Noteworthy Chemistry

January 9, 2012

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Thiadiazole derivatives may help treat type 2 diabetes. Widespread type 2 diabetes is marked by insulin resistance and abnormally high blood glucose levels. The anomalous glucose levels appear to be related to dysregulation in leptin and insulin signaling in the hypothalamus.

Earlier studies have shown the correlation of insulin signaling with the action of neurotransmitters, including H3-mediated dopamine and serotonin. H3 histamine receptor antagonists directly influence glucose homeostasis and may be effective therapeutic alternatives for treating type 2 diabetics.

A. U. Rao and co-workers at Merck Research Laboratories (Kenilworth, NJ) developed a new series of H3 receptor antagonists. They used the thiadiazole scaffold to synthesize 21 potential drugs for structure–activity correlations. Compound 1 gave the optimum glycemic control in laboratory animals; its preparation is shown in the figure.

The synthesis begins with the bromination of commercially available 2-aminothiadiazol (2) to form derivative 3. Further bromination produces dibromide 4, which undergoes selective displacement with 4-piperidinopiperidine (5) to form the key intermediate 6. Coupling 6 with morpholine derivative 7 leads to the target structure 1 as a racemic mixture.

Because H3 activity is centrally mediated, the authors concentrated on removing the hydrogen-bond donors in this lead structure to improve its pharmacokinetic properties and penetration of the central nervous system. They carried out in vivo antidiabetes efficacy studies for this series in streptozotocin diet–induced obesity type 2 diabetic mice for 2 or 12 days. The H3 binding affinity for 1 was very low—7.0 nM. When the two enantiomers of 1 were separated by supercritical fluid chromatography, the active isomer had an even lower binding affinity of 4.0 nM.

The study included measurements of the marker hemoglobin A1c, routinely used as an indicator of long-term glycemic control. The authors found that following the 12-day treatment of diabetic mice, appropriate doses of 1 blocked the increase of hemoglobin A1c. These studies suggest that 1 may be an effective therapeutic agent for managing type 2 diabetes. (ACS Med. Chem. Lett. 2012, 3, Article ASAP DOI: 10.1021/ml200250t; W. Jerry Patterson)

Incorporating melanin enhances polymers’ thermal stability. C. J. Ellison and colleagues at the University of Texas at Austin and Epitek (Medford, NJ) explored the role of natural and synthetic melanin in the thermooxidative behavior of poly(methyl methacrylate) (PMMA). They determined that synthetic melanin from L-Dopa is more thermally stable in air and nitrogen environments than natural melanin derived from cuttlefish (Sepia officinalis).

Adding 0.5 wt% synthetic melanin raised the decomposition temperature of neat PMMA from 230 °C to an onset temperature of ≈300 °C while maintaining sufficient film transparency. Incorporating melanin increased the activation energy required for PMMA decomposition. The authors hypothesized that melanin disrupts PMMA depolymerization by interacting with the unsaturated chain ends. When they heated PMMA–5% synthetic melanin blends under nitrogen to 320 °C, they found that melanin was covalently attached to the chain ends of the degradation products

In a more realistic air environment, adding synthetic melanin also raised the PMMA onset decomposition temperature by as much as 80 °C and therefore may help maintain PMMA molecular weight during processing at elevated temperatures. This method might also apply to other polymers such as polystyrene. (Macromolecules 2011, 44, 9499–9507; LaShanda Korley)

Make β-adrenergic blockers in one pot with an organocatalyst. Organocatalysts generated in situ in one-pot transformations can in principle enhance the synthesis of complex molecules—enantioenriched drugs in particular—with reduced workup and purification procedures.

S. Wei, R. Messerer, and S. B. Tsogoeva* at the University of Erlangen–Nuremberg (Erlangen, Germany) used this concept to synthesize β-adrenergic blockers nifenalol (1), pronethalol (2), and dichloroisoproterenol (3). They used a synthetic route that includes reducing an amino acid with BH3, generating an oxazaborolidine catalyst, using the catalyst for the enantioselective reduction of an acetophenone, forming an epoxide, and finally aminolyzing with i-PrNH2 (see figure).

The authors found that BH3·THF is superior to BH3·Me2S for reducing amino acids in the first step and that L-valine is a better amino acid than L-leucine or L-phenylalanine in terms of yield and enantiomeric excess (ee). In the second step, B(OMe)3 was used to generate oxazaborolidine organocatalyst 5 from amino alcohol 4. The catalyst was used directly to reduce a phenacyl bromide (6) to make an epoxide (7), which was opened with i-PrNH2 to produce each of the three target compounds (1-3) in good yield and ee. This straightforward method may reduce material costs and labor requirements for synthesizing these compounds. (Chem. Eur. J. 2011, 17, 14380–14384; JosÉ C. Barros)


Protocol changes improve a drug synthesis scale-up. PF-04191834 is a selective 5-lipoxygenase inhibitor that contains a diaryl thioether functionality. The sulfur atom is introduced with i-Pr3SiSH. The order in which the aryl fragments are added is determined by using the one that gives the most crystalline intermediate last to aid purification.

P. D. de Koning, J. P. Lawson, and co-workers at Pfizer (Sandwich, UK, and Chesterfield, MO) optimized the catalyst–ligand combination and solvent used for the reaction, but the catalyst addition protocol was also important for scale-up. Adding the catalyst at room temperature followed by slow heating to mimic scale-up conditions resulted in incomplete conversion, whereas adding the catalyst at the reaction temperature (75 °C) avoided this problem.

The workup was also important because of concerns about the hydrolytic stability of the intermediate during longer workup times inherent to scale-up. The reaction was run in toluene, and water was added mainly to remove byproduct NaBr. The use of water can be avoided, however, by filtering NaBr from the product mixture. (Org. Process Res. Dev. 2011, 15, 1046–1051; Will Watson)

Organic radicals efficiently emit phosphorescence at room temperature in the solid state. Inorganic compounds and organometallic complexes can phosphoresce under ambient conditions, but inorganics are normally difficult to process, and complexes are often expensive and unstable. Organic molecules have advantages in characteristics such as processibility, cost, stability, variety, and color tunability. Few purely organic materials, however, emit phosphorescence at room temperature. Now, G.-P. Yong and co-workers at the University of Science and Technology of China (Hefei) developed two organic radicals that are highly phosphorescent under ambient conditions.

In the solid state, zwitterion radical 1 and anion radical 2 emit bright white and blue light with phosphorescence lifetimes of 19.43 and 22.81 μs and quantum yields of 5.2 and 7.5%, respectively. The authors believe that the phosphorescence derives from the aromatic carbonyl group or free single-electron effects in the molecules. The high water solubility and good processibility of these organic phosphores make them promising candidates for use in biological sensing systems and organic light-emitting diodes. (J. Mater. Chem. 2011, 21, 18520–18522; Ben Zhong Tang)

Fine-tune silk by using protic ionic liquids. N. Byrne and co-workers at Deakin University (Geelong, Australia) used protic ionic liquids (PILs) to reconstitute silk. Although silk is known best for its use in lustrous fabrics, its remarkable mechanical properties can be applied to modern tissue engineering and energy devices.

Silk is commonly regenerated by using organic solvents. In recent work, the authors showed that PILs act as excellent coagulation solvents for regenerating silkworm silk. (Coagulation plays a dominant role in the material’s final properties.) But the challenge is to regenerate silk that retains the properties of native silk.

This work suggests that the use of PILs may solve this problem. The authors show that the compositional structure of the regenerated silk varies widely depending on the choice of PIL. The ability to manipulate and control the self-assembly and composition of regenerated silk is a significant step toward developing “designer” silk materials. According to the authors, PILs may make it possible to regenerate silk with properties that surpass those of native silk. (Chem. Commun. 2012, 48, Advance Article DOI: 10.1039/C2CC17143K; Gary A. Baker)

Solid-state metathesis polymerization makes conjugated polymers. Poly(thienylenevinylene)s (PVTs) are used to prepare electroactive materials with relatively low band gaps and high conductivities. Unfunctionalized PVT is ordinarily an intractable material, which limits its processing capabilities. This deficiency is overcome by functionalizing the prepolymer, but this change introduces defects in the final polymer.

In situ solid-state synthesis of PVTs under metathesis conditions may eliminate these problems. Even though they are alkyl-substituted, these materials may lead to methods for depositing unsubstituted analogues. K. B. Wagener and co-workers at the University of Florida (Gainesville) report a way to prepare difunctional thiophene monomer 1 that has a structure suitable for subsequent metathesis polymerization.

Monomer 1 is formed by initially alkylating bromothiophene 2 via a coupling reaction to form compound 3. Formylating 3 in the presence of base provides dialdehyde 4. A Wittig reaction with a phosphorus ylide yields desired divinyl structure 1. Monomer 1 forms as a mixture of the four possible stereoisomers. It is unstable in air or light and requires cold storage in the dark under inert conditions.

The authors placed 1 in a PTFE mold and used acyclic diene metathesis (ADMET) polymerization with the second-generation Grubbs catalyst to form solid prepolymer 5 with a molecular weight (Mn) of 4 kDa. They sprinkled the catalyst over the prepolymer surface under heating and vacuum conditions to induce step growth polymerization. This process was repeated every 3 days to maximize molecular weight increase to give polymer 6 with a final molecular weight of 14 kDa. This amounts to a 3.5-fold increase while the polymer is in the solid state.

The solid-state polymerization creates a polymer that has similar thermal and electrochemical properties to ones made by using conventional polymerization techniques. The authors’ goal is to use solid-state techniques to create unsubstituted polymers that cannot be obtained by any other direct method. For example, using the ADMET technique to create thienylenevinylene polymers without the solubilizing alkyl branches should create a “cleaner” material with greater potential for electrooptic applications. They are currently pursuing the preparation of pure conjugated polymers in this fashion. (Macromolecules 2011, 44, 9529–9532; W. Jerry Patterson)

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