Enzyme tacks bromine or iodine onto terminal alkynes

Alkynes are prized among chemists for their uniquely reactive carbon-carbon triple bonds, which make them excellent coupling partners in click chemistry, for example. Now, chemists at the University of California, San Diego, have discovered and characterized the first enzyme—known as JamD—that can tack either a bromine or an iodine onto terminal alkynes. This biocatalytic route to alkynyl halides could help scientists make complex molecules or could be used to create reactants for chemical reactions in cells or other living systems.

JamD was first isolated from the cyanobacterium Moorena producens JHB, collected in Hector’s Bay, Jamaica. The enzyme is a flavin-dependent halogenase that the cyanobacterium uses to make the natural product jamaicamide A (shown), which contains an alkynyl bromide.

Making alkynyl bromides “is a reaction that is easily done using chemical methods. But the enzyme could be advantageous because it’s very chemoselective,” says April L. Lukowski, who led the project. Even in the presence of other electron-rich groups, such as aromatic rings, JamD only adds halogens to the ends of terminal alkynes (J. Am. Chem. Soc. 2023, DOI: 10.1021/jacs.3c05750).

Jason Micklefield, who studies biosynthesis at the University of Manchester and was not involved in the work, says that it will be interesting to study JamD’s structure and mechanism to establish how it differs from halogenases that only react with aromatic substrates.

Lukowski and coworkers also showed that JamD can convert a range of terminal alkynes to either alkynyl bromides or iodides. “So far, whatever I’ve been able to throw at it that had a terminal alkyne, it’s been able to work,” she says.

Because JamD reacts with a variety of terminal alkynes, it could be a useful biocatalyst in reactions that would otherwise require a strong base not amenable to the presence of sensitive functional groups, says Rebecca Goss, who studies the biosynthesis of natural products at the University of St. Andrews and was not involved in the work. “Carbon-halogen bond formation is one of the most important reactions in organic chemistry, opening the door to almost any derivatization imaginable,” she says in an email.