Elucidating Heterocyclic Chemistry in Pharmaceuticals - Pharmaceutical Technology

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Elucidating Heterocyclic Chemistry in Pharmaceuticals
Researchers at the Scripps Research Institute advance heteorcylic chemistry trhough new reagents and reaction-tracking techniques.


Pharmaceutical Technology
Volume 37, Issue 6, pp. 44-46

Click chemistry

Other researchers at TSRI recently reported on reaction-tracking techniques used to elucidate the mechanism behind the copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction. This reaction involves the use of copper compounds to catalyze the linkage of two functional groups, a nitrogen-containing azide and a hydrocarbon alkyne, to make a stable five-membered heterocycle, 1,2,3-triazole. The CuAAC process is an example of click chemistry, a term coined in 2001 by Nobel Laureate K. Barry Sharpless to describe a set of bond-forming reactions useful for the rapid assembly of molecules with desired function (3). Click transformations are easy to perform, give rise to their intended products in high yields with little or no byproducts, and work well under many conditions (3). Organic azides, as highly energetic and selective functional groups, were used in organic dipolar cycloadditions with olefins and alkynes among the reactions fulfilling the click criteria, but the low reaction rate of the azide–alkyne cycloaddition did not make them useful in the click context until the copper-catalyzed reaction (3). The copper-catalyzed reaction was reported separately by Sharpless et al. in the United States and Melda et al. in Denmark (3). It transforms organic azides and terminal alkynes into the corresponding 1,4-disubstituted 1,2,3-triazoles, in contrast to the uncatalyzed reaction, which requires higher temperatures and provides mixtures of 1,4- and 1,5-triazole regioisomers (3).

The simplicity and reliable performance of CuAAC under diverse conditions, including in water and in the presence of oxygen, has made it a useful method whenever covalent stitching of small molecules or large biopolymers is needed, exemplified by protein and nucleic-acid labeling, in vitro and in vivo imaging, and drug synthesis, according to an Apr. 4, 2013 TSRI press release.

"Despite its many uses, the nature of the copper-containing reactive intermediates that are involved in the catalysis had not been well understood, in large part due to the promiscuous nature of copper, which rapidly engages in dynamic interactions with other molecules," said Valery Fokin, an associate professor at TSRI, who was principal investigator for the new study examining the reaction-tracking techniques of CuAAC, in the TSRI April 2013 release.

The researchers explained that despite the widespread use of copper-catalyzed cycloaddition reactions, the mechanism of these processes was difficult to establish due to multiple equilibria between several reactive intermediates (4). They reported that real-time monitoring of a representative cycloaddition process by means of heat-flow reaction calorimetry showed that monomeric copper acetylide complexes are not reactive toward organic azides unless an exogenous copper catalyst was added. Additional experiments with an isotopically enriched exogenous copper source showed the stepwise nature of the carbon–nitrogen bond-forming sequence and the equivalence of the two copper atoms within the cycloaddition steps (4).

The research revealed that in the CuAAC reaction, two copper-containing catalytic units—copper centers—are needed to help build the new triazole structure. "By monitoring the reaction in real time, we showed that both copper atoms are needed and established the involvement of copper-containing intermediates that could not be isolated or directly observed," said Brady Worrell, a co-author in the study in the TSRI April 2013 release. The researchers used isotopic copper as one of the copper centers to track the reaction. "We hypothesized that the two copper centers would have distinct roles, but found unexpectedly that their functions during key steps in the reaction are effectively interchangeable," said Jamil Malik, also a co-author, in the TSRI 2013 release.

The research not only provides insight into the CuAAC reaction, but also enables development of new reactions that exploit weak interactions of copper catalysts with carbon–carbon triple bonds. Fokin and his team have begun to devise new reactions in which one copper center can be replaced with a different element, to pursue complementary biocompatible and efficient techniques, notes TSRI.

Patricia Van Arnum is a executive editor of Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072,
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References

1. P.S. Baran et al., Nature 492 (7427), 95-99 (2012).

2. I.B. Seiple et al., Angew. Chemie Int. Ed. Engl. 49 (6), 1095-1098 (2010).

3. J. Hason and V.V. Fokin, Chem. Soc. Rev. 39 (4), 1302-1315 (2010).

4. B. T. Worrell, J. A. Malik, and V.V. Fokin, Science 340 (6131), 457-460 (2013).


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