Noteworthy Chemistry

June 4, 2012

Cyclopropylindole derivatives may be new AIDS drugs. Despite significant progress in developing therapeutic agents, a cure for AIDS remains elusive. Moreover, because drug-resistant virus strains have emerged, new treatments must continually be developed.

One anti-HIV agent targets the reverse transcriptase enzyme, which is necessary to convert single-stranded viral RNA to double-stranded DNA. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are important drugs for preventing AIDS dementia complex because they are small enough to cross the blood–brain barrier. Currently, however, very few NNRTIs are available.

S. C. Pelly and coauthors at Stellenbosch University (Western Cape, South Africa), the National Institute for Communicable Diseases (Johannesburg, South Africa), and Emory University (Atlanta) are working to develop new NNRTIs. Their studies on the structure–function relationship of existing drugs led them to design cyclopropylindole derivative 1. Compound 1, unfortunately, is a rather poor inhibitor, but the authors modified the substituents on 1 to produce analogues 24. All had improved potency and low cytotoxicity, similar to the commercially available NNRTI nevirapine (5).

Further optimization is needed, but these cyclopropylindole derivatives offer a promising new AIDS treatment. (ACS Med. Chem. Lett. 2012, 3, Article ASAP DOI: 10.1021/ml3000462, Chaya Pooput)

Use kinetic resolution to improve enantiomeric excess. Most enantioselective reactions produce only a moderate enantiomeric excess of the desired product. To obtain highly enriched enantiomers, a second “polishing” step must be added to the reaction sequence. M. I. Klauck, S. G. Patel, and S. L. Wiskur* at the University of South Carolina (Columbia) used a novel nonenzymatic resolution step in a tandem reaction sequence to improve enantiomeric excess.

The group studied the enantioselective reduction of acetophenone mediated by the Corey–Bakshi–Shibata catalysts (S)-MeCBS (S-1) and its (R)-enantiomer to produce (R)- and (S)-1-phenylethanol [(R)-2 and (S)-2, respectively] with moderate enantioenrichment. After the reduction step, they used Ac2O and the acyl transfer reagent (–)-tetramisole (3) to enhance enantioselectivity by kinetic resolution. Catalyst 3 is selective for acylating (S)-2, so the choice of CBS catalyst determines whether highly enantiopure (R)-2 or (S)-1-phenylethyl acetate (4) is produced. Both resolutions produce minor amounts of the opposite alcohol or acetate.

The authors expanded the method to propionic anhydride instead of Ac2O and α-tetralone or thiochromanone as the ketone. Expanding the technique to asymmetric allylations of aldehydes, however, produced only moderate enantiomeric excesses. This procedure is a quick way to access highly enriched enantiomeric compounds by optimizing a synthetic method. (J. Org. Chem. 2012, 77, 3570–3575; JosÉ C. Barros)

Tailor assembly and mechanics with noncovalent interactions in latex films. S. A. F. Bon and his team of researchers at the University of Warwick (Coventry, UK) used the supramolecular interactions of acrylate monomers functionalized with 2-ureido-4-pyrimidinone (UPy) to make colloidal particles that can form robust cellular polymer films. They prepared colloidal latexes from equimolar amounts of butyl acrylate (BA) and methyl methacrylate (MMA) via emulsion polymerization in the presence of an amphiphilic UPy monomer. UV–vis spectroscopy confirmed that UPy units were incorporated within 3-nm colloidal particles and were highly associated.

When the aqueous emulsions were dried, they formed transparent films. The presence of the UPy groups mechanically enhanced the films to give a threefold greater storage modulus at 30 °C than unfunctionalized PMMA–PBA films. Immersing the films in water for 2 h did not significantly affect their mechanical properties.

“Film” assembly in water modulated the UPy association constant, leading to the development of a polyhedral crystalline array that is kinetically “frozen” when the water evaporates. Although the UPy-network latex films swelled in a range of organic solvents, they maintained their mechanical integrity for months, unlike the PMMA–PBA films.

The authors point out that the multiple hydrogen bonding sites in the UPy-functionalized latexes drive the cellular framework of the films and lead to tough, transparent, solvent-resistant materials. (ACS Macro Letters 2012, 1, 603–608; LaShanda Korley)

Air-oxidize arenes at room temperature with a copper catalyst. Oxidative functionalization—especially oxidative hydroxylation—of C–H bonds is a well-established synthetic tool. Existing protocols for oxidatively hydroxylating arenes, however, usually require high catalyst loadings, a pure oxygen atmosphere, high reaction temperatures, and/or expensive metal catalysts. A. Lei and coauthors at Wuhan University and the Lanzhou Institute of Chemical Physics (both in China) report an efficient method for oxidizing electron-deficient aromatic compounds in air at room temperature with an inexpensive copper catalyst.

The authors found that benzothiazole (1) in DMF can be air-oxidized in the presence of CuCl2 and base to benzothiazolinone (2) by hydroxylation followed by tautomerization. Under optimized conditions (5 mol% CuCl2 and 1.2 equiv NaO-t-Bu), 2 is obtained in 70% yield. increasing the amounts of CuCl2 and base give even higher yields. The reaction proceeds better in polar solvents than nonpolar. Cu(I) and Cu(II) salts both have catalytic activity; Cu(I) increases the reaction rate.

This oxidation protocol is compatible with a variety of substrates. Caffeine, 2-aryl-1,3,4-oxadiazoles, and benzoxazoles can be oxidized to their corresponding ketone oxidation products in good yields (36–84%). Polyhalogenated benzenes are oxidized to the corresponding phenols in 58–89% yield.

A mechanistic study showed that the reaction is an oxygenase type of oxidation, which transfers oxygen atoms directly to substrates—this is very rare in aerobic C–H oxidation. The authors’ proposed mechanism involves a typical organometallic catalytic cycle that is initiated by single-electron transfer and generates the key active copper species CuO-t-Bu. (Angew. Chem., Int. Ed. 2012, 51, 4666–4670; Xin Su)

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