Olfactory Chemistry: beta-Santolol Derivatives- Figuring Out Sandalwood


In my job as a medicinal chemist one of the ways I analyze data is through a process called Structure-Activity Relationship (SAR). What that means is I make a change to a molecule and see whether that gives me better binding (activity) or less. Through putting that data set together I come to understand the biological interaction I am working on. The same holds true for the chemists working on aromachemicals. They call their version Structure-Odor Replationship (SOR).

The gathering of SOR data is two-fold. The primary reason is to create a new raw material to be used as a fragrance. The secondary reason is to continue to add to the data set of molecules and how we perceive them. The hypothesis is the broader the amount of data points the more insight we will gain into the biological process which governs our sense of smell. A recent 2014 publication (Delasalle et. al.; Chemistry & Biodiversity, vol. 11, pg. 1843-1860, 2014) from the chemistry department at the University of Nice. In this study they were focused on the molecule which makes up most of sandalwood essential oil, beta-santolol.

The reason for looking for alternatives to sandalwood essential oil is the overharvesting which nearly drove the Mysore version to extinction. Now that particular version is tightly controlled by the Indian government. There have been more sustainable version cultivated in New Caledonia and Australia which have taken their place in newer perfume constructions. If an easily synthesizable beta-santolol could be discovered or alternatively a deeper understanding on how beta-santolol binds to allow for a more intelligent design then this would be another step to easing the stress on the natural sources.


The research team  took beta-santolol and did a number of chemical transformations on the long sidechain indicated above. Also the OH group was hypothesized to be an important part of the molecule in creating the sandalwood odor profile. The results showed if that OH group was oxidized to an aldehyde in that specific configuration seen above it resulted in a much fainter sandalwood odor. If you changed the geography around the double bond at the end of the side chain it retained the same odor profile as beta-santolol. All of the remaining changes to the side chain or the OH group resulted in molecules describes as “sweaty” or odorless.

They would go on to analyze a set of 21 variations. This provided a further confirmation of the necessity of the OH group in that particular position for the molecule to have a strong sandalwood scent profile similar to beta-santalol.

This research team would purchase a number of other beta-santolol variations focused on the ring instead of the side-chain also looking for further insight into the SOR.

This research has added a new data set which allows for a further refinement on the biological reaction behind our sense of smell of sandalwood.

Mark Behnke