Noteworthy Chemistry

September 3, 2012

Replace lanthanides with calcium in the Luche reduction. The regioselective 1,2-reduction of α,β-unsaturated ketones by NaBH4 is usually performed in presence of stoichiometric quantities of lanthanide Lewis acids in a process called Luche reduction. N. V. Forkel, D. A. Henderson, and M. J. Fuchter* at Imperial College London and Pfizer (Sandwich, UK) replaced lanthanide salts with Lewis acid calcium salts in this reaction.

The authors screened several hydrides and solvents and compared CeCl3 with CaCl2 in a model reaction, the reduction of 3-cyclopentenone (1) to a mixture of 3-cyclopentenol (2) and cyclopentanol (3). MeOH–THF, NaBH4, and CaCl2 were a good combination, but yields were lower than with CeCl3.

Screening several calcium salts indicated that calcium trifluoromethanesulfonate (triflate) was the best choice (see figure). In the reduction of cyclopentenone, Ca(OTf)2 gave 2 and 3 in a 92:8 ratio; using CeCl3 resulted in a ratio of 97:3.

When the substrate was chalcone, both salts gave 100% of the corresponding unsaturated alcohol. This method improves the standard Luche reduction by replacing expensive lanthanide salts with inexpensive, readily available calcium salts. (Green Chem. 2012, 14, 2129–2132; JosÉ C. Barros)

What is the best precursor to cetirizine? In most manufacturing routes, the carboxylic acid group in cetirizine, a second-generation nonsedating antihistamine, is generated by hydrolyzing a precursor amide, nitrile, or ester. The amide and nitrile hydrolyses require forcing conditions, and the ester is too hydrolytically unstable to isolate.

L. Pongó and co-workers at EGIS Pharmaceuticals (Budapest) discovered an alternative to these precursors: the N,N-dimethylamide. It is prepared by alkylating an alcohol precursor with commercially available N,N-dimethyl-2-chloroacetamide. It is readily isolated and easily purified; and it can be base-hydrolyzed under relatively mild conditions. The authors describe the route as “non-infringing”, which presumably refers to existing patents. (Org. Process Res. Dev. 2012, 16, 1279–1282; Will Watson)

Phototriggerable nanogels deliver proteins intracellularly. K. S. Anseth and co-workers at the University of Colorado at Boulder developed a class of hydrophilic, photoresponsive gel nanoparticles whose degradation can be controlled for drug release. They used an inverse microemulsion method to prepare the acrylate-based nanogels that contain a photosensitive cross-linker, ethylene glycol units for water solubility, and a covalently incorporated fluorescent protein payload.

The spherical, relatively monodisperse nanogels are ≈50 nm in diam unloaded and ≈100 nm in diam when loaded. Light activation at 365 nm increases the nanogel size in proportion to the degree of exposure, consistent with swelling induced by de-cross-linking.

The larger, protein-incorporated (50% efficiency) nanogels are photocleavable, and the loaded protein is bioactive. Gel electrophoresis showed that light exposure releases the protein from the nanogel particle as a result of controlled degradation and enhances enzymatic activity.

Using click chemistry, the authors introduced a cell-targeting peptide on the nanogel surface that promotes cellular uptake. The nanogels are also capable of two-photon light triggering, which offers a way to mediate intracellular delivery. (Biomacromolecules 2012, 13, 2219–2224; LaShanda Korley)

Structure–activity evaluation identifies potential pain drugs. Sodium channel NaV1.7 is linked to pain-related conditions, which makes it a good target for pain drugs. All sodium channels, however, are very similar, so finding a ligand selective for NaV1.7 is a challenge.

I. Macsari and coauthors at AstraZeneca (Södertälje, Sweden), Uppsala University (Sweden), and the University of KwaZulu-Natal (Durban, South Africa) used high-throughput screening to discover NaV1.7-selective blockers. They identified oxoisoindolinecarbamide 1, which has modest NaV1.7 potency but no selectivity over other ion channels. They used 1 as the starting template for optimization by evaluating structure–activity relationships.

The authors synthesized a series of analogues by replacing the aniline group in 1 with various aromatic rings. The products were tested for potency against NaV1.7 and ion-channel selectivity. An enantiomer of compound 2 exhibited potency and selectivity. [The authors did not determine the absolute structure of any of the oxoisoindoline derivatives.—Ed.]

Preserving the benzylamine group in 2, the authors probed the effect of substituents on the oxoisoindoline moiety. They identified an enantiomer of compound 3 that had high NaV1.7 potency and much higher selectivity over several other sodium channels. Compounds 2 and 3 were tested in rat pain models; the results from 3 were particularly promising. (J. Med. Chem. 2012, 55, 6866–6880; Chaya Pooput)

Reversibly photodeform a polymer composite via UV irradiation. Azobenzene-containing liquid-crystalline polymers (ALCPs) photodeform reversibly because azobenzene’s trans–cis isomerization can be induced by alternating UV- and visible-light irradiation. If an ALCP can be made to deform reversibly when it is irradiated by one of the two light sources, it could be used in a simple photomechanical actuator. H. Peng and co-workers at Fudan University (Shanghai) synthesized an ALCP that has this capability and prepared a nanocomposite of it with aligned carbon nanotubes (CNTs).

A strip formulated from the nanocomposite responds rapidly and reversibly to irradiation by a UV beam alone. The strip moves away from the beam source: It bends to the left when irradiated from the right side and to the right when irradiated from the left side. A left–right–left bending cycle is completed in as little as 2 s. The reversible deformation can be repeated for >100 cycles with preservation of the high sensitivity and stability of the actuator.

The nanocomposite strip has very high mechanical strength (≈1 GPa) and electrical conductivity (350 S/cm), neither of which can be attained by the ALCP alone. Its photomechanical actuation produces a stress of almost 260 times that of the strongest natural skeletal muscle. The authors fashioned a remote photocontrollable electric switch that makes use of the high electrical conductivity and reversible photomechanical deformation of the strip. (Angew. Chem., Int. Ed. 2012, 51, 8520–8524; Ben Zhong Tang)

Generate acid by “squeezing” a mechanorepsonsive polymer. Research on self-healing polymers has produced materials that use light and heat as energy sources for self-healing. The ideal scenario, however, would be healing without external intervention—autonomic healing. Mechanochemical transduction is seen as the most likely candidate to accomplish this objective.

J. S. Moore and colleagues at University of Illinois at Urbana–Champaign generated acid from cross-linked poly(methyl acrylate) (PMA) integrated with a mechanophore. Their system promotes self-healing by acid-catalyzed cross-linking polymerization.

Under mechanical stress, fused gem-dichlorocyclopropane structures (e.g., 1) undergo electrocyclic ring-opening aromatization (2) to release acid, in this case, HCl (Figure 1). The authors synthesized mechanophore 3, analogous to structure 1, from indene and caprolactone in three steps (Figure 2). Methacrylation of diol 3 formed cross-linking monomer 4, which is subsequently polymerized with methyl acrylate in the presence of the cross-linker ethylene glycol dimethacrylate (EGDAMA) to form cross-linked, mechanophore-containing polymer 6. The authors similarly prepared reference polymer 5 with mechanophore 3 added as a dopant instead of being attached to the polymer.

PMA 6 was compressed at various pressures. As the pressure increased, increasing amounts of HCl were generated. At 352 MPa pressure, up to 20% of the mechanophore was activated to release HCl. By comparison, only 6% of mechanophore-doped PMA 5 released acid. This result indicates that mechanophore incorporation is required for efficient acid release under compression.

The release of acid from 6 could be visualized by dipping the compressed polymer in a pH indicator solution. Methyl red in MeCN turned from orange to pink when exposed to compressed 6, No change was observed for non-compressed 6 or compressed 5. (J. Am. Chem. Soc. 2012, 134, 12446−12449; Xin Su)

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