intermediates, including HO2, O2, and H2O2, are also generated and convert organic foulants to CO2 and water. These processes help preserve the membrane’s separation function. (Angew. Chem., Int. Ed. 2011, 50, 2148–2150; Sally Peng Li)

Copper-based nanoparticles catalyze aromatic substitution. Metal nanoparticles are the subject of intensive research, in part because they are useful as semi-heterogeneous catalysts. Their exceptionally high surface areas typically lead to high catalytic reactivity for organic synthesis under mild conditions.

H.-J. Xu, Y.-S. Feng, and coauthors at Hefei University of Technology (China) and Anhui Key Laboratory of Controllable Chemistry Reaction & Material Chemical Engineering (Hefei) used CuI nanoparticles to promote efficient, selective conversion of aryl iodides or bromides to the corresponding phenols, anilines, and thiophenols in aqueous media without ligands.

Product yields are typically very high for all three reactions, although individual yields are a function of the substituents on the aryl ring. The reactions do not seem to be affected significantly by electron-withdrawing or -donating groups, but they are sensitive to steric effects on the substrate. The high chemoselectivity of this procedure is illustrated by the formation of the thiophenol derivative from a substrate that contains iodide and chloride functions.

The authors demonstrated the recovery and reuse of the nanoparticle catalyst with only a slight decrease in activity. X-ray diffraction analysis showed identical diffraction patterns for fresh and recovered CuI nanoparticles. (J. Org. Chem. 2011, 76, 2296–2300; W. Jerry Patterson)

Here’s a metal-free click chemistry reaction. Click chemistry is an organic synthesis tool that uses selective, high-yielding, atom-efficient reactions to form cyclic molecules. The reaction between azides and terminal alkynes to obtain triazoles, known as the Huisgen cycloaddition, is the best known example of click chemistry. To be selective, however, this reaction requires a potentially toxic copper catalyst.

J. Wang and co-workers at the National University of Singapore developed a click chemistry reaction between enamines and azides. They treated PhN3 with ethyl acetoacetate in presence of various amines to obtain 1,2,3-triazoles regiospecifically. They found that 5 mol% Et2NH is the best catalyst, 70 °C is the optimum temperature, and DMSO solvent is superior to DMF, toluene, and MeOH.

The authors expanded the method to include aryl azide substrates that contain electron-withdrawing or -donating groups without affecting yields, although the reactions take longer with electron-donating substituents. PhCH2N3 can be used if the amount of catalyst is increased. In addition, 1,3-diketones or 1,3-keto nitriles can be used in place of β-ketoesters.

In the authors’ proposed mechanism for the transformation, the amine catalyst reacts with the β-ketoester to form an iminium ion, which tautomerizes to an enamine. The enamine reacts with the azide similarly to an electron-rich olefin in a Huisgen [3 + 2] cycloaddition to form the triazole. This method is a transition-metal–free improvement to traditional click chemistry reactions. (Chem.—Eur. J. 2011, 17, 3584–3587, JosÉ C. Barros)

Scale up a continuous ozonolysis process. A. D. Allian and co-workers at Abbott (North Chicago, IL) developed a continuous process for ozonolyzing a 1,1-disubstituted alkene. The first scale-up reactions were carried out in a continuously stirred tank reactor (CSTR) by using styrene as a model compound to optimize the reaction settings and conditions. The safety attributes of operating a highly exothermic reaction that generates unstable intermediates can be judged from the maximum ozonide concentration. On a 300-g scale, the concentration is ≈2.88 mol in a semibatch process; but it is reduced to <46 mmol in the CSTR.

On a larger scale (2.5 kg), maximum ozonide levels are reduced from ≈24 mol in semibatch to 0.95 mol in continuous mode. Because of increased gas flow on this scale, concerns about the entrainment of solvent required a change in reactor design to a continuous bubble reactor. (Org. Process Res. Dev. 2011, 15, 91–97; Will Watson)

Polycyclic alkaloid boehmeriasin A is significantly cytotoxic. Boehmeriasin A (1) was first isolated from the Chinese plant Boehmeria siamensis. A racemic mixture of (R) and (S)-1 was evaluated against leukemia and several primary organ cancer cell lines; in most of the evaluated cell lines, 1 is more potent than the anticancer drug paclitaxel. In addition, 1 inhibits the proliferation of breast cancer cell line MDA-MB-231 by altering the expression levels of several genes.

Although an asymmetric synthesis of the naturally occurring (R)-isomer was recently reported (Dumoulin, D., et al. Eur. J. Org. Chem. 2010, 1943–1950), it requires 13 steps and does not include the (S)-isomer, whose bioactivity was unknown at that point.

Recognizing the need to optimize the synthesis of this class of compounds, M. W. Leighty and G. I. Georg* at the University of Kansas (Lawrence) and the University of Minnesota (Minneapolis) devised an efficient seven-step preparation of both enantiomers of 1 starting from commercially available tert-butoxycarbonyl-protected amino acid 2. The (R)-isomer of 2 is shown in the figure; it leads to the formation of (R)-1.

EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; NMM is N-methylmorpholine; L-Selectride (Sigma-Aldrich) is lithium tri-sec-butylborohydride; Comins’s reagent is N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)ethanesulfonamide. Converting 2 to the corresponding Weinreb amide 3 and subsequent treatment with an alkyne-substituted Grignard reagent give ynone 4. The cyclization of 4 is carried out in a two-step, one-pot sequence to form enaminone 5.

The authors then used their previously developed C–H functionalization technique to convert 5 to arylated structure 6. Reducing 6 gives the enolate, which is trapped in situ to produce trifluoromethanesulfonate 7. Negishi cross-coupling provides the necessary diarylated scaffold 8, followed by a vanadium salt–mediated oxidative biaryl ring closure to form target structure 1.

This sequence was carried out with an overall 33% yield and (R)-enantiomer selectivity of 97.5:2.5 er. The (S)-isomer was prepared with comparable yield and enantioselectivity.

The authors’ in vitro cytotoxicity assays verified the reported biological activity of 1 and established structure–activity relationships for breast, drug-resistant ovarian, and colon cancer cell lines. The results indicate that the naturally occurring (R)-configuration is essential for potent cytotoxic activity, whereas the (S)-isomer is significantly less potent.

Most significantly, (R)-1 is active against the drug-resistant cancer cell line NCI-ADR-RES, a cell type for which paclitaxel is inactive. In this case, the IC50 value for (R)-1 is 36.7 nM, compared with paclitaxel at >6400 nM. (IC50 is the concentration of substance needed to inhibit a given biological process by 50%; it is also called the half-maximal inhibitory concentration.) (ACS Med. Chem. Lett. 2011, 2, Article ASAP DOI: 10.1021/ml1003074; W. Jerry Patterson)

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