A new method to synthesize ambrox

Since ancient times, man has been looking for pleasant smells and is therefore interested in perfumes. Refined smells have always been considered a source of inspiration and a good perfume has always been a sign of health. (−)-ambrox, a rare natural product, traditionally isolated from ambergris, a waxy substance from the digestive tract of sperm whales, has long been one of the most popular perfumes in the world.

More than 30 tons are produced each year. It is important to note that only one mirror image of the 16 possible variants of the chiral molecule produces the particularly pleasant olfactory sensation, which requires a stereoselective synthesis that produces only the desired mirror image.

Fortunately, it is no longer necessary to harvest it from whales, but can be obtained by partial synthesis from (−)-sclareol, a natural product present in large quantities in a certain type of sage. However, the plant process to obtain ambrox requires several steps and depends on the availability of clary sage, which is subject to fluctuations.

A research group led by Professor Benjamin List, Director of the Max Planck Institute for Egg Research, has succeeded in synthesizing this fragrant and extremely complex chiral molecule in the laboratory. The researchers published their results in the journal Nature in their article entitled “Asymmetric catalytic polyene cyclization of homofarnesol to ambrox”.

“In biology, polyene cyclizations are complex reactions that transform simple starting materials into complex molecular structures in a single step,” explains Mathias Turberg, one of Professor List’s doctoral students and one of the lead authors of the study. “We were inspired by nature: we also wanted to provide a method for synthesizing complex molecules from relatively simple starting materials.”

His colleague, Dr Na Luo, a postdoctoral researcher in List’s group and lead author of the paper, says: “Imitating nature in the laboratory is a major but attractive challenge for chemists.” List himself says that this reaction is “a provocation of nature for us chemists”, because nature, with its large enzymes, can guide the polyene to fold in such a way that it easily produces the desired isomer.

For the List group method, the renewable C₁₅ The basic component nerolidol, which is present in many plant sources and can also be synthesized on a technical scale, is the raw material. In cooperation with the chemical company BASF, nerolidol is converted from a C₁₅ in the C₁₆ homofarnesol building block, which is then selectively converted to (−)-ambrox.

“With our strongly acidic, confined catalyst and a special fluorinated solvent, we were able to selectively synthesize the desired natural product, one of 16 possible isomers,” Luo explains. Although the List group has expertise in this particular type of confined catalyst, Luo was tasked with refining the “molecular tool” for this specific reaction.

While the catalyst pre-organizes the raw material and initiates the transformation into product, the specific solvent stabilizes the reactive intermediates and serves, among other things, as a “booster” for the catalysts, making things even faster. A definite success: while the state-of-the-art biocatalytic reaction takes three to four days, the new method delivers the product in one night.

“We managed to carry out our reaction under relatively mild conditions, and in a single step. The result is very selective,” Luo explains.

“The key to the high selectivity of the process is the conversion of homofarnesol to (−)-ambrox in a concerted manner, which mimics enzyme-catalyzed polyene cyclizations,” Turberg adds.

The scientists were also able to demonstrate that their approach is easily scalable. Another advantage of the List group synthesis is that the catalyst and solvent can be recovered and reused for other reactions. Both aspects are promising for possible future industrial applications.