Synthesis and Olfactory Properties of Lower-Ring Homologues of the Linear Alicyclic Musk Romandolide

Abstract

In order to expand the knowledge on linear alicyclic musks, a set of 29 small-ring (racemic) analogues of the biodegradable and renewable alicyclic musk Romandolide was designed, prepared, and evaluated. The common short and modular synthesis employs either commercially available or easily accessible (substituted) cyclopropyl/cyclobutyl ketones and acids. These were transformed in three/four steps to the target compounds. Their qualitative olfactory analysis reveals that contraction of cyclohexane ring of Romandolide to smaller rings annihilates the genuine musk scent, though many of these share the metallic hot-iron off-note of some macrocyclic musks. Indeed, these new derivatives exhibit a plethora of pleasant, interesting, and potentially useful scents including herbal, green, fruity, or chocolate ones accompanied by various undertones. The powdery, fruity ionone odor of the dimethyl cyclobutyl compound was found to be most interesting as it possesses a very natural raspberry and violet character. Computational modelling suggest that the lowest-energy conformers of the target compounds do either not adopt a true U-shape as was speculated to be a prerequisite for a musk odor, or that the quaternary carbon atom of the dimethyl-substituted cyclobutane is not well placed to fit into a hydrophobic binding pocket on the corresponding receptor site.