Noteworthy Chemistry

April 16, 2012

Another Newcomer!

This is a big year for new Noteworthy Chemistry contributors. We welcome Chaya Pooput of Georgetown University Medical Center to the NC family.

An unusual motif improves a potential Alzheimer’s drug. Although scientists do not yet know what causes Alzheimer’s disease, they believe that β-amyloid (Aβ) peptides with 40–42 amino acids are plausible contributors. A. F. Stepan and 26 co-workers at Pfizer Worldwide Research & Development (Groton, CT) are designing potential drugs—in the same length range as Aβ peptides—that inhibit γ-secretase, an enzyme that produces Aβ.

Citing previous work, the authors note that N-substituted arylsulfonamides such as compound 1 inhibit γ-secretase (Gillman, K. W., et al. ACS Med. Chem. Lett. 2010, 1, 120–124). (Compound 1 is already in advanced clinical trials.) To improve the potency of 1, they synthesized and tested a series of analogues and found that the fluoroaromatic group serves mainly as a spacer and that bicyclo[1.1.1]pentane analogue 2 may be more effective. Compound 2’s dihedral angles, distances between substituents, and degree of γ-secretase inhibition are comparable with those of 1; and 2 has higher aqueous solubility (possibly because of the 3-D structure of the bicyclic system that prevents intermolecular π-stacking) and greater permeability than 1. A pharmacological study showed that mice absorbed oral doses of 2 significantly better than doses of 1.

This work provides a promising drug candidate for treating Alzheimer’s disease and merits further preclinical evaluation. (J. Med. Chem. 2012, 55, 3414–3424; Chaya Pooput)

They reduced costs by 50% in 2 months! Such a short time to improve the economics of a three-step synthesis of a proprietary compound did not allow A. A. Desai*, E. J. Molitor, and J. E. Anderson of Dow Chemical (Midland, MI) to make changes to the synthetic route, but they show how telescoping and process intensification can dramatically reduce process economics. They improved the first step, a Suzuki coupling, by crystallizing the starting material to give a purer crude product. They brought the product up to specification by using a silica gel filtration followed by a true crystallization as opposed to two filtrations and three triturations in the original method.

The authors then telescoped steps 2 and 3 (aryllithium addition to a cyclohexanedione followed by aromatization) and crystallized the final product directly from the reaction mixture. This eliminated intermediate isolation and required only one solvent wash and one crystallization step, compared with the original process that required one intermediate isolation, two aqueous extractions, nine triturations, and two silica gel filtrations. The authors developed a costing model for this process intensification procedure. (Org. Process Res. Dev. 2012, 16, 160–165; Will Watson)

Make tunable luminescent “inks” from solvent-free liquids. Liquid luminescent compounds offer numerous advantages over their solid-state equivalents, such as flexibility, easy tunability, and solvent-free processing. Maintaining their fluorescence quantum yields in the pure liquid state, however, remains a challenge. T. Nakanishi and coauthors at the National Institute for Materials Science (Tsukuba, Japan), Osaka University, the National Institute for Interdisciplinary Science and Technology (Thiruvananthapuram, India), and the Max Planck Institute for Colloids and Interfaces (Golm, Germany) synthesized a series of blue light–emitting oligo(p-phenylenevinylene) (OPV) derivatives (14) that are liquids at room temperature. These fluorophores have moderate quantum yields under solvent-free conditions and are not quenched when made into liquid composites.

The properties of the side chains and the substitution positions are crucial for making low-viscosity OPV derivatives. In general, a combination of “swallow-tailed” alkyl chains and (2,4,6)-substituted phenyl groups (as in 4) most effectively decreases the viscosity. These modifications disrupt the π–π stacking of the aryl groups and reduce the van der Waals forces of the alkyl groups, which are significant in reference compounds 5 and 6, respectively. The absorption and emission spectra of 14 as pure liquids are only slightly broader than those of the compounds in solution, indicating that the OPV units are well dispersed but in a highly dense state. Therefore, the neat liquids 14 emit in the blue wavelength range with relatively high quantum yields (45–48%).

Compounds 14 can also serve as solvents for white light–emitting mixtures. For example, compound 2 mixed with tris(8-hydroxyquinolinato)aluminum (green emission) and rubrene (orange emission) in a 1:1.65:0.23 mol ratio can generate white light under UV irradiation at 365 nm with coordinates of (0.33, 0.34) in the CIE 1931 chromaticity diagram. [Pure white is (0.33, 0.33); CIE is the Commission Internationale de lÉclairage.] Researchers can fine-tune the emission further, if they wish, by varying the ratio of components. The resulting emissions can range from blue-white to yellow-white. (Angew. Chem., Int. Ed. 2012, 51, 3391–3394; Xin Su)

“Sweet” block co-oligomers may help deliver drugs. R. Borsali, S. Halila, and fellow researchers at CERMAV-CNRS (Grenoble, France) developed saccharide-based amphiphilic block co-oligomers by using an azide–alkyne click reaction of a hydrophilic maltoheptaose derivative (Mal7) with a hydrophobic peracetylated maltoheptaose (AcMal7) block. They identified reactant solubility, product purification, and copper catalyst contamination as challenges to this synthesis strategy.

The Mal7–AcMal7 click reaction forms stable, spherical ≈27-nm–diam micelles at a 0.1 mg/mL critical micelle concentration in an aqueous solution. The core of the block co-oligomers consists of aggregated AcMal7, and the shell contains Mal7.

The authors demonstrated the utility of the Mal7-“click”-AcMal7 micelles as drug-delivery vehicles. Exposure to glucoamylase causes the maltoheptaose shell to hydrolyze, destabilizing the micelle and releasing potentially encapsulated drug molecules. (Biomacromolecules 2012, 13, 1129–1135; LaShanda Korley)

Autoxidative coupling uses sulfonic acids and oxygen pressure. Xanthene and acridone are versatile building blocks for synthesizing biologically active compounds, natural products, dyes, and molecular switches. Modifying these compounds via nucleophilic substitution, however, usually requires prefunctionalization of a C–H bond with a leaving group.

Á. PintÉr and M. Klussmann* at the Max Planck Institute for Coal Research (MÜlheim an der Ruhr) and the University of Duisburg–Essen (Essen, both in Germany) modified the target compounds by using an autoxidative coupling. They used high-pressure oxygen and methanesulfonic acid [MsOH] or trifluoromethanesulfonic acid [TfOH]) as catalysts. They believe that the reaction proceeds by hydroperoxide formation, autoxidation, and finally alkylation.

Xanthene or acridanes are the preferred substrates. (Cbz is carbobenzoxy.) Nucleophiles (Nu) can be cyclic or acyclic ketones, diketones, β-ketoesters, and aromatics substituted with electron-releasing groups (ERGs). This method is resource-efficient and therefore a “green” protocol. (Adv. Synth. Catal. 2012, 354, 701–711; JosÉ C. Barros)

How much hazardous material is in the reactor headspace? G. Zhou and co-workers at Merck (Rahway, NJ) used in situ Fourier transform (FT) IR analysis to quantitate several volatile off-gases that occur in reactor headspaces. They looked at four compounds:

  • diborane (B2H6), which can form during borane reductions;
  • hydrazoic acid (HN3), a frequent byproduct when one of the reagents is NaN3 or Me3SiN3;
  • acetylene (C2H2), released when LiC≡CH·(CH2NH2)2 complex is used; and
  • chloromethane (MeCl), produced in demethylation reactions and reactions that involve MeOH and HCl.

In each case, the authors undertook a calibration exercise, typically correlating a range of concentrations of the investigated gas in nitrogen with the FTIR spectra of the gas mixture. (Org. Process Res. Dev. 2012, 16, 204–213; Will Watson)

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