Ambrox is one of the important components associated with the scent of ambergris. Producing the desired fragrance material requires not only connecting atoms but also controlling the molecule’s three-dimensional orientation. Even molecules made from the same atoms can have different odor properties when their spatial arrangements differ.
A study published in 2024 sought to place that control in the hands of a catalyst made from a small molecule. Its model was the enzymes used by living organisms: the idea was to guide the folding of a chain-shaped molecule and the formation of several rings within a confined space resembling an enzyme’s reaction environment.
Shaping the reaction site, as an enzyme does
The target reaction converted a chain-shaped starting material called homofarnesol into three-ring (−)-ambrox. The “(−)” notation distinguishes which of two mirror-related forms is meant. The aim here was to make this form of ambrox selectively.
The reaction must control four stereochemical positions while forming several bonds. If a different shape develops partway through, or the reaction begins at another site, unwanted products increase. Enzyme-based processes had already been studied and developed, but the researchers asked whether an artificial catalyst smaller than an enzyme could also achieve such precision.
They used an acidic catalyst called IDPi. Besides initiating the reaction, it has a structure that encloses the space occupied by the starting material. Tests varying catalyst shape, solvent, and temperature showed that the shape of this confined space strongly affected the product proportions. Another strongly acidic but less confined catalyst produced a more complex mixture.
Making a large amount and selecting a shape are different achievements
In the optimized small-scale reaction, the yield of ambrox was 54%. The ratio of the two mirror-image forms was 95 parts of the target form to 5 of the opposite form. The ratio to other, non-mirror-related stereoisomers also exceeded 20:1, favoring the desired configuration.
The researchers also tested a reaction using 10 g of starting material. In the fluorinated solvent PFTB, they reacted it for 12 hours at −40°C followed by 8 hours at 0°C, then isolated and purified approximately 5.2 g of ambrox. The yield was 52%, the enantiomeric ratio was 95:5, and the ratio to other stereoisomers was 92:8.
Here, 95:5 does not mean that 95% of the starting material became product. Yield, which describes how much was recovered, and stereoisomer ratios, which describe the distribution of molecular forms, are different measures. The larger-scale experiment also produced by-products, including partially cyclized compounds, in 47% yield, making separation necessary.
How were the multiple bonds formed?
To understand the stereoselectivity, the researchers also investigated the reaction pathway. Possibilities included a route in which several bonds form in a coordinated process and a stepwise route through intermediates containing one ring.
Using deuterium, a heavier isotope of hydrogen, as a label, they found that the IDPi-catalyzed reaction in PFTB at −40°C introduced the label mainly at one position. A less confined catalyst introduced it at several positions. Together with carbon-isotope effects on reaction rate and experiments starting from molecules proposed as intermediates, these results led the authors to favor a predominantly coordinated bond-forming pathway in low-temperature PFTB.
This does not mean that the researchers directly filmed molecules moving. They narrowed down pathways consistent with several experiments. With HFIP as the solvent, evidence indicated that a stepwise route also contributed; they did not claim that one pathway operates under every condition. Their interpretation is that the combination of catalyst confinement and reaction conditions favors the route to the desired form.
Recovery and reuse do not remove the environmental questions
In a separate experiment, the catalyst and PFTB were recovered and reused in another reaction. Both the initial and reuse runs gave 51% yield, with the same stereoisomer ratios. Reusing catalysts and solvents provides one lead for improving a process.
Fluorinated solvents nevertheless require care to prevent environmental release. In the supplementary information, the authors also discuss the importance of containment and recovery in view of mobility and persistence. The reuse experiment did not demonstrate that the overall manufacturing process has a lower environmental burden or cost than existing enzyme-based methods. Cooling, separation, and purification must also be evaluated.
The research received support from the Max Planck Society, the German Research Foundation, the European Research Council, and other sources. Researchers from the chemical company BASF were among the coauthors. Patents concerning the catalyst class and this ambrox synthesis were disclosed.
Summary
Beyond making ambrox, the achievement was to favor a particular stereochemical form of a complex molecule by designing the space around a small-molecule catalyst. The idea is that enzyme-like precision comes not just from using a strong acid to drive a reaction, but from guiding the starting material’s orientation and reaction pathway.
The researchers also applied the method to making (+)-sclareolide from a related starting material. Sclareolide is an intermediate in another route to ambrox, illustrating scope beyond a single fragrance compound. The authors anticipate applications to complex molecules relevant to fragrances, natural products, and medicines. Alongside that wider scope, reducing by-products and improving the process, including its solvents, remain future challenges.
References
Luo, N., Turberg, M., Leutzsch, M., Mitschke, B., Brunen, S., Wakchaure, V. N., Nöthling, N., Schelwies, M., Pelzer, R., & List, B.(2024). The catalytic asymmetric polyene cyclization of homofarnesol to ambrox. Nature, 632, 795–801. DOI: 10.1038/s41586-024-07757-7 / Full original article and supplementary information.
© The Author(s) 2024. Original article license: CC BY 4.0.
