Issue Date: April 30, 2012
Streamlining Tetrazine Synthesis
Facile synthesis of promising tetrazine biochemical probes could be a big step forward for researchers who examine biochemistry as it happens in cells and live animals (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201201117). The advance, utilizing Lewis acid catalysts, might allow more researchers to make the probes in one pot from commercially available starting materials.
Thus far, the tetrazine labels, which feature nitrogen-rich rings, have been relegated to labs with the chemistry chops to work with the multistep and low-yielding syntheses required to make them. Researchers who are looking deeply at biochemistry as it happens value these and other so-called bioorthogonal coupling agents because they can monitor a particular target while avoiding side reactions with the stew of other cellular components.
Tetrazines, in particular, are prized for their selectivity and speed in reacting with cyclooctene labels. However, the most convenient tetrazine synthesis requires two steps: nucleophilic addition of hydrazine to a nitrile followed by oxidation. That synthesis doesn’t work for alkyl nitriles, and syntheses from other precursors, such as amidine salts, are low-yielding.
Now, a team led by Neal K. Devaraj of the University of California, San Diego, has streamlined tetrazine production with Lewis acid catalysts such as nickel triflate. The Lewis acids are thought to bind to the nitrile or hydrazine. This promotes the first step in tetrazine synthesis enough to get results with alkyl nitriles and swap an oxidative workup for the separate oxidation step.
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, so this method is certainly welcomed,” says Joseph P. A. 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.”
Devaraj notes the new synthesis should be useful not only to biochemists but also to materials scientists and explosives researchers, who use tetrazines as well.
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