Noteworthy Chemistry

April 30, 2012

Develop latent fingerprints by aggregation-induced emission. Latent fingerprints (LFPs) are important forensic evidence for identifying suspects. As the name implies, LFPs are rarely clear enough to detect visually, so they must be revealed by methods that include powder dusting, metal deposition, fuming, and staining. These time-consuming methods can damage details of the fingerprints, and they can be hazardous to the examiners’ health.

Y. Li, L. Xu, and B. Su* Zhejiang University (Hangzhou, China) developed a user-friendly method for visualizing LFPs by using the aggregation-induced emission (AIE) of tetraphenylethylene (TPE, 1).

AIE occurs in fluorophores that emit in the aggregated or solid state because intramolecular rotation is restricted. TPE is an iconic AIE luminogen—it does not emit in solution but emits strongly when its molecules aggregate. Adding >50% water to a TPE solution in MeCN causes the TPE to aggregate. The hydrophobic aggregates cause TPE’s fluorescence intensity to increase rapidly as the water content increases from 50 to 90 vol%.

The researchers soaked glass, stainless steel, and aluminum substrates containing LFPs in a MeCN–H2O TPE solution, rinsed them with water, and dried them in an argon stream. The TPE nanoaggregates adhered preferentially to the ridges of the sebum-rich fingerprints via hydrophobic interactions. The adsorbed aggregates emitted strongly under UV illumination, imaging the LFPs in great detail and high resolution. The best results came from LFPs on stainless steel and aluminum; the glass LFPs had lower resolution and higher background emission because glass is the most hydrophobic of the three substrates.

The three steps of the simple, rapid process can be performed in minutes. It is safe because no powders or fumes are involved. (Chem. Commun. 2012, 48, 4109–4111; Xin Su and Ben Zhong Tang)

Reverse the addition order of epoxide–Grignard reactions. Chemists cannot scale up the copper-catalyzed addition of vinyl magnesium chloride to benzyl (S)-glycidyl ether if they follow a published procedure (i.e., the rapid addition of the Grignard solution to the epoxide at cryogenic temperatures). M. Alam, C. Wise, and co-workers at Merck (Hoddesdon, UK) added the epoxide solution to the Grignard reagent solution in a controlled manner to carry out the reaction at –5 to 0 °C.

The authors applied this protocol to other epoxides (n-butyl and tert-butyl glycidyl ethers and 1,2-epoxy-5-hexene) and other Grignard reagents (allyl, cyclohexyl, phenyl, and benzyl magnesium chlorides). They obtained yields from 80 to 97%. (Org. Process Res. Dev. 2012, 16, 435–441; Will Watson)

Here’s a practical synthesis of (+)-erythro-mefloquine. The 40-year-old drug mefloquine is approved in racemic form for treating malaria and as a prophylaxis. Only one of the four possible stereoisomers is the active drug; the others can cause central nervous system side effects.

In 2009, a partnership of a small biotech company, Treague Ltd. (Cambridge, UK), and the Medicines for Malaria Venture (Geneva, Switzerland) initiated phase 1 clinical trials on the single enantiomer (R,S)-(+)-erythro-mefloquine (1), which is primarily responsible for the drug’s antimalarial activity. This project required a scaled-up route to the target molecule.

R. Bryant and coauthors at Creative Chemistry (Uxbridge, UK) and Development Chemicals (Kent, UK) developed a process for making the desired enantiomer. They used ruthenium-catalyzed asymmetric transfer hydrogenation to prepare carbinol 3 from pyridyl ketone 2 in almost quantitative yield and 96% ee. The 5:2 mol ratio of HCO2H to Et3N is critical for the optimum rate and enantioselectivity of the reaction.

In the following step, the researchers hydrogenated the pyridyl ring in 3 over Pt/C to produce the target molecule high yield and >98% ee. (Org. Process Res. Dev. 2012, 16, 461–463; JosÉ C. Barros)

Separate gases and alcohols with ultramicroporous frameworks. Developing new porous materials and technologies for alternative low-energy processes is becoming increasingly important. Ultramicroporous metal–organic frameworks (MOFs) with pore sizes <0.7 nm have exceptional potential for use in guest-molecule separation and storage because of their size- and shape-exclusion effects and the deep van der Waals–type potential energy wells in their pores. Although great advances have been made for using larger-pore supermicroporous MOFs, little attention has been paid to ultramicroporous MOFs—probably because their surface areas are lower than those of supermicroporous MOFs.

By introducing lanthanide metal ions with special coordinating characteristics and a bulky organic ligand, R. Zou, A. K. Burrell, and coauthors at Peking University (Beijing), Argonne National Laboratory (IL), and Nankai University (Tianjin, China) synthesized lanthanide–organic frameworks (LOFs) with ultramicroporous structures that efficiently separate gas and alcohol mixtures. They used a solvothermal reaction between Ce(NO3)3·6H2O and 1,3,5-benzenetris(4-benzoic acid) (H3BTB) to form the homochiral ultramicroporous LOF Ce(BTB)(H2O).

Characterization studies showed that Ce(BTB)(H2O) has high thermal stability (as high as 500 °C), high surface area (1091 cm2/g), and two types of open ultramicropores with average pore sizes of 0.46 and 0.53 nm. Ce(BTB)(H2O) exhibits unusual stepwise hysteretic adsorption of molecular oxygen and nitrogen at 77 K and efficiently separates CO2–N2 and CH4–N2 gas mixtures at 0 °C with selectivities of 19.2 and 4.9, respectively.

The ultramicropores provide unprecedented separation of the propanol isomers. Ce(BTB)(H2O) adsorbs 11 times as much n-PrOH as i-PrOH because of slight differences in their geometries and dipole moments. The authors summarize their methods to provide a procedure that can be used to simulate the surface areas and gas-separation properties of ultramicroporous materials. (J. Mater. Chem. 2012, 22, 7813–7818; Gary A. Baker)

These compounds may improve type 2 diabetes treatment. Type 2 diabetes mellitus is characterized by high blood glucose from insufficient insulin secretion and/or insulin resistance in the target tissues. The sulfonylureas used to treat type 2 diabetes stimulate continuous insulin release independently of blood glucose levels and can provoke hypoglycemia in the patient. New drugs are needed that promote insulin secretion in response to high blood glucose.

Recent reports show that agonists to G protein–coupled receptor 40 (GPR40) can initiate glucose-stimulated insulin secretion (GSIS) and show promise as insulinotropic drugs. S. Mikami and co-workers at Takeda Pharmaceutical (Kanagawa, Japan) previously identified compound 1 as novel GPR40 agonist (J. Med. Chem. 2011, 54, 1365–1378). Compound 1, however, is highly cytotoxic; the researchers did not investigate it further but worked to optimize its structure.

Because the cytotoxicity of 1 may result from its strong lipophilicity, the authors synthesized numerous more-hydrophilic derivatives and conducted binding and cytotoxicity assays. They identified the 4’-position on the biphenyl ring as the best one for tolerating polar functionality without losing potency. By optimizing the substituents on that position and in the linker that connects the biphenyl group to the phenylpropanoic acid moiety, they produced three compounds with polar sulfone groups in substituents at the 4’-position.

Compound 2 had agonist activity similar to 1, but much lower cytotoxicity. In vivo evaluations of 2 showed that it decreases glucose levels better than 1 and lowers the risk of hypoglycemia. A toxicity study in rats indicated that there were no significant adverse effects.

By targeting GPR40, the potent, safe compound 2 provides a new therapeutic approach to type 2 diabetes. (J. Med. Chem. 2012, 55, 3756–3776, Chaya Pooput)

Tailor drug release from peptide-based micelles. P. T. Hammond and her team of researchers at MIT (Cambridge, MA) studied a series of micelle-forming poly(ethylene glycol)-b-poly(γ-propargyl L-glutamate) (PEG-b-PPLG) block copolymers. The interior micelle functionality of the copolymers was tuned via click chemistry of the propargyl triple bonds with p-substituted 4-azidobutylbenzenes. The key to their investigation was discovering how the embedded core functionalities influence drug encapsulation via noncovalent interactions.

The authors incorporated aliphatic, phenolic, N-phenylacetamide, and phenyl units into the micellar core by using this efficient synthetic strategy. The inclusion of more hydrophobic, less polar groups resulted in more stable spherical micelles with <200 nm hydrodynamic diam. When these block copolymer micelles were loaded with 5–7 wt% of the cancer drug paclitaxel, the size distribution of the micelles narrowed. Hydrogen-bonding interactions gave more compact micelles that expanded by two- to threefold upon paclitaxel encapsulation.

The release of paclitaxel from the micelles was diffusion controlled. The PEG-b-PPLG with a phenolic core was kinetically stable and exhibited an extended release profile and a minimal burst release. None of the PEG-b-PPLG copolymers with modified cores were significantly cytotoxic. The phenol-modified, paclitaxel -loaded PEG-b-PPLG micelle, however, was less potent than the other functionalized micelles because of its slower release of paclitaxel. (Biomacromolecules 2012, 13, Article ASAP DOI: 10.1021/bm201873u; LaShanda Korley)

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