Noteworthy Chemistry

January 23, 2012

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Use fluorescent polymers to identify cancer cells. Certain polymers can be used to recognize proteins and enzymes. Fluorescence spectroscopy is a clinical tool for detecting tumor growth at early stages, but fluorescent polymers have not been used for cancer diagnosis. S. Mallik and co-workers at North Dakota State University (Fargo) carried out clinical trials with fluorescent polymers to distinguish between cancerous and noncancerous cells.

The authors prepared two water-soluble polymers with multiple components. They assembled the polymers from monomers 15 shown in the figure; each monomer serves a specific function. Monomer 1, with hydroxyl groups on its side chain, can intermolecularly hydrogen-bond to cells; lysine derivative 2 and aspartic acid derivative 3 interact with complementary charges on enzyme surfaces; 4 introduces a fluorophore for spectrometric detection; and 5 provides a metalloproteianse-9 (MMP-9) inhibitor to help differentiate cancer cells. The polymers are convenient to prepare and have no special requirements for storage or handling.

The polymers can differentiate among diverse prostate cancer cells, but they cannot distinguish prostate from pancreatic cancer cells. The authors are investigating whether incorporating more selective MMP-9 inhibitors in the polymers will improve their ability to differentiate among cancer cells. (Anal. Chem. 2012, 84, 17–20; Sally Peng Li)

Here’s an accidental discovery of safer reaction conditions. In the process of scaling up a synthesis of a stearoyl-CoA desaturase inhibitor, S. J. Dolman and co-workers at Merck (Kirkland, QU, and Rahway, NJ) found that the reaction of a 5-cyanoisoxazole with NaN3 and pyridine hydrochloride in water to produce a tetrazole was not safe. Instead, they used Sharpless conditions (NaN3 and ZnBr2 in aq THF at 85 °C). This gave good conversion, but as much as 2000 ppm of toxic, explosive HN3 was detected in the reactor headspace.

Buffering with K3PO4 avoided this problem, but it formed a precipitate, which the authors suspected to be ZnO. Serendipitously, they discovered that ZnO catalyzes the reaction, so they modified the conditions further by running the reaction with NaN3 and ZnO (0.1 equiv) in aqueous THF. This change gave full conversion and released only 2 ppm HN3 into the headspace. (Org. Process Res. Dev. 2011, 15, 1073–1080; Will Watson)

How to selectively monobenzoylate 1,2- or 1,3-diols in water? Regioselective functionalization of polyols is an important synthetic tool for making natural products and drug-candidate molecules. A problem with many polyols is their limited solubility in organic solvents. One solution would be the selective acylation of polyols in water—a reaction that has not been accomplished without using enzymes.

W. Muramatsu*, J. M. William, and O. Onomura at Nagasaki University (Japan) have made progress with this problem by using the monobenzoylation of 1,2-diols as a test reaction. A key to their method is the use of catalytic Me2SnCl2 and an organic base. They selectively monobenzoylated cyclooctanediol 1 to produce 2 with yields as high as 97%. [DMT is 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; DMAP is dimethylaminopyridine.] In the absence of the tin catalyst, essentially no reaction occurs.

Under the same conditions, 1,3-propanediol (3) is converted to the corresponding monobenzoylated product 4 in up to 92% yield. Competitive benzoylation between secondary diol 1 and primary alcohol cyclooctylmethanol gives monobenzoylated product 2 in 95% yield, with no product from the methanol derivative.

The authors attempted to extend their procedure to the asymmetric benzoylation of meso-1,2-diols such as 5. The tin-based catalyst was ineffective, however; instead they used CuCl2, which leads to chiral product 6 in almost enantiopure form (99% ee). [(R,R)-PhBox is 2,2’-isopropylidenebis(4-phenyl-2-oxazoline).]

This method attains the goals of green chemistry by using an aqueous medium. The mild, benign esterification process also provides an efficient, highly regioselective technique for hydroxyl group protection. (J. Org. Chem. 2011, 76, 754–759; W. Jerry Patterson)

Add guanidine to improve AZT production. Zidovudine (AZT, 1) was the first drug to be approved for treating HIV. It was originally made from thymidine in six steps with an 18% overall yield, but this process requires several purification steps. The major impurity from AZT manufacture is a dimer (2) that requires a large volume of solvents to selectively crystallize the target molecule.

B. K. Radatus at Apotex Pharmachem (Brantford, ON) developed a process that improves the yield of AZT and reduces the number of purification steps. The author discovered that the dimeric impurity can be decomposed by treating it with guanidine. The decomposition product is then used to produce additional AZT.

The author’s method begins with an aqueous solution of the sodium salt of AZT contaminated with 3–7% of the sodium salt of 2. Treating the mixture with guanidine hydrochloride in aqueous solution converts the dimer to an AZT–guanidine salt (3) that remains in solution. Acidifying the salt precipitates AZT, which is recrystallized to give >99.8% pure AZT in an overall yield of 62%. This process improvement has been incorporated into the author’s company’s commercial AZT production. (Org. Process Res. Dev. 2011, 15, 1281–1286; JosÉ C. Barros)

Use click chemistry to cross-link conjugated polymers. A. R. Davis, J. A. Maegerlein, and K. R. Carter* at the University of Massachusetts Amherst used thiol–ene click chemistry to photo-cross-link 4-vinylphenyl–end-capped poly(dihexylfluorene) (xDHF) to improve emission stability in light-emitting–diode (LED) applications. They developed this method to lower cross-linking temperatures, to avoid the use of additives, and to decrease cross-linking times compared with other curing methods.

The authors synthesized low–molecular weight (4.5 kDa) xDHF by using Yamamoto coupling and spin-coated the polymer with excess tetrafunctional thiol cross-linker. The xDHF thin film rapidly cross-linked when it was exposed to UV irradiation at its glass-transition temperature of 85 °C. UV–vis absorption and photoluminescence spectra of the rigid xDHF film confirmed that aggregate formation was suppressed because green-light emission was minimized even after high-temperature annealing.

The authors incorporated the films as device-active layers and demonstrated that the photocured xDHF performs similarly to as-spun or thermally cross-linked poly(dihexylfluorene). The thiol–ene click chemistry technique also allows robust photopatterning of xDHF films. This research may lead to advances in display technology and may become a model for advanced manufacturing strategies. (J. Am. Chem. Soc. 2011, 133, 20546–20551; LaShanda Korley)

Tune a fluorogen’s emission by changing its molecular structure. Borondipyrromethene (BODIPY) fluorophores have attracted much attention because of their high fluorescence quantum yields (ΦF) in the solution phase. In the solid state, however, they barely fluoresce, which limits their technological applications. I. Aprahamian and coauthors at Dartmouth College (Hanover, NH) and the University of Oregon (Eugene) developed a family of borondifluorohydrazone (BODIHY) fluorogens with the general structure of compound 1. Some of these compounds emit efficiently in the solid state.

In contrast to BODIPY fluorophores, none of the BODIHY fluorogens emit strongly in the solution state (ΦF = 0.03–0.07). Their emission becomes more efficient in the solid state, and their ΦF values can be tuned to a large extent by changing their molecular structures.

In general, BODIHY fluorogens with more planar conformations and fewer π–π interactions in the solid state emit more efficiently. Their ΦF values can be manipulated by controlling their dipole moments by judiciously choosing donor and acceptor units. For example, films of BODIHY 2 emit bright blue-green light with a ΦF value of ≈1 order of magnitude greater than that of its solution in CH2Cl2. (Chem. Sci. 2012, 3, 610–613; Ben Zhong Tang)

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