Noteworthy Chemistry

June 27, 2011

A molecular rotator has anisochronous dynamics in the solid state. Molecular rotors are promising nanotechnology applications that offer potential entries to artificial molecular machines. Whereas progress has been made in studies of molecular rotors in the solution state, little is known about the dynamic processes of molecular rotors in solids.

R. Santillan, M. A. Garcia-Garibay, and coauthors at the Research and Advanced Studies Center of the National Polytechnic Institute of Mexico (Mexico City), the National Autonomous University of Mexico (Mexico City), and the University of California, Los Angeles studied the solid-state dynamics of molecular rotator 1 that consists of a p-phenylene rotor (red in the figure) flanked by two ethynylsteroidal stators (blue).

Rotator 1 exhibits polymorphism in the crystalline state. One of its polymorphs adopts a packing motif with 1-D columns of nested rotors arranged in helical arrays. The central phenylene groups are disordered over two sites related by an 85° rotation about their 1,4-axes.

The rotational dynamics of 1 consist of two anisochronous processes that involve a relatively slow switching motion (2 × 104–1.5 × 106 s–1) between two distinct twofold flipping trajectories in the fast-exchange regime (>108 s–1). The slower 85° exchange involves a negative activation entropy [–23 cal/(mol·K)] and a low enthalpic barrier (2.2 kcal/mol). (J. Am. Chem. Soc. 2011, 133, 7280–7283; Ben Zhong Tang)

Tricyclic isothiazoloquinolones are effective against MRSA. Emerging drug-resistant bacterial strains are implicated in an increasing number of serious infections. Several of these strains resist first-line antibiotics such as vancomycin.

One of the more dangerous strains is methicillin-resistant Staphylococcus aureus (MSRA). Current antibiotics such as ciprofloxacin (1) are based on the fluoroquinolone scaffold and historically have been effective against these infections. Variations of this structure to improve drug resistance are the target of intense research activity.

Isothiazoloquinolone-based compounds appear to resemble quinolones in their mechanism of action: inhibition of DNA replication and rapid bacterial cell death. B. J. Bradbury and co-workers at Achillion Pharmaceuticals (New Haven, CT) noted that structures such as 2 are direct analogues of 1 and feature the isothiazoloquinolone core. This group has reported variants of 2 that demonstrate excellent in vitro activity against MSRA (Wiles, J. A., et al. Bioorg. Med. Chem. Lett. 2006, 16, 1272–1276, 1277–1281; J. Med. Chem. 2006, 49, 39–42; Wang, Q., et al. J. Med. Chem. 2007, 50, 199–210). They now describe further elaboration of isothiazoloquinolone-based structures that enhance anti-MSRA activity.

This study targeted a series of 8-methoxyisothiazoloquinolones with 7-aminocyclic substituents. The standout candidates are 3 and 4.

The authors describe general synthesis and purification techniques and report the compounds’ antibacterial activity. They demonstrate the exceptional potency of 3 and 4 against a panel of MSRA strains. The minimum inhibitory concentrations of 3 (0.06 μg/mL) and 4 (0.09 μg/mL) are superior to commercially established Gram-positive antibacterial agents. These compounds also appear to be much less affected by mutations of the targeted enzymes. This finding translates to improved antibacterial activity against MSRA strains. (J. Med. Chem. 2011, 54, 3268–3282; W. Jerry Patterson)

Substitute titanium tetraisopropoxide for titanium tetrachloride as the catalyst for making Schiff bases. The formation of the benzophenone imine of allylamine is conventionally catalyzed by TiCl4. A higher yield (92% vs 88%) is obtained by using Ti(O-i-Pr)4 as catalyst; and the reaction time is decreased from 48 h to 6 h. Ti(O-i-Pr)4 is less expensive and easier to handle than TiCl4.

M. Roy and co-workers at Piramal Healthcare (Mumbai) and Piramal Healthcare (UK) (Huddersfield) used this technique while developing important intermediates for HIV protease inhibitors. (Org. Process Res. Dev. 2011, 15, 331–338; Will Watson)

Take new routes to functionalized polymer–virus conjugates. M. G. Finn and colleagues at the Scripps Research Institute (La Jolla, CA) and Montana State University (Bozeman) functionalized the surface of virus nanoparticles by using controlled radical polymerization. They modified bacteriophage Qβ VLP (1) with azide-containing succinimide 2 to produce structure 3 and then used click chemistry to attach triglyme initiator 4 for atom-transfer radical transfer polymerization (ATRP) to 25% of the surface of 3. ATRP macroinitiator 6 surface-polymerized oligo(ethylene glycol) methacrylate (OEGMA) terminated by hydroxyl (7) or azide (8) groups.

The authors’ synthetic strategy resulted in low-polydispersity virus nanoparticles with a ≈70% increase in hydrodynamic radius (24 nm vs 14 nm unmodified). They also initiated additional functionalization or fluorescent labeling of hydroxyl-terminated polymer–protein conjugate 9 with a two-step treatment of the tertiary bromide. The degree of dye attachment was limited, which they suggest was caused by the density of previously attached chains.

Azide-terminated, Qβ VLP–poly(OEGMA) 10 allowed postfunctionalization with dye molecules, including a gadolinium complex that can be used in magnetic resonance imaging. The authors also explored drug loading and release with doxorubicin using the terminal and pendant azide sites for click attachment. Functionalization maintained the structural integrity of the polymer–virus nanoparticles, although only ≈3% attachment was achieved.

The authors demonstrated pH-sensitive release in fluorescence studies, and they report cytotoxicity for internalized particles in a cervical cancer cell line. This contribution highlights the role of synthetic routes for structural control and functionalization in designed therapeutic loading and release. (J. Am. Chem. Soc. 2011, 133, 9242–9245; LaShanda Korley)

Achieve significant fluorescence enhancement in a nanoshell. The luminescence of a fluorophore can be enhanced close to (but not in direct contact with) certain metallic surfaces, typically silver or gold. This enhancement may arise from factors such as a stronger local electromagnetic field, and it can be accompanied by a modification of the fluorophore’s radiative decay rate.

Most studies focus on the fluorescence enhancement of fluorophores located near a metal surface or various metallic nanostructures. Only a few studies have addressed, experimentally or theoretically, a situation in which a fluorophore is placed inside a well-defined metallic nanocavity, although moderate fluorescence enhancement has been observed in those cases.

P. Zhang and coauthors at New Mexico Tech (Socorro) and the University of Cincinnati report that large enhancement factors can be achieved by trapping a fluorophore [in this case, meso-tetra(4-carboxyphenyl)porphine, TCPP] inside a colloidal TiO2 nanoparticle that is then coated with a silver nanoshell. The researchers demonstrated a fluorescence enhancement of >50-fold by measuring the fluorescence spectra of these dye-embedded TiO2@Ag core–shell nanostructures in an aqueous dispersion before and after their reaction with NaCN (a reagent that rapidly dissolves the metallic shell).

They suggest that the enhancement is the result of the localized electromagnetic field associated with the metal surface plasmon, similar to phenomena that cause strong surface-enhanced Raman scattering effects. Embedding a fluorophore inside a metal nanoshell also increases resistance to photobleaching.

The researchers point out that, with further optimization (e.g., geometry of the parent colloid, dielectric core size, spacer layer, and metal shell thickness and composition), it should be possible to achieve higher enhancement factors. Fluorescence enhancement is expected to have important implications for numerous applications of fluorescence in various fields. (Chem. Commun. 2011, 47, 5834–5836; Gary A. Baker)

Nitrone–alkyne coupling gives regioisomerically pure isoxazoles. 3,5-Disubstituted isoxazoles are important structural elements in a variety of pharmaceutical compounds. They have spurred research on high-yielding regioselective syntheses. S. Murarka and A. Studer* at the University of MÜnster (Germany) achieved this goal with a method that uses dehydrogenative cross-coupling between substituted nitrones and terminal alkynes.

Their method begins with the reaction of tert-butyl substituted nitrone 1 and alkyne 2 with a zinc salt catalyst and the tetramethylpiperidine-N-oxyl radical (TEMPO) and oxygen as the oxidants. This aerobic dehydrogenative cross-coupling reaction gives alkynylated nitrone intermediate 3. Quantitative cleavage of the tert-butyl group produces an intermediate oxime, which is cyclized to form target 3,5-disubstituted isoxazole 4 in regioisomerically pure form.

The authors emphasize that the reaction spans a wide range of substituted alkyne and nitrone starting materials and gives high yields under relatively mild conditions. They believe that this is an unprecedented procedure for isoxazole synthesis. (Org. Lett. 2011, 13, 2746–2749; W. Jerry Patterson)

Prepare new arylboronic esters by a noncryogenic route. Organoboronic acids and esters are important intermediates in palladium-mediated coupling reactions. Esters are preferred because they are easy to purify and can be analyzed by gas or liquid chromatography. Organoboronic esters are usually prepared by treating an alkyl or aryl halide with a lithium base or magnesium and then esterifying the organometallic intermediate with a trialkyl borate at –78 °C (for Li) or –10 °C (for Mg).

P. Y. Chavant and co-workers at Joseph Fourier University (Grenoble, France) developed a noncryogenic preparation of arylboronic esters. They used a boronic ester (1) derived from 2-methyl-2,4-pentanediol instead of expensive pinacol. Borylation reagent 1 is prepared by the reaction of H3BO3, 2-methyl-2,4-pentanediol, and i-PrOH, followed by azeotropic distillation.

The reaction of methyl 4-iodobenzoate (2) with 1 in the presence of “turbo-Grignard” reagent i-PrMgCl·LiCl at 0 °C, followed by an aq NH4Cl quench, gives the desired boronic ester in 77% yield. The authors believe that this reaction proceeds by an initial Mg–I exchange to form an iodo Grignard reagent; this is followed by an instantaneous reaction with 1. The ester group remains unchanged during the reaction.

Experiments with several substrates showed that

  • o-halo iodobenzenes form boronic esters and not aryne byproducts;
  • diiodobenzenes selectively produce monosubstituted boronic esters;
  • bromobenzenes and nitro-substituted iodobenzenes do not react;
  • pyridineboronic esters—whose corresponding boronic acids are unstable—can be made with this method;
  • pinacol boronic esters can be obtained from the pinacol boronating agent instead of 1; and
  • o-iodo trifluoromethylbenzene can be converted to the boronic ester in 95% yield at the 100 mmol scale.

This method is experimentally simple and ready to scale up, requires less energy than established procedures, and gives high yields. (Org. Process Res. Dev. 2011, 15, 710–716, JosÉ C. Barros)

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