Noteworthy Chemistry

November 28, 2011

Zanamivir phosphonate derivatives combat resistant flu strains
Upgrade stereopurity by isolating the unwanted material
Substitute fluorine at key sites to improve antitumor drugs
Mechanically “unclick” triazole polymers
BODIPY molecules self-assemble into NIR–emitting particles
Copper nitride crystals remove a fuel-cell roadblock
Prepare phenylacetic acids by using iodide-catalyzed reduction

Zanamivir phosphonate derivatives combat resistant flu strains. Current treatments for influenza include neuraminidase inhibitors such as the inhaled drugs zanamivir (1) and oseltamivir (2). Oseltamivir is a prodrug that is hydrolyzed in vivo to produce oseltamivir carboxylic acid (3), but influenza strains that are resistant to 3 have been reported.

C.-H. Wong and coauthors at Academia Sinica (Taipei, Taiwan [Province of China]) and National Taipei University prepared phosphonate congeners of 1 that are active against several strains of influenza. They hypothesized that as an isosteric replacement for carboxylate, phosphonate would create stronger electrostatic interactions with the guanidine group in arginine residues at the neuraminidase active site.

The authors prepared two phosphonate derivatives of zanamivir, 4 and 5, in quantities suitable for pharmacological evaluation (IC₅₀ and EC₅₀) against influenzas H1N1, H3N2, and H5N1. (IC₅₀ is the concentration needed to inhibit half of the flu organisms; EC₅₀ is the concentration needed to achieve half of the maximum response after a given time.) The results indicate that 4 and 5 are more active than 1 and 3, particularly against influenza strains that are resistant to 2. These new compounds also are nontoxic even at high concentrations. These compounds may be the first choice for treating oseltamivir-resistant influenza. (J. Am. Chem. Soc. 2011, 133, 17959–17965, JosÉ C. Barros)

Upgrade stereopurity by isolating the unwanted material or resolving an intermediate with chiral chromatography. D. J. Wallace and coauthors at Merck (Hoddesdon, UK, and Rahway, NJ) and WuXi APPTec (Shanghai) produced (S)-2-[4-(piperidin-3-yl)phenyl]-2H-indazole-7-carboxamide p-toluenesulfonate monohydrate, an oral poly(ADP-ribose) polymerase (PARP) inhibitor, in 95% ee in kilogram quantities via initial fit-for-purpose modifications of the medicinal chemistry route. Slurrying the salt in a 1:1 MeCN–H₂O mixture and filtering it produced a 4–6% yield of a solid with ≈30% ee. The stereopurity of the filtrate, however, was now >99.5% ee. Distilling the MeCN from the filtrate resulted in a white slurry from which the product was readily isolated in >99.5% ee and 85% recovery.

In a subsequent iteration of the synthesis, the key separation of an earlier intermediate was carried out by chiral chromatography, instead of an inefficient kinetic classical resolution. This change gave a higher overall yield and eliminated the need to upgrade the stereopurity of the final product. (Org. Process Res. Dev. 2011, 15, 831–840; Will Watson)

Substitute fluorine at key sites to improve antitumor drugs. The vinca alkaloid family of compounds contains vinblastine (1) and vincristine (2), which are efficacious antitumor drugs that inhibit microtubule formation and mitosis.

As part of a study of the biomimetic synthesis of 1 and 2, D. L. Boger and co-workers at the Scripps Research Institute (La Jolla, CA) substituted fluorine at the 10’-positions of these compounds. This position is an oxidative metabolism site, and fluorine substitution would block metabolite formation. Structural analysis indicates that this site is located in an area of the tubulin-bound molecule deeply embedded in the protein, where it makes contact at a place sensitive to steric interactions. Substitution at the 10’-position could provide potentially useful structural variations.

The authors’ synthetic strategy involved Fe(III)-mediated biomimetic coupling of catharanthine (3) and vindoline (4) to produce intermediate anhydrovinblastine (5). Oxidation of 5 leads to the target fluorine-modified vinblastine 6, the structure that shows the greatest activity enhancement.

The fluorine atom at the 10’-position of 6 enhances the activity of 1 with minimal alteration of the natural product. This activity is manifested in sensitive HCT116 and L1210 cell lines (IC₅₀ = 0.7–0.8 nM) and in vinblastine-resistant lines HCT116/VM46 (IC₅₀ = 80 nM). (IC₅₀ is the concentration needed to inhibit half of the tumors.) These IC₅₀ values are much lower than the control values for 1: 6.0–6.8 nM and 600 nM, respectively. Vinblastine derivative 6 represents an attractive alternative for initial clinical treatment and secondary treatment for resistant or re-emergent tumors.

The authors also conducted an encouraging preliminary in vivo study of 6 against a vinblastine-resistant human colon cancer cell line. The results suggest that 6 gives much better dose–response results than an equivalent dose range of 1.

The Fe(III)-mediated biomimetic coupling to form 6 is a useful synthetic pathway to measure and optimize substituent effects in this antitumor drug family. (ACS Med. Chem. Lett. 2011, 2, Article ASAP DOI: 10.1021/ml200236a; W. Jerry Patterson)

Mechanically “unclick” triazole polymers. Organic chemists and biochemists use “click” reactions routinely these days, but until now there has been no good way to run this reaction in reverse. In the most common click reaction, an azide reacts with an alkyne to form a 1,2,3-triazole under mild conditions. Triazoles are extremely stable and cannot be cleanly chemically or thermally “unclicked”.

J. N. Brantley, K. M. Wiggins, and C. W. Bielawski* at the University of Texas at Austin developed a mechanochemical technique that “pulls apart” triazole click-reaction products. To destabilize the ground state of the molecules and dissociate them into their original components, other researchers have attached polymeric substituents to molecules with mechanically labile bonds and applied mechanical energy in the form of ultrasound to solutions of the polymers. The authors used this principle to “unclick” triazoles.

The triazole system used in the study had poly(methyl acrylate) (PMA) chains attached to triazoles at the 1- and 4-positions. Specifically, bis(2-hydroxyethyl)-1,4-triazole was treated with 2-bromoisobutyryl bromide to add tertiary bromo side chains. The dibromo product then underwent copper-mediated single-electron–transfer living radical polymerization to produce PMAs with the triazole group at the center.

The authors subjected an MeCN solution of PMA–triazole with 96-kDA molecular weight (M_n) and a 1.3 polydispersity to ultrasound for 2 h at 0 °C. The molecular weight decreased to 48 kD, indicating that the chains cleaved into two smaller chains with the same length, consistent with a reverse click reaction. IR spectroscopy of the polymeric products showed the presence of azide and terminal alkyne groups. The polydispersity of the products was almost the same (1.4) as the starting polymer.

Sonication of PMA–triazoles with 160- and 63-kDA M_n gave similar results. Shorter polymers (36- and 16-kDA M_n), however, were cleaved little or not at all, indicating that the polymeric chains must be sufficiently long to respond to ultrasound force. When the 96-kDA polymer was heated to 258 °C for 19 h, no chain scission occurred, excluding the possibility that heat generated by sonication caused the polymer to decompose.

The authors also showed that the unclicked polymers can be “reclicked” in yields of ≈86%. This work demonstrates the power of mechanochemistry that may have applications such as dye-sensitize force sensors and force-responsive fluorescent tags for biological assays. (Science 2011, 333, 1606–1609; Michael J. Block)

BODIPY molecules self-assemble into NIR–emitting particles. The large amount of research on fluorescent organic nanoparticles (FONs) is due in part to their potential applications as advanced materials for biological imaging and drug delivery. J.-H. Olivier, J. Widmaier, and R. Ziessel* at the National Center of Scientific Research and the Charles Sadron Institute (both in Strasbourg, France) developed a new type of FON that emits near-IR (NIR) fluorescence by using the self-assembly of amphiphilic molecules of a lipidic boron–dipyrromethene (BODIPY) fluorophore (1).

The self-assembly of 1 in aqueous media is quantitative. The FONs formed in this way have narrow size distributions (1.4–1.6 nm) that are consistent with the accretion of four or five molecules of 1. The paraffin chains in the cores of the FONs shrink, and the polar heads at the peripheries are solvated by water molecules. The controlled aggregation is driven by the cooperative balance of electrostatic repulsion at the periphery and lipophilic association at the core.

The FONs are stable after many weeks. The FONs’ specific composition is determined by the amount of water added to a THF solution of monomeric 1; it can be cycled many times by changing the mol fraction of water. The FONs act as a sponge (host) for other fluorophoric molecules (guests), provided that the guests are equipped with complementary lipophilic chains. In this way, advanced photon collectors that emit at 760 nm can be assembled and dismantled at will. (Chem.—Eur. J. 2011, 17, 11709–11714; Ben Zhong Tang)

Copper nitride crystals remove a fuel-cell roadblock. Fuel cells, a clean-energy technology, use chemical reactions to generate electricity. Reactions occur at both electrodes: hydrogen oxidation at the anode and oxygen reduction at the cathode. Current fuel cells require nanostructured platinum or palladium catalysts. The cost of these metals is more than one-fourth the cost of the cells, creating a great incentive to find less expensive replacements. H. Wu and W. Chen* at the Chinese Academy of Sciences (Changchun) report a key breakthrough in fuel-cell metal catalysis: They discovered that a copper compound can be used as the cathode to catalyze oxygen reduction.

Copper(I) nitride (Cu₃N), prepared by heating Cu(NO₃)₂ in a 1-alkylamine–terminal olefin solution at 150 °C for <3 h, is an efficient catalyst. The presence of the alkene and the primary amine is critical for Cu₃N crystal formation. The chain length of the amine determines the crystal size; for example, 1-octadecylamine (used with 1-octadecene) forms 26-nm particle size copper crystals, whereas 1-hexadecylamine gives smaller crystals that aggregate.

Crystalline Cu₃N catalyzes oxygen reduction, but it is less efficient than platinum cathodes. The authors are confident, however, that the catalytic efficiency of Cu₃N will improve when the crystal structure is optimized. (J. Am. Chem. Soc. 2011, 133, 15236−15239; Sally Peng Li)

Prepare phenylacetic acids by using iodide-catalyzed reduction. The phenylacetic acid group is a key feature in the structures of several pharmaceutical and natural products, for example, widely used nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and diclofenac. The numerous methods available to form phenylacetic acids and esters have drawbacks that limit their value as simple, highly scalable, economical processes with green chemistry principles.

Perhaps the most straightforward route to phenylacetic acid scaffolds is the reduction of the α-hydroxy group of the corresponding mandelic acids. These precursors are usually commercially available or easily prepared. J. E. Milne and co-workers at Amgen (Thousand Oaks, CA) describe an optimized modification of this approach that overcomes many of the limitations.

A simple example of the authors’ method is the iodide-catalyzed transformation of α-hydroxyphenylacetic acid (1) to phenylacetic acid (2) that uses reductant H₃PO₃ and strong acid MeSO₃H to form 2 in good yield. The optimization studies showed that 8 M HCl can be used in place of MeSO₃H with no significant changes in product yield or purity. The method can be modified to form α-substituted products such as 3 in high yield.

To meet a requirement in one study, the authors used their process to produce a substituted phenylacetic acid on a multikilogram scale. They crystallized mandelic acid derivative 4 directly from the reaction mixture as the monosodium salt and recovered it by filtration. This technique allowed the synthesis of 25 kg of 4 in a single batch. Applying the iodide-catalyzed reduction method led to an 84% yield of the desired phenylacetic acid 5 on a similar scale; this product was also recovered by simple cooling, recrystallization, and filtration. This large-scale process has a minimum number of operations and high volumetric efficiency that lead to reduced cycle times and manufacturing costs. (J. Org. Chem. 2011, 76, 9519–9524; W. Jerry Patterson)

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