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Natural Products

Natural tropolones form via radical route

Scientists find figure out how ring expands from 6 to 7

by Leigh Krietsch Boerner
August 29, 2020 | A version of this story appeared in Volume 98, Issue 33


Scheme showing that the six-membered starting material can go through a radical mechanism to form stipitaldehyde or a nonradical pathway to form trihydroxybenzaldehyde.

Tropolones are a class of seven-membered aromatic rings that are naturally occurring, have unusual electronic properties, and are hard to synthesize. TropC, a fungi-based α-ketoglutarate-dependent enzyme, can catalyze the synthesis of tropolones, but scientists have long struggled to understand the mechanism. Using a combination of experimental and computational techniques, Alison Narayan and coworkers at the University of Michigan found that the enzyme goes through radical ring expansion of a six-membered compound. The work appears on a preprint server and has not been peer reviewed (ChemRxiv 2020, DOI: 10.26434/chemrxiv.12780044). The researchers crystallized TropC, then ran calculations on the active site by plugging in intermediates thought to play a role in three distinct reaction pathways. They then made 12 enzyme mutants, containing various amino acid residues in the active site, and found that only residues capable of one-electron radical chemistry made the tropolone stipitaldehyde, while other residues made a six-membered trihydroxybenzaldehyde (shown). Many tropolones are bioactive, and there are hundreds of tropolone-based natural products, according to Narayan. “It is not uncommon to see people going through routes that are 10–20 steps in order to access these types of cores,” she says. This class of enzymes is widespread, and this work can help chemists create new, useful biocatalysts and understand their behavior, says Yudai Matsuda, a biosynthetic chemist at the City University of Hong Kong.


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