Noteworthy Chemistry

June 13, 2011

A new amphiphilic surfactant promotes cross-coupling reactions in aqueous media. B. H. Lipshutz, R. C. Gadwood, and coauthors at the University of California, Santa Barbara, and Kalexsyn (Kalamazoo, MI) created a group of amphiphiles that they call “designer surfactants”. These materials meet green chemistry requirements and provide enabling technology for various metal-catalyzed, aqueous, room-temperature reactions.

The authors used a previously reported first-generation surfactant (1), based on an α-tocopherol scaffold, to form nanomicelles (Lipshutz, B. H., et al. Org. Lett. 2008, 10, 1329–1332, 1333–1336, 3793–3796, 5329–5332). Structure 1 mediates important reactions such as Heck, Suzuki–Miyaura, and Sonogashira couplings. They now describe a second-generation amphiphile 4 with a particle size that promotes faster coupling rates and higher conversions and yields. Surfactant 4 is more easily synthesized than 1 and may be useful for transition metal–based catalysis.

Like original amphiphile 1, surfactant 4 contains α-tocopherol (2) as the main lipophilic component, but it differs in its diester linker chain length and the size of the terminal poly(ethylene glycol) (PEG) chain. The reaction of 2 to give initial adduct 3 (vitamin E succinate) is almost quantitative. Adduct 3 also is available commercially.

The conversion of 3 to 4 is likewise almost 100%. The efficient use of 3 is especially important and significantly enhances the economic advantages of 4 over 1, the route to which is <50% as efficient. The example of a cross-coupling reaction in the figure illustrates the optimum reaction conditions for using 4; dtbpf is di-(tert-butylphosphino)ferrocene.

Longer PEG chains (such as used in 4) result in much larger surfactant particles that improve the efficiency of aqueous cross-coupling reactions. Also, the solubility of 4 in water allows recycling of the aqueous phase. After eight recycles, 4 promotes almost complete conversion to the desired product in a ring-closing metathesis test reaction.

In almost every cross-coupling reaction studied (Heck, Suzuki–Miyaura, Sonogashira, Buchwald–Hartwig, Negishi, and cross-metathesis), surfactant 4 leads to higher yields than 1 with better economics and purity levels. The authors report that amphiphile 4 will soon be available commercially. (J. Org. Chem. 2011, 76, 4379–4391; W. Jerry Patterson)

“See” the HIV-1 virus with the help of gold nanoparticles. Ribonuclease H (RNase H) of HIV-1 reverse transcriptase (HIV-1 RT) damages the RNA strand of an RNA–DNA hybrid. Despite the effort that has been devoted to developing antiretroviral drugs, few RNase H inhibitors with therapeutic value have been identified. The lack of suitable assay systems is a major barrier. Electrophoresis and chromatography techniques are cumbersome and time-consuming. Fluorescence methods are useful, but the DNA–RNA strands must be modified with fluorophores and quenchers before they are examined.

X. Liu and coauthors at the National University of Singapore, the Institute of Materials Research and Engineering (Singapore), and Nanyang Technological University (Singapore) developed a rapid process for a colorimetric assay of HIV-1 RNase H activity by using unmodified gold nanoparticles (AuNPs).

In the authors’ process, a synthetic RNA–DNA duplex is incubated with HIV-1 RT. Under proper buffering conditions, HIV-1 RT cleaves the RNA strands and causes the DNA and RNA probes to dissociate. When AuNPs are added, the dissociated probes form charged protecting layers on the particle surfaces, which stabilize them. If HIV-1 RT is absent, however, or if the enzyme is inactive, the duplex remains intact.

When the AuNPs are added, they undergo salt-induced aggregation with a color change. The advantage of this process is that the AuNPs and RNA strands can be used without previous modification. (Small 2011, 7, 1393–1396; Ben Zhong Tang)

Hydrogel sensors change volume in the presence of analytes. S. A. Asher and colleagues at the University of Pittsburgh developed a modular, 2-D colloidal array technology for sensing analytes. Using spherical polystyrene (580 nm diam) self-assembled from solution onto a mercury surface for enhanced reflectivity, they formed a well-ordered, hexagonal assembly with a ≈10 µm domain size and 80% incident light diffraction.

The authors used an in situ polymerization strategy to transfer the 2-D array to a poly(acrylamide-co-acrylic acid) hydrogel with embedded recognition molecules to allow chemical sensing via hydrogel volume changes. The integrity of the 2-D polystyrene array is maintained during the partial embedding and polymerization process to produce ≈10-µm thick films. Exposure to an aqueous environment expands the array dimensions and produces a swelling-driven diffraction red shift, and paves the way to correlating diffraction wavelength and colloidal domain spacing.

The authors also demonstrated reversible pH-modulation of the array lattice spacing by using the acrylate functionality. This method was varied to include crown ether derivatives for capturing and sensing lead in polyelectrolyte hydrogels. The swelling and color changes are proportional to the amount of Pb2+ captured below the saturation limit. A Pb2+ detection threshold of <10–12 mol is possible with this robust, functional sensing platform. (J. Am. Chem. Soc. 2011, 133, Article ASAP DOI: 10.1021/ja201015c; LaShanda Korley)

Cherry tomatoes contain two effective antioxidants. Flavonoids are compounds that color fruits and vegetables, and some can enhance human health. For example, flavonoids in tomatoes are antioxidants and can help prevent cancer. Chalconaringenin (CN, 1) and quercetin 3-rutinoside (rutin, 2) are flavonoids present in larger amounts than lycopene in cherry tomatoes, but the study of their antioxidant activity has been largely neglected. Most studies have focused on naringenin, a CN isomer.

R. Slimestad* at the Saerheim Research Center and M. Verheul at the Norwegian Institute for Agricultural and Environmental Research—Bioforsk Vest Saerheim (both in Klepp Station, Norway) used a variety of methods to characterize the antioxidant properties of CN and rutin.

The authors discovered that UV irradiation converts CN to its isomer in storage, which explains why naringenin is the most studied flavonoid. In this study, however, CN was stable during sample preparation. Both flavonoids are capable of reducing Fe(III) to Fe(II) in aqueous media.

Rutin has the higher antioxidant efficiency of the two. Both flavonoids can capture radicals such as 2,2’-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH). Rutin is superior to ascorbic acid, the analysis standard, for scavenging NO before it is air-oxidized to nitrite. (J. Agric. Food Chem. 2011, 59, 3180−3185; Sally Peng Li)

Form a spiro acetal with 1-methoxycyclopentene and no catalyst. During the scale-up of a phosphodiesterase type 4 isozyme inhibitor, A. Yanagisawa and co-workers at Kyowa Hakko Kirin (Osaka) found that precursor 2,3-dihydroxy-4-methoxybenzoic acid spiro cyclopentanone acetal forms smoothly without a catalyst in high-boiling solvents such as xylene and PhCl. In the original synthesis, they used cyclopentanone dimethyl acetal to form the spiro compound; but upon scale-up, they found that MeOH removal is rate-determining.

They replaced the dimethyl acetal with 1-methoxycyclopentene, which has the advantage of generating half the amount of MeOH; it can also act as a MeOH trap. The final optimized process was carried out in cyclopentanone as solvent and produced the acetal in 89% yield. (Org. Process Res. Dev. 2011, 15, 376–381; Will Watson)

Use catalytic diazonium salts in the Heck–Matsuda reaction. The reaction between diazonium salts and olefins in the presence of palladium catalysts—the Heck-Matsuda reaction—is a useful process because of the high reactivity of the diazonium salt as a substitute for expensive halides. One of the most important applications of this reaction is Syngenta’s preparation of the herbicide prosulfuron, but the diazonium salts are unstable.

F. Le Callonec, E. Fouquet, and F.-X. Felpin* at the University of Bordeaux (France) developed a protocol for the Heck–Matsuda reaction that uses catalytic amounts of diazonium salts, generated in situ from anilines in the presence of acids and tert-butyl nitrite. They screened various acids for the model reaction between 4-nitroaniline and methyl acrylate in presence of MeOH, t-BuONO, and Pd(OAc)2. They found that MeSO3H works best, better even than HBF4 or BF3·Et2O. Adding anisole improves yields, presumably by stabilizing cationic palladium intermediates.

The authors expanded their method to several other amines, to butyl acrylate in place of methyl, and to 2-nitro-substituted aniline 1. Reducing 1 with hydrogen gives quinolone 2. A proposed mechanism involves the reaction of 1 with the alkyl nitrite to produce a hydroxydiazene (ArN=NOH), which in acidic media generates a diazonium salt. This reaction operates under mild conditions, generates environmentally benign byproducts such as t-BuOH, H2O, and N2, and does not require the isolation of potentially explosive diazonium salts. (Org. Lett. 2011, 13, 2646–2649, JosÉ C. Barros)

Synthesize chiral α-amino acids by reducing ketimine esters. The α-amino acid structure is an essential feature of many pharmaceuticals, including vancomycin, amoxicillin, enalapril (an antihypertensive), and the cardiovascular agent clopidogrel (Plavix). L. R. Reddy*, A. P. Gupta, and Y. Liu at Novartis Pharmaceuticals (East Hanover, NJ) report a route to highly enantiomerically enriched α-amino acids that is based on reducing N-tert-butanesulfinyl ketimine esters.

The highly regio- and diastereoselective method begins with the condensation of readily available α-ketoesters (e.g., 1) with the chiral auxiliary tert-butanesulfinamide (2) to form the desired sulfinyl ketimine ester 3. The synthesis of the (RS) isomer is shown in the figure; either enantiomeric product can be formed, depending on whether the (RS) or (SS) auxiliary is used to initiate the reaction.

Reducing 3 provides α-amino acid derivative 4 in high yield and diastereospecificity (dr ≥ 98:2). A key feature of the reduction is the use of L-Selectride (LiBH-s-Bu3), which is slowly added by a syringe pump over 1 h. The chiral auxiliary in 4 is selectively removed with HCl to form amino acid hydrochloride salt 5 in high yield without loss of stereochemical purity.

This procedure applies to aromatic and aliphatic chiral α-amino acids. The tert-butanesulfinyl group can also serve as an efficient nitrogen protecting group in subsequent modifications of the carboxylic acid group. For example, the ester group in 4 can be hydrolyzed to give N-protected amino acid 6. (J. Org. Chem. 2011, 76, 3409–3425; W. Jerry Patterson)

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