Noteworthy Chemistry

December 3, 2012

This enzyme may be a prime target for new antimalaria drugs. Malaria kills almost one million people worldwide every year. Continually developing resistance to antimalaria drugs makes the development of new treatments necessary. The enzyme N-myristoyltransferase (NMT) is essential to the functioning of the malaria parasite Plasmodium falciparum and may be a good target for antimalaria drugs.

To identify NMT inhibitors, E. W. Tate, R. J. Leatherbarrow, and coauthors at Imperial College London, the University of York (UK), and the National Institute for Medical Research (London) first screened a focused library of NMT inhibitors reported for other parasites for potential P. falciparum NMT (PfNMT) inhibition. They found that compound 1 moderately inhibits PfNMT and is potentially selective over human NMT (hsNMT1).

To improve the potency of structure 1, the authors varied the benzofuran side chains at C4 and C2. Optimizing the C4 side chain produced compound 2, which has much better potency than 1 and retains selectivity against hsNMT1. Experiments on the C2 side chain showed that compound 3 has better properties; however, because the ester function at C2 may make the compounds biologically unstable, the authors substituted other functional groups for the ester.

Oxadiazole derivative 4 is less potent than 3, but its greater biological stability may make it a more efficient drug. The authors plan to test additional oxadiazole analogues and study the effects of the physiochemical properties of these compounds on their cellular potency. (J. Med. Chem. 2012, 55, 8879–8890; Chaya Pooput)


Where has the maleic acid gone? The maleate anion is often used in salts of commercial drugs. The appearance of some monomethyl maleate salt during maleate salt formation from maleic acid and an amine led I. W. Ashworth and colleagues at AstraZeneca (Macclesfield, UK, and Bangalore, India) to perform kinetic studies on the self-catalyzed esterification of maleic acid in MeOH.

The authors used dilute solutions of relatively strong maleic acid to study the esterification reactions. (Maleic acid has a pKa of 5.5 in MeOH). Their key findings were:

  • The rate of the self-catalyzed esterification reaction is 1.5-order based on maleic acid concentration.
  • The rate is affected by the acid used. Oxalic acid is the most likely dibasic acid to exhibit behavior similar to maleic acid because its pKa in MeOH is almost as low. Other dibasic acids such as fumaric and succinic, with higher pKa values, are much less likely to undergo self-catalyzed esterification.
  • The reaction rate is expected to decrease when the MeOH solvent is replaced by EtOH or i-PrOH because carboxylic acid pKa values increase with increasing alcohol carbon number.

Based on the last finding, the authors conclude that the undesirable side reaction should be minimized by forming maleate salts in higher alcohols than in MeOH. (Org. Process Res. Dev. 2012, 16, 1646–1651; Will Watson)


Complexation with (S)-proline produces enantiopure binols. Derivatives of C2-symmetric 1,1’-bi-2-naphthols (binols) are used as chiral ligands and catalysts. Enantioselective complexation is a simple, convenient method for isolating enantiopure binols from their racemic mixtures; but the method requires expensive chiral amines or alkaloids. X. Hua*, Z. Shan, and Q. Chang at South-Central University for Nationalities (Wuhan, China) and Wuhan University used readily available (S)-proline to separate the enantiomers.

The authors heated an equimolar mixture of rac-binol (1) and (S)-proline (2) in MeCN at reflux for 3 h. The white precipitate that formed was filtered and recrystallized from EtOH to give a complex that consists of two molecules of binol and one of proline. The complex was characterized by X-ray crystallography.

The authors hydrolyzed the complex in H2O–EtOAc at room temperature. Extracting the aqueous phase with Et2O, evaporating the solvent, and recrystallizing from toluene produced enantiopure (S)-binol in 47% yield. (S)-Proline was recovered by evaporating the aqueous phase. Finally, (R)- binol was retrieved by evaporating the MeCN filtrate.

The authors confirmed the chiral recognition ability of (S)-proline to (S)- binol by subjecting a mixture of the two to the conditions outlined above and obtaining the same 2:1 complex. The equivalent mixture of (S)-proline and (R)-binol did not produce the inclusion complex. Changing the solvent from MeCN to EtOAc or toluene lowered the resolving efficiency. (Tetrahedron: Asymmetry 2012, 23, 1327–1331; JosÉ C. Barros)


Exploit ring strain to functionalize metal–organic frameworks. C. Liu, T. Li, and N. L. Rosi* at the University of Pittsburgh developed a strategy for covalently functionalizing mesoporous metal–organic frameworks (MOFs). They first prepared an azide-tailored mesoporous MOF that contained metal adeninate tetrahedral units and biphenyldicarboxylate linkers. They then used strain-induced click chemistry to “decorate” the pores inside the MOF.

This process overcomes such challenges as suppressing byproduct formation and ensuring efficiency, scaffold integrity, and functional-group accessibility. Strained alkynes (e.g., cyclooctyne derivatives) were efficiently incorporated via click reactions into the mesoporous interior of the MOF without disrupting its crystallinity. These studies show promise for functionally tailoring MOFs. (J. Am. Chem. Soc. 2012, 13, 18886–18888; LaShanda Korley)


Here’s a safe substitute for methyl isocyanate. Despite its hazardous nature, as exemplified by the 1984 disaster in Bhopal, India, methyl isocyanate (MIC) is still used for synthesizing many N-methylcarbamoyl compounds. The production of current MIC replacements has drawbacks such as low yields or the need to use a large excess of reactants.

While researching safer, easier-to-handle carbamoylating reagents, R. A. Batey and co-workers at the University of Toronto developed an efficient synthesis of highly reactive N-methylcarbamoylimidazole (2), which is a solid, stable substitute for MIC.

The authors first prepared 2 in 45% yield by treating 1,1-carbonyldiimidazole (1) with MeNH2 in THF. The yield was low because 2 reacts further with MeNH2 to give N-methylurea. They then replaced MeNH2 with its HCl salt. The yield increased to ≈100%, even on a 20-g scale. Reagent 2 was obtained as a white, crystalline solid that is highly resistant to hydrolysis.

The researchers showed that 2 is an efficient carbamoylation reagent. The reaction of 2 with 1 equiv of a secondary amine in the presence of 1 equiv Et3N gives the corresponding N-methylurea in excellent yields (81−100%). Compound 2 also reacts with various nucleophiles to make bioactive compounds. Strong bases such as NaH activate alcohols so that they react with 2 to produce carbamates. (J. Org. Chem. 2012, 77, 10362–10368; Xin Su)


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