Even when the same atoms are connected in the same order, a different three-dimensional arrangement can change how a substance smells. Could we therefore selectively make the form associated with a desirable odor?
A study published by Silvia Venturi and colleagues in 2022 examined a route to the jasmine-like synthetic fragrance Jessemal that combines enzyme reactions with conventional chemical reactions. Its focus was not comparing newly created scents, but deliberately synthesizing a particular stereochemical form that had already attracted attention.
What does it mean to select a molecule’s “shape”?
Stereoisomers have the same atomic connectivity but different arrangements in space. Some come in pairs that are mirror images yet cannot be superimposed, like right and left hands.
Jessemal has three positions important for distinguishing these arrangements. The target here was the form called (3R,4R,5R). R and S describe how atoms are arranged at each position; they are not scores for odor strength or quality.
In an earlier study from 2006, this form had been judged to have a particularly pleasant, distinctive floral odor among the isomers compared. The 2022 paper took that finding as its starting point. It did not recruit a new consumer panel and establish that everyone prefers this form.
Using two enzymes to establish stereochemistry
The researchers prepared an intermediate from commercially available starting materials for use in enzyme reactions. They then applied two types of enzymes with different roles in sequence.
One helps add hydrogen across a carbon–carbon double bond. The other helps convert the resulting structure into an alcohol. Linking the reactions in one vessel was designed to establish stereochemistry without isolating the intermediate at every stage.
Enzymes tend to accommodate reacting molecules in particular orientations, providing a way to select the side from which a reaction proceeds. However, it was not as simple as assuming that a given enzyme would always favor the same orientation.
An unexpected configuration was an important finding too
The initially promising enzyme combination gave good conversion, but the intermediate’s stereochemistry differed from expectations. Checking the product revealed that the relative arrangement of its three positions was not the one required by the synthetic plan.
The researchers therefore changed the enzyme combination and investigated again. After confirming configurations using methods including crystal X-ray analysis, they found that FDR-Mha together with EVO440 gave the intermediate needed to advance toward the target. These names identify the enzymes used in the study.
The work shows that reaction stereochemistry depends not only on the choice of the second enzyme but also on the configuration already present in the reacting intermediate. Because detailed structures of the commercial enzymes were not publicly available, however, the researchers could not determine exactly how the molecules fitted inside them.
The next challenge: where to open the ring
The enzyme-made intermediate was then converted into a compound containing a small, oxygen-containing three-membered ring. Opening this ring and attaching a carbon chain brings the structure closer to the Jessemal framework.
Here, the problem is not only spatial orientation but also which position on the ring receives the chain. When the researchers tested the carbon-chain addition, the main reaction site differed from the one expected from earlier work on similar molecules.
Under one set of conditions, the ratio of the product connected at the desired position to the product connected at the alternative position was 82:18. The reaction did not give only one product, and separation was used to obtain the desired one.
To understand this preference, the researchers calculated energies along the reaction pathways. The calculations favored the route to the desired position and predicted a product ratio of 72:28, showing the same directional preference as the experiment. The numbers did not match exactly, but they helped explain which pathway was more accessible.
Other reagents gave different preferences for the reaction site, sometimes consistent with established explanations. The authors identify this dependence of ring opening on the detailed molecular structure and reagent combination as another contribution of the study.
95% in the final step, but 18% overall
After obtaining the alcohol with the desired connectivity and stereochemistry, the researchers added an acetate group in the final step to obtain the target Jessemal. This last step gave a 95% yield.
The overall yield through all steps from the commercial starting material, however, was 18%. Losses during reactions and separations accumulate, so a high final-step yield does not mean that 95% of the starting material becomes the final fragrance.
The team thus obtained Jessemal enriched in the target stereochemical form. The value lies in bringing enzyme stereoselectivity and chemical regioselectivity together within one route to select the desired structure.
What does this mean for fragrance manufacturing?
As background motivation, the authors suggest that selecting an odor-active stereoisomer could allow smaller amounts of material to be used in formulations. The paper did not, however, compare actual perfume usage levels, environmental degradation, or effects on the human body. Making the target form alone does not establish reduced health or environmental risks.
Nor does using enzymes mean that the entire process consists of enzyme reactions. Several chemical reactions and purification operations are also needed. The study did not evaluate industrial-scale costs or environmental impacts; its first achievement was to demonstrate a synthetic route to the desired molecule.
The paper acknowledges funding from the POR-Lombardia VIPCAT project and computing resources from CINECA. The authors declare no competing financial interests.
Summary
This study combined enzyme and chemical reactions to synthesize the Jessemal stereoisomer previously judged to have a pleasant floral odor. By reassessing unexpected enzyme selectivity and then controlling where a ring opened, the researchers established a route to the target.
The aim is to select not only which fragrance compound to make, but which three-dimensional form of that compound. The work advances both the synthetic methods needed to do this and our understanding of reaction selectivity.
References
Venturi, S., Trajkovic, M., Colombo, D., Brenna, E., Fraaije, M. W., Gatti, F. G., Macchi, P., & Zamboni, E. (2022). Chemoenzymatic Synthesis of the Most Pleasant Stereoisomer of Jessemal. The Journal of Organic Chemistry, 87(9), 6499–6503. DOI: 10.1021/acs.joc.2c00427 / Full original article. Original article license: CC BY 4.0.
