Olfactory Chemistry: Calone Part 2- The Search for a Better Mousetrap


Last month I introduced you to Calone the molecule which launched thousands of marine fragrances. It should come as no surprise that a molecule as important as Calone has attracted much interest for the chemists at the big perfume houses. As I showed in the article on Hedione there is always a better mousetrap to be discovered. In the case of Hedione it was through purifying a mixture down to one specific molecule to find Paradisone. The method used for Calone improvements is more similar to my “day job” in pharmaceutical research.

When I have a new molecule I methodically make changes around the molecule looking for an increase in activity against a particular target. Over time I learn the key pieces of the parent molecule which are necessary for that activity. We call that the pharmacophore. A researcher at Firmenich Jean-Marc Gaudin believes there is an aromachemical equivalent called an olfactophore; that there are essential pieces of a molecule to produce a desired odor profile. He presented this hypothesis in a paper published in January of this year (European Journal of Organic Chemistry, p. 1437-1447, 2015). Following up on a previous 2007 paper ( Helvetica Chimica Acta, vol. 90, p. 1245-1265, 2007) he has used Calone as his basis to explore this. In the figure below I show what was known about Calone.

Calone SAR

The Firmenich group had shown in the 2007 paper that increasing the size of the CH3 group made a “better” Calone. By lengthening it by two carbons they could reduce the “low tide” aspect in Aldolone. By branching it they both attenuated the “low tide” smell and enhanced the floral quality in Lilial.

Aldolone Lilial

Now it was time to work on the spacing and the double bonded carbon on the other side of the molecule. They quickly discovered if they reduced that oxygen to an alcohol they made it much weaker. The Lilial alcohol shown below is described as “fruity, without character, very weak”

Lilial Alcohol

The next idea was to open the ring up allowing for the double-bonded oxygen some flexibility to find the key interaction. The closest they would come is the Aldolone analog shown on the left below which carried a description of “perspiration, aldehydic, slightly aldehyde muguet, vanillic, slightly metallic, nice, too weak”

open and five membered calone analogs

The final idea was to decrease the size of the ring from seven atoms to five. This would keep the sheer flexibility of the molecule in check a bit. They also wanted to give the double-bonded oxygen a little flexibility by attaching it to the five membered ring instead of making it part of it. Here is where they found some success as the molecule on the right above was described as “watermelon, aldehydic, Aldolone, Cyclosal, green, oyster, ozone, watery” This sounds like a different level Calone as now the watermelon is made more prominent plus the idea of a greener Calone sounds really interesting to me.

This paper makes a small incursion into the hypothesis that an olfactophore exists but it is but one part of the biochemical enigma that our sense of smell presents to scientists.

Mark Behnke

Header: Picture of the Board Game "Mouse Trap"

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