Noteworthy Chemistry

July 11, 2011

Here’s a total synthesis of a GABA-containing heptapeptide. The unguisins—naturally occurring cyclic peptides—contain the unusual feature of a γ-aminobutyric acid (GABA) residue within the macrocycle. L. Hunter* and J. H. Chung at the University of Sydney report the first synthesis of unguisin A (1).

The authors’ synthetic strategy was guided by the selection of a cyclization site for the linear peptide-based precursor 3 between L- and D-amino acid residues. This tactic helps reduce epimerization. This site also positions the GABA residue in the center of 3 to enhance the folded conformation needed to facilitate macrocyclization.

Linear peptide 3 is prepared by using conventional Fmoc-based solid-phase peptide synthesis techniques that start with a Wang resin preloaded with Fmoc-L-phenylalanine 2. (Fmoc is 9-fluorenylmethoxycarbonyl; Boc is tert-butoxycarbonyl.) This structure is subjected to a standard iterative deprotection–peptide coupling sequence that builds the chain of heptapeptide 3.

Subsequent cleavage from the Wang resin and simultaneous removal of the D-tryptophan side chain protecting group, followed by another coupling reaction, produces desired macrocycle 1 in relatively high purity and a high 96% yield from 2. The DMTMM coupling agent for the cyclization is 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate.

Macrocycle 1 is isolated in 81% yield after preparative reverse-phase HPLC purification, with no epimerization or cyclooligomeriation side products. 1H NMR analysis confirmed that the region of 1 containing the GABA residue is conformationally flexible.

The authors suggest that this method may have broader implications for simplifying challenging syntheses of macrocyclic analogues. (J. Org. Chem. 2011, 76, 5502–5505; W. Jerry Patterson)

Teach students to use Wikipedia carefully. Wikipedia is the world's largest online encyclopedia. The content is free; and anyone may use, edit, copy, or redistribute the published information. It is widely used as a reference in academia. Undergraduate students cite the content in their assignments and project reports.

But students often find it difficult to evaluate the reliability of Wikipedia’s information. E. Martineau* and L. Boisvert at Collège Jean-de-BrÉbeuf (Montreal) teach their undergraduates to examine this and other online information critically.

To help their students, the authors select a series of Wikipedia articles on topics covered in a first-year chemistry course. The students are divided into groups, and each group is asked to find errors in and supply missing content for its assigned articles. When the corrected and supplementary content is approved by the professor, the students import it into Wikipedia. Based on their findings, they write an essay on how to improve Wikipedia content.

This project develops students’ analytical skills. The students agree to investigate further before they cite Wikipedia or other online information, even if they believe the content is valid. The authors found that this project works well and recommend it to other educators. (J. Chem. Educ. 2011, 88, 769–771; Sally Peng Li)

A stable, processible heteroleptic iridium complex electroluminesces efficiently. The 2,2’-dipyridylamido (dpa) ligand is a widely used ancillary for synthesizing metal complexes. Reported dpa-coordinated iridium complexes, however, are limited to a few ion-paired species. These ionic complexes are not suitable for use in organic light-emitting diodes (OLEDs) because of their low vapor pressures.

A team led by Z. Hou at RIKEN Advanced Science Institute (Saitama, Japan) and Saitama University presents the first example of a neutral heteroleptic (multiligand) Ir(III) complex (1) that contains an ancillary dpa ligand in addition to an o-2-pyridylphenyl ligand. Complex 1 is readily processible and exhibits highly efficient green electroluminescence.

The authors prepared the complex in a one-pot reaction with 70% yield. The structure was characterized by XRD crystallography. The phosphorescence quantum yield of 1 in CHCl3 solution is a high 87%. Its thermal stability is also high, with an onset decomposition temperature of ≈350 °C. Its macroscopic processibility is excellent; it can be easily sublimed under vacuum.

At a current density of 2 mA/cm2, an OLED based on 1 showed current and power efficiencies of 123.5 cd/A and 43.2 lm/W, respectively. These efficiencies are greater than those reported for other Ir(III)-doped green OLEDs. (Chem. Commun. 2011, 47, 5726–5728; Ben Zhong Tang)

Optimize a classical resolution of a chiral amine. C. A. Baxter, E. Cleator, and co-workers at Merck Sharpe and Dohme Research Laboratories (Hoddesdon, UK, and Rahway, NJ) report the first large-scale synthesis of a dual orexin receptor antagonist for treating insomnia. In the course of their work, they found that dibenzoyl-D-tartaric acid (DBT) is the only chiral acid that works well for resolving a racemic 1,4-diazepane intermediate to isolate the (R)-configuration of the amine.

The crude DBT salt had 76% ee in the initial resolution attempt. A study of THF–CH2Cl2 solvent systems for a potential ee upgrade did not improve the resolution. The authors believe that resolution is impeded by the formation of a 2:1 acid–amine salt in addition to the desired 1:1 salt with DBT.

They also evaluated several other solvents. The 2:1 salt is more soluble than the 1:1 salt in MeOH, and the ee can be upgraded to 97%—but with low yield. Using 4 equiv i-PrOAc as a MeOH “antisolvent”, the authors isolated the 1:1 salt in 76% yield and 96% ee. (Org. Process Res. Dev. 2011, 15, 367–375; Will Watson)

These ionic liquids for dissolving cellulose are distillable. The dissolution and processing of cellulose from woody materials is a requirement for biomass refineries. It is possible to dissolve cellulose in some task-specific ionic liquids (ILs), but recovering the ILs is a problem.

A. W. T. King, I. Kilpeläinen, and co-workers at the University of Helsinki developed distillable ILs that can dissolve cellulose by breaking their hydrogen bonds. The compounds are salts of the “superbase” 1,1,3,3-tetramethylguanidine (TMG, 1) with carboxylic acids. Some of the ILs prepared by the authors are not new, but they have not been used for dissolving cellulose.

The ILs (2) were prepared from various organic acids and ranked according to the basicity of the anion, from the carboxylates (most basic) to bis(trifluoromethanesulfonyl)imide (least basic). The results indicated ILs with more basic anions dissolve cellulose better and are easier to distill.

The ILs were used to dissolve 5 wt% microcrystalline cellulose (MCC) at 100 °C in 18 h. TMG:AcOH was the best solvent. Raising the temperature to 105 °C and heating for 20 h allowed 10 wt% MCC to be dissolved. Above 110 °C, the cellulose begins to saccharify; this broadens the usefulness of the process.

The IL can be distilled for reuse with 99% recovery by using a kugelrohr apparatus (bulb-to-bulb distillation). This method is an improvement over available IL techniques for processing cellulose. (Angew. Chem., Int. Ed. 2011, 50, 6501-6503; JosÉ C. Barros)

Ionic liquids can elicit unexpected behavior in short peptides. Recent studies of protein behavior in ionic liquids (ILs) showed that these solvents affect thermal protein folding and unfolding. To examine the effects of an IL on simple secondary structural elements, M. R. Bunagan and co-workers at the College of New Jersey (Ewing) used circular dichroism (CD) spectroscopy to follow the solvent effects of pure 1-butyl-1-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide, [C4mpy][Tf2N], on the folding of several short “designer” peptides, including the alanine-based α-helical peptide AKA2, the α-helical miniprotein Trp-cage, and the β-hairpin tryptophan zipper Trpzip4.

Temperature-dependent CD spectra of the peptides in [C4mpy][Tf2N] indicated unusual temperature-induced helix formation for AKA2 and Trp-cage; stable structures persisted at 96 °C. In contrast, the β-hairpin structure of Trpzip4 dissolves as the temperature increases.

The authors believe that the IL imposes kinetic control over peptide conformational distributions at low temperature. This hypothesis is supported by data for AKA2 that show that the peptide retains a helical structure after an initial heating (folding) step and cooling. The limited hydrogen-bonding ability of [C4mpy][Tf2N] compared with water may enhance the stability of intrapeptide hydrogen bonding, which stabilizes the helical structure within AKA2 and Trp-cage. In the case of the Trpzip4 peptide, the authors believe that interactions of the hydrophobic alkyl chains of [C4mpy][Tf2N] with the hydrophobic peptide core destabilize tryptophan stacking interactions that are essential for proper folding of the β-hairpin.

These results highlight the complexity of IL–peptide interactions and underscore the difficulty of predicting the effects of ILs on protein structures. Once these effects are understood, ILs may play a significant role in controlling solvent–biomolecule interactions. (Chem. Commun. 2011, 47, 8007–8009; Gary A. Baker)

Take an easy route to α-methylene-γ-butyrolactones. The methylenebutyrolactone heterocyclic scaffold exists in a variety of natural products, particularly sesquiterpene lactones, and may contribute to their biological activity. An efficient chiral synthesis of this class of compounds would be useful in natural products research.

D. M. Hodgson*, E. P. A. Talbot, and B. P. Clark at the University of Oxford (UK) and Eli Lilly (Windlesham, UK) describe studies that led to a concise synthesis of β-substituted α-methylene-γ-butyrolactones from commercially available tulipalin (1). A key intermediate in their strategy is β-substituted bromomethyl derivative 2, which provides an effective site for Barbier-type coupling with aldehydes to provide regio- and stereocontrolled access to β-substituted hydroxymethyl lactones 3.

This method produces 3 and its analogues in good-to-high yields with diastereoselectivities as high as 99:1. Aromatic or aliphatic aldehydes may be used in the second step; the latter, however, give consistently higher diastereoselectivities.

To demonstrate the utility of their procedure, the authors synthesized two valuable natural products. Vanillin-derived alcohol 4 was converted by 1,4-addition to hydroxymatairesinol (5), a member of a class of plant-based phytoestrogen lignans that exhibit antioxidant properties and can be metabolized in vivo to form mammalian lignans. The cod ligand in the rhodium catalyst is 1,5-cyclooctadiene.

Secondary alcohol 6 was first converted to primary alcohol 7 via translactonization. The oxidation of 7 formed the target carboxylic acid 8, the naturally occurring antibacterial and antitumor agent (±)-methylenolactocin. (Org. Lett. 2011, 13, 2594–2597; W. Jerry Patterson)

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