Web Date: April 24, 2012
Streamlining Tetrazine Synthesis
Thanks to zinc and nickel catalysts, a newfangled motif for biomolecule labeling might catch on more easily than it could before (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201201117). Thus far, the labels, which feature nitrogen-rich rings called tetrazines, have been relegated to labs with the chemistry chops to work with the multistep and low-yielding syntheses required to make them. The advance might allow more researchers to make them in one pot from commercially available starting materials.
Researchers who want to examine biochemistry as it happens in cells and live animals are increasingly turning to bioorthogonal coupling agents, which are designed to monitor a particular target while avoiding side reactions with the stew of other cellular components. Among the newest molecules to be adapted for bioorthogonal purposes, tetrazines are prized for their selectivity and speed in reacting with cyclooctene labels. However, they’re less distinguished in the “ease of synthesis” department.
Now, a team led by Neal K. Devaraj of the University of California, San Diego, reports that it’s possible to streamline tetrazine production with Lewis acid catalysts such as zinc triflate. Lewis acids promote the first step in tetrazine synthesis: nucleophilic attack of a nitrile by hydrazine.
Devaraj’s group used their technique to make unsubstituted tetrazines and asymmetric tetrazines; the latter are so named because they have two different substituents. “We have had problems generating such compounds using traditional techniques, and so this method is certainly welcomed,” says Joseph P. Harrity, a chemist at the University of Sheffield in England. However, he points out that it might be challenging to separate some asymmetric tetrazines from symmetric by-products.
So far separations have been straightforward, but improvements to cut down on troublesome by-products are in the works, Devaraj says. For example, he elaborates, “we plan on tweaking the procedure by immobilizing one nitrile on a solid support and reacting it with another nitrile in solution.” In addition, because the reaction currently requires the unstable reagent anhydrous hydrazine, his team is planning to look into safer alternatives.
“Devaraj presents a catalytic method that is direct and general, and it should enable broader access to these important compounds,” says University of Delaware organic chemist Joseph M. Fox, whose group first adapted tetrazines for bioorthogonal chemistry (C&EN, Oct. 6, 2008, page 8).
Devaraj notes the new synthesis should be useful not only to biochemists—materials scientists and explosives researchers also use tetrazines. He hopes the work will also facilitate in-depth studies on the mechanism of tetrazine formation. “Though this is a classic synthetic method, there is surprisingly little that has been done to mechanistically understand this reaction,” he adds.
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