Chemists discover biology’s version of the Friedel-Crafts alkylation

By chemistry standards, the Friedel-Crafts alkylation is a venerable reaction. First reported by chemists Charles Friedel and James Crafts in 1877, the reaction attaches an alkyl substituent to an aromatic ring using an alkyl halide as one of the reactants. It turns out that Nature has been doing this reaction for even longer—scientists just didn’t know it until now.

Harvard University’s Emily P. Balskus, Hitomi Nakamura, and Erica E. Schultz have discovered an enzyme, dubbed CylK, that accomplishes this same transformation during the biosynthesis of cylindrocyclophanes, natural products made by cyanobacteria that are toxic to cells (Nat. Chem. Bio. 2017, DOI: 10.1038/nchembio.2421). “Because aromatic-alkyl linkages are such important motifs in synthetic compounds, we’re hoping that the enzyme we found will ultimately be useful for chemical production,” says Balskus, who led the research effort.

Her team also found a new type of metal-dependent halogenating enzyme, named CylC, that creates secondary alkyl chlorides. Secondary alkyl halides can be tricky to prepare in the lab because the intermediates en route to making them tend to rearrange. The same can be said for using secondary alkyl halides as reactants in the Friedel-Crafts alkylation.

“Secondary alkyl halides have been notoriously problematic substrates for that reaction,” Balskus points out. “They’re not very electrophilic, and because the Friedel-Crafts alkylation involves generating a carbocation intermediate, you get a lot of competing side reactions and rearrangements,” she says. “If we can engineer these enzymes to accept substrates that would be useful building blocks for chemical synthesis, they would fill gaps in our synthetic chemistry toolbox.”

Next, Balskus hopes to pin down the mechanisms of the two novel enzymes discovered by her group. X-ray crystal structures of CylC and CylK with bound substrates could be particularly informative, she notes.

Balskus and coworkers “have performed an outstanding study—remarkable in its breadth, notable in the novelty of biochemistry encountered, and impactful for its importance to understanding cyanobacterial secondary metabolism as well as biotechnological applications,” comments William Gerwick, an expert in the biosynthesis of marine natural products at Scripps Institution of Oceanography.

“While much work remains to further characterize both reactions, the current studies place these on a solid biosynthetic foundation,” Gerwick continues. This is important, he adds because an informatics analysis of available sequenced cyanobacterial genomes suggests the halogenation to be a highly prevalent mechanism in these organisms and underpins their potential use in biocatalysis applications.