Enantioselective Synthesis and Olfactory Evaluation of Bicyclic r- andγ-Ionone Derivatives: The 3D Arrangement of Key Molecular FeaturesRelevant to the Violet Odor of Ionones

(Chemical Equation Presented) Violet smelling ionones 1-3, occurring in the headspace of different flowers, are well-known perfumery raw materials. With the goal to recognize the still ill-defined spatial arrangement of structural features relevant to the binding of ionones to olfactory G-protein coupled receptors, through B3LYP/6-31G(d) modeling studies we identified bicyclic compounds 7-9 as conformationally constrained 13-alkyl-substituted analogues of monocyclic α- and γ-ionones. They were thus synthesized to evaluate the olfactory properties. The enantioselective syntheses of 7-9 entailed two common key steps: (i) a Diels-Alder reaction to construct the octalinic core and (ii) a Julia-Lythgoe olefination to install the α,β-enone side chain. The odor thresholds of synthetic 7 and 9 were significantly lower than the corresponding parent ionones, and 9 showed the lowest threshold value among violet-smelling odorants examined so far. Modeling studies suggested a nearly identical spatial orientation of key hydrophobic and polar moieties of compounds 1, 3, and 4-9. Presumably, interaction of these moieties with ionone olfactory receptors (ORs) triggers a similar receptor code that is ultimately interpreted by the human brain as a pleasant woody-violet smell. These results open the way to studies aimed at identifying and modeling complementary binding sites on α-helical domains of ionone receptor proteins.