Noteworthy Chemistry

April 23, 2012

Tame diazomethane for in situ iron-catalyzed cyclopropanation. Diazomethane (CH2N2) is a useful synthesis reagent, but its utility is compromised by its explosiveness and toxicity. B. Morandi and E. M. Carreira* at ETH ZÜrich (Switzerland) developed a protocol for generating CH2N2 in tandem with iron-catalyzed cyclopropanation, thus avoiding the hazards of isolating CH2N2.

CH2N2 is generated from the water-soluble sodium salt of N-methyl-N-nitroso-m-carboxybenzenesulfonamide (1) by treating it with concd aq KOH. The catalyst, a carbene-transfer reagent, consumes the free CH2N2 immediately and transfers it to the organic phase of the two-phase reaction medium.

The authors chose p-methoxystyrene (2) as a model compound for screening several catalysts for the cyclopropanation reaction. An important requirement for the catalyst was that it be stable toward strongly oxidizing 1 and a strong base in aqueous solution. The readily available iron porphyrin complex FeTPPCl (3) emerged as the best catalyst. With 0.1 mol% of the catalyst, the reaction turnover number was 600.

The protocol is compatible with a range of substrates, including mono- and disubstituted styrenes with electron-withdrawing, electron-releasing, conjugated alkenyl, and alkynyl substituents. Mechanistic studies showed that a two-phase medium is crucial to the success of the reaction. Retaining compound 1 and the base in the aqueous phase avoids interference with the cyclopropanation. The use of water-soluble substrates or EtOH cosolvent results in lower yields.

The authors believe that this concept can be expanded to create safe protocols for reactions of azides and other diazo compounds. (Science 2012, 335, 1471–1474; Xin Su and JosÉ C. Barros)

Triblock copolymers with tapered interfaces form nanonetworks. T. H. Epps III and colleagues at the University of Delaware (Newark) and Stony Brook University (NY) prepared poly(isoprene-b-isoprene–styrene-b-styrene-b-styrene–methyl methacrylate-b-methyl methacrylate) [P(I-IS-S-SM-M)] triblock copolymers with two tapered interfaces by using a click coupling method.

The authors synthesized a P(I-IS-S) tapered block copolymer via anionic polymerization and terminated it with an azide unit. They used atom-transfer radical polymerization with a propargyl 2-bromoisobutyrate initiator to form a tapered P(SM-M) block with an alkyne terminus. The similar reactivity ratios of styrene and methyl methacrylate allow a linear SM tapered profile to develop.

A Huisgen 1,3-cycloaddition click reaction between P(I-IS-S) and P(SM-M) produced the P(I-IS-S-SM-M) triblock in 96% yield. Its molecular weight (Mn) was 46 kDa, and its polydispersity index was 1.3. The dual-tapered P(I-IS-S-SM-M) formed an alternating gyroid morphology that likely was stabilized by the tailored interface. This technique paves the way for using interface modification to develop more complex architectures with network morphologies. (ACS Macro Letters 2012, 1, 519–523; LaShanda Korley)

Two-layer membranes separate proteins with less fouling. Fouling is a serious drawback to membrane technology. The accumulation of unusable materials minimizes efficiency and adds unnecessary post-treatment expense.

For example, poly(carboxybetaine)s (pCBs) are widely used in biomembranes. Some pCB membranes efficiently isolate specific proteins via intermolecular forces, but they also absorb other components from the medium. Other membranes do not foul, but their protein-separating efficiency is poor. Until now, no feasible design has emerged to solve these problems.

C.-J. Huang, Y. Li, and S. Jiang* at the University of Washington (Seattle) devised two-layered pCB membranes that efficiently absorb specific protein molecules from human blood. They covered an inert substrate with a densely dispersed amphoteric polymeric membrane that has excellent antifouling properties. A less dense pCB layer with biorecognition substituents is grafted to the first layer. The density of functional groups in the second layer can be controlled to adjust the loading level. The dual membrane fouls much less than one-layer pCBs and separates proteins more efficiently. (Anal. Chem. 2012, 84, 3440−3445; Sally Peng Li)

Indole–fibrate hybrids fight hyperlipidemia and obesity. Obesity is a primary cause of dyslipidemia, which is characterized by elevated low-density lipoprotein (LDL, “bad” cholesterol) levels in the bloodstream and lowered high-density lipoprotein (HDL, “good” cholesterol). Very few antiobesity drugs are commercially available; the ones that are mainly reduce dietary fat absorption or suppress the appetite. K. V. Sashidhara and coauthors at the CSIR–Central Drug Research Institute (Lucknow) and the National Institute of Pharmaceutical Education and Research (Raebareli, both in India) set out to design bioactive molecules that have antiobesity and anti-dyslipidemic properties.

The researchers combined indole structures that have antiobesity activity with fibrate moieties that have lipid-lowering properties to make a series of bisindole–fibrate hybrids. They tested these molecules for anti-dyslipidemic activity and found that compounds 1 and 2 in the figure are the most potent. Their investigation indicated that supplementing 1 or 2 in the diet suppressed weight gain and reduced visceral fat mass in rats that were fed a high-fat diet (HFD). Moreover, the molecules significantly reduced LDL levels and increased HDL levels in HFD-induced hyperlipidemic rats. The lipid level changes are comparable with those of commercially available fenofibrate.

These two compounds are good candidates for developing a new class of dual-acting hypolipidemic antiobesity agents. (J. Med. Chem. 2012, 55, 2769–2779, Chaya Pooput)

This rating tool can help you select the best synthetic route. In this article on holistic manufacturing route selection, R. B. Leng and co-workers at Dow Chemical (Midland, MI) describe a useful rating tool for alternative synthetic routes to a given molecule. The user identifies important criteria or route-selection factors such as cost, safety, and waste generation and assigns a weighting value for the relative importance of each on a scale of 1 to 10.

Each route under consideration is given a score of 1, 3, or 9 for each criterion. The score is multiplied by the importance-weighting figure for each selection factor. The products are then summed to produce an overall score for each route so that the routes can be objectively compared. The tool can be easily incorporated into an Excel spreadsheet. (Org. Process Res. Dev. 2012, 16, 415–424; Will Watson)

Use DMF–benzoyl chloride to prepare β-lactams. Azetidin-2-ones, usually called β-lactams, are the cores of several antibiotics such as penicillins and cephalosporins. Current routes to this heterocyclic structure are based on the Staudinger reaction, a cycloaddition between a ketene and an imine. Frequently the ketene is obtained from the corresponding activated carboxylic acid in presence of Et3N.

M. Zarei at Hormozgan University (Bandar Abbas, Iran) developed a way to activate the carboxylic acid by using DMF and PhCOCl. The reagents are stirred at room temperature for 5 min in a dry solvent to produce zwitterionic adduct 1. A carboxylic acid, an imine, and Et3N are then added to the suspension of the adduct to yield the desired β-lactam.

The author tested several reaction conditions and obtained the best results with CH2Cl2 as the solvent, ambient temperature, and a 1/imine mol ratio of 1.3:1. He proposes a mechanism that involves deprotonation of the acid by Et3N, activation by 1, ketene formation, and a reaction between ketene and imine to produce the target molecules.

The stereochemistry of the lactam product is usually cis. Trans isomers are obtained when there is an equilibrium between two zwitterionic intermediates. Yields are >50% after crystallization from EtOAc. This activation protocol is a safer, less costly, industrially viable alternative to existing methods (Bull. Chem. Soc. Jpn. 2012, 85, 360–368; JosÉ C. Barros)

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