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Noteworthy Chemistry

March 9, 2015


Here’s a safer lactam reduction to use on an industrial scale. Lactam reduction reactions are usually run with potentially explosive lithium aluminum hydride (LiAlH4) as the reducing agent. During the development of a τ protein kinase inhibitor, T. Naka and co-workers at Mitsubishi Tanabe Pharma Corp. (Osaka) used sodium borohydride (NaBH4) and trifluoroacetic acid (CF3CO2H or TFA) to promote this reaction.

When the authors studied the reaction mechanism with 11B NMR, they found that the active reducing species is sodium mono(trifluoroacetoxy)borohydride (1 in the figure). Intermediate 1 reduces the lactam directly or decomposes to borane, which also acts as a reducing agent. Guided by calorimetry, they controlled heat and gas evolution by adjusting the rate of TFA addition.

Mechanism of NaBH4–TFA reduction

In pilot plant studies, the authors dissolved the lactam in tetrahydrofuran (THF) and added it to a mixture of NaBH4 and THF. Then they slowly added TFA in THF so that the internal reaction temperature was <20 °C. To contain the evolved diborane, they used two scrubbers, each containing 15% aqueous NaOH, to transform diborane into aqueous sodium borate. The yield at the 30-g scale was 85%. The reaction was scaled up to 35-kg batches. (Org. Process Res. Dev. DOI: 10.1021/op500284e; José C. Barros).

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Engineer a stronger lysozyme to ward off bacteria. Multidrug-resistant pathogenic bacteria have emerged as a severe threat to public health. Much effort has been made to discover small-molecule antibacterial compounds, but few of them have been successful because of their high toxicity and/or low bioavailability.

One of the most ancient bactericidal enzymes, human lysozyme (hLYZ) is naturally compatible with the human immune system. Its activity can be suppressed, however, by inhibitory proteins derived from pathogens, such as the Escherichia coli inhibitor of vertebrate lysozyme (Ivyc). To overcome this difficulty, K. E. Griswold and co-workers at Dartmouth College (Hanover, NH) designed and developed hLYZ variants that resist Ivyc inhibition.

The researchers first assembled large combinatorial libraries on the basis of computational modeling of molecular interactions between Ivyc and hLYZ. Then, using a gel microdroplet–based high-throughput screening platform, they identified hLYZ variants with >1000-fold higher Ivyc resistance than wild-type hLYZ but with similar capabilities for killing E. coli.

The authors found, however, that the engineered Ivyc-escape hLYZ variants were more susceptible than wild-type hLYZ to other pathogen-derived inhibitors. This unexpected result suggests that multiple lysozyme inhibitors should be targeted simultaneously to engineer variants with enhanced antimicrobial activity.

This work should help researchers to better understand interactions between hLYZ and its various pathogenic inhibitory proteins. It also suggests the future direction of engineering hLYZ into biotherapeutics for clinical applications. In addition, the innovative coculturing strategy reported in this study should be valuable for discovering antibacterial reagents with the use of microbial natural-product libraries. (ACS Chem. Biol. DOI: 10.1021/cb500976y; Xin Su)

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Combine isomerization and cycloaddition in a flow reactor. J. A. Rincón and co-workers at Eli Lilly (Alcobendas-Madrid, Spain, and Indianapolis) describe the optimization and scale up of an intramolecular 1,3-dipolar cycloaddition reaction in which an oxime is heated to form a fused bicyclic isoxazolidine.

The starting oxime and the product exhibited exothermic decomposition reactions at ≈250–260 ºC in differential scanning calorimetry studies. To obtain good yields of the isoxazolidine, however, the oxime isomers in the starting material must be heated to convert all of the isomers to the desired one.

Under the optimized reactions conditions, a 0.3 M toluene solution of oximes is pumped through a stainless steel tube at 210 ºC with a residence time of 15 min to give a 50% yield of isoxazolidine. This procedure was scaled up to a 120 g/h flow rate to produce 2.2 kg of acceptable product. The larger-scale reaction has the advantage that steady-state conditions can be maintained for longer periods of time. (Org. Process Res. Dev. DOI: 10.1021/op500350y; Will Watson)

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What secrets can 170-year-old beer divulge? Modern beer making is a sophisticated chemical science; analytical techniques help guarantee precise results for specific recipes. When the wreck of an 1840s schooner was found in the Baltic Sea off the Åland Islands (Finland), scientists were given a rare opportunity to analyze 170-year-old beer. Divers recovered 150 bottles of champagne and 5 bottles of what looked like 19th century beer (see figure). When one bottle cracked in the divers’ boat, the divers reported that a liquid foamed from the bottle and tasted like beer!

A 170-year-old beer bottle

According to B. Gibson and coauthors at VTT Technical Research Center of Finland (Espoo) and the Technical University of Munich (Freising, Germany), “The presence of hop components (extensively degraded), maltose, and maltotriose identified the bottles’ contents as beers.”

Experts confirmed that the bottles were from the 19th century, but the technology used to produce the bottles did not exist in Finland at the time. Bottles such as these were produced 20 or 30 years earlier in central and northern Europe.

Using state-of-the-art tools and methods, the authors investigated the biology and chemistry of the beers in two of the bottles in their current condition, compared them with modern beers, and learned a piece of the history of beer-making. Methods approved by the European Brewery Conventions were used to test color, bitterness, sulfur dioxide content, and free amine nitrogen content. The authors also tested for such components as ethanol, glycerol, acetic acid, lactic acid, fermentable sugars, carbonyl compounds, fatty acids, phenolic acids, amino acids, and proteins. The tests revealed that the two beers were distinctly different.

The effects of aging and contamination made the two beers unpalatable, but tests did reveal some of the original traits and production methods. Optical and electron microscopy revealed four species of live non–spore-forming bacteria that have been metabolizing for ≈170 years. When normalized, the yeast-derived flavor compounds in the shipwreck beers were within or close to the normal range of modern beers. The original amounts of ethyl hexanoate in both beers and ethyl decanoate in one would have given the fresh beers a fruity, apple-like flavor.

The hops found in the beers were identified as cereal grain, but the tests could not determine whether it was barley or wheat. An absence of α- and β-acids and the presence of iso-α-acids and hulupones told the authors that the hops were added to the worts before kettle-boiling. At the same time, the degradation products of the β-acids confirmed the use of old hops varietals; modern hops are bred to maximize the α-acids. The lack of Pad1 (peptidylarginine deiminase) enzyme means that the brewers did not use wild yeast.

Although the name of the ship, its country of origin, and its last port of call are not known, chemical evidence has revealed a nugget of information about 19th century beer making. (J. Agric. Food Chem. DOI: 10.1021/jf5052943; Beth Ashby Mitchell

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Convert a biomass component to value-added hydrocarbons in one step. Lignocellulosic biomass is an abundant, inexpensive chemical feedstock that does not compete with food supplies. Pentanediols derived from this biomass have been evaluated as potential monomers for polyesters and polyurethanes, but they could also help to replace petroleum compounds as a source of transportation fuels.

Previous attempts to generate benzene, toluene, ethylbenzene, and xylenes (BTEX) from biomass gave high yields of CO, CO2, coke, and other unwanted byproducts. Other attempts to convert biologically derived gases to liquefied petroleum gas (LPG; hydrocarbons in the C2–C5 range) were energy-intensive and produced unwanted polynuclear aromatics and oxygenates.

J. Lauterbach and coauthors at the University of South Carolina (Columbia) and the University of Delaware (Newark) deoxygenated pentanediols by using zeolite HZSM-5 as a solid acid catalyst. At temperatures between 325 and 450 ºC at atmospheric pressure, they produced LPG and BTEX, obtaining as much as 94% carbon yield. Over a 40-h production run, they sustained a 91.5% carbon yield of the desired products, with a relatively steady product distribution. (There was a gradual shift away from paraffin products toward olefins and xylenes.) They observed minimal production of CO, CO2, and coke; and they were able to regenerate the HZSM-5 catalyst multiple times.

The researchers passed a mixture of helium and vaporized 1,5-pentanediol or 1,2-pentanediol through a fixed-bed quartz reactor that contained the catalyst. They cooled the effluent gas to condense the less-volatile products, mostly toluene and xylenes with lesser amounts of benzene, ethylbenzene, and C9+ aromatics. Higher reaction temperatures shifted selectivity toward smaller hydrocarbon products. No oxygenated compounds were found in the organic liquid phase.

Water in the production stream did not severely degrade the catalyst. In fact, feeding water along with the pentanediol reduced coke formation and produced a higher carbon yield of BTEX and LPG, especially C2−C4 olefins. Water reduced the interaction between the pentanediol and the catalyst acid sites and contributed to the partial gasification of carbon deposits. The aqueous effluent was >99 wt% water. No unreacted pentanediol was detected. (ACS Sustainable Chem. Eng. DOI: 10.1021/sc500815c; Nancy McGuire)

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