Chemists make the popular fragrance compound ambrox via asymmetric catalysis

Chemists have made (–)-ambrox—a compound that’s popular in perfumes—starting from (3E,7E)-homofarnesol. A team led by the Max Planck Institute for Kohlenforschung’s Benjamin List developed the route, which achieves asymmetric cyclization of a polyene using a scant amount of a chiral imidodiphosphorimidate catalyst in a fluorinated alcohol solvent (Nature 2024, DOI: 10.1038/s41586-024-07757-7).

This type of asymmetric polyene cyclization has long eluded synthetic chemists, who have been looking for alternatives to gathering (–)-ambrox from ambergris, a waxy substance vomited by sperm whales. List calls the reaction “a provocation by nature to us chemists” because nature can guide the polyene to fold itself in a way that it easily makes the desired isomer, but synthetic chemists struggle to achieve the same selectivity. Previous attempts have used stoichiometric amounts of chiral acids and were not as successful as the new route.

David Sarlah, a synthetic chemist at Rice University who was not involved in the work, calls the synthesis a significant leap forward. “It exemplifies the best case of achieving catalytic and highly selective classical polyene cyclization that mimics nature,” he says in an email. “Although they reported a limited substrate scope, this work can pave the way for translating biomimetic polyene cyclizations toward asymmetric synthesis of many important molecules.”

In recent years, fragrance scientists have developed enzymes that can make (–)-ambrox, and List says his group’s route might be competitive with that biocatalytic synthesis. The team demonstrates that its synthesis works on a multigram scale.

The synthesis uses a chiral imidodiphosphorimidate catalyst, which possesses an enzyme-like microenvironment. This catalyst coaxes (3E,7E)-homofarnesol into the perfect position to become (–)-ambrox upon protonation. List says using a fluorinated alcohol solvent was key to the reaction’s success because it helped boost the ionizability of the reactants. The use of fluorinated solvents raises environmental concerns, but Mathias Turberg, a graduate student in List’s lab, says it was easy to recover and recycle the solvent.

The chemists say the approach might also be used on the polyene cyclization of squalene, which is an important step in sterol synthesis. “We’ve barely scratched the surface of this exciting type of transformation,” Turberg says. “It holds great promise for efficiently producing natural products” that are currently made only by enzymes.