Muscone

Chemical structure and synthesis

The chemical structure of muscone was first elucidated by Leopold Ružička. It is a 15-membered ring ketone with one methyl substituent in the 3-position. It is an oily liquid that is found naturally as the (−)-enantiomer, (R)-3-methylcyclopentadecanone. Muscone has been synthesized as the pure (−)-enantiomer as well as the racemate. It is very slightly soluble in water and miscible with alcohol.

One asymmetric synthesis of (−)-muscone begins with commercially available (+)-citronellal, and forms the 15-membered ring via ring-closing metathesis:

A more recent enantioselective synthesis involves an intramolecular aldol addition/dehydration reaction of a macrocyclic diketone.

Isotopologs

Isotopologs of muscone have been used in a study of the mechanism of olfaction. Global replacement of all hydrogen atoms in muscone was achieved by heating muscone in heavy water (D2O) at 150 °C in the presence of a rhodium on carbon catalyst. It was found that the human musk-recognizing receptor, OR5AN1, identified using a heterologous olfactory receptor expression system and robustly responding to muscone, fails to distinguish between muscone and the so-prepared isotopolog in vitro.

References

References

1. Kamat, V. P.. (2000). "Ring Closing Metathesis Directed Synthesis of (R)-(−)-Muscone from (+)-Citronellal". [[Tetrahedron (journal).
2. Knopff, O.. (2007). "Enantioselective Intramolecular Aldol Addition/Dehydration Reaction of a Macrocyclic Diketone: Synthesis of the Musk Odorants (''R'')-Muscone and (''R'',''Z'')-5-Muscenone". [[Angewandte Chemie.
3. Block, E.. (2015). "Implausibility of the Vibrational Theory of Olfaction". [[Proc. Natl. Acad. Sci. USA]].
4. Ahmed, L.. (2018). "Molecular Mechanism of Activation of Human Musk Receptors OR5AN1 and OR1A1 by (R)-Muscone and Diverse Other Musk-smelling Compounds". Proc. Natl. Acad. Sci. USA.