Enantioselective Synthesis and Olfactory Evaluation of Bicyclic α- and γ-Ionone Derivatives: The 3D Arrangement of Key Molecular Features Relevant to the Violet Odor of Ionones

Abstract

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 alpha- and gamma-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 alpha,beta-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 alpha-helical domains of ionone receptor proteins.

Biomimetic Cyclization of Geraniol Derivatives, a Useful Tool in the Total Synthesis of Bioactive Monocyclic Terpenoids

“…Finally, hydroxyl group deprotection, followed by oxidation with the Dess-Martin periodinane reagent [22], uneventfully produced (S)-α-ionone 20 (ee ≥99% by GC analysis) in 65% overall yield from sulfone 27 [16]. The same procedure was also used by us, always with excellent yields, for the construction of the enone moiety of ionones 23-25 [18] and 35-38 [24,25], as well as of irones 79 and 80 [26] (vide infra).…”

“…Compared to ionone derivatives, the odors of the three alcohols 43, 49, and 50 were significantly weaker and had no violet tonality, underlying the importance of an oxidized side-chain in the chemoreception of ionones. In contrast, the three bicyclic enones 35-37 maintained an intense violet ionone odor; in addition, each isomer showed individual pleasant characters [24]. Odor threshold of the α-ionone derivative 35 was even slightly lower than the open-chained ethyl homologue 23 (0.076 vs 0.085 ng/L of air), while odor characteristics were quite similar, including pronounced raspberry nuances [24].…”

“…In fact, the basic structures of key intermediates 43, 49, and 50 were smoothly assembled by two thermal Diels-Alder reactions between phenyl vinyl sulfone and dienes 41 and 47, respectively, both prepared from 10 (Schemes 6 and 7). Subsequently, alcohols 43, 49, and 50 were readily converted to the target products 35-37 via the usual Julia-Lythgoe olefination protocol (see Scheme 4) [24].…”

Scents and sensibility

“…Even when the targets are intended to smell, such as the violet-scented ionone derivatives synthesized by Giovanni Vidari and co-workers, they scrupulously avoid any mention of a person smelling the compounds 6 . The scant twelve lines detailing the 'olfactory evaluation' of the ionones -in which five perfume experts smell the compounds as they come off a gas chromatograph -are tucked away on Or an ge blo sso m thesis page 120 of the supporting information, rather than reported in the body of the paper.…”

2.03 Prins Reactions and Carbonyl, Imine, and Thiocarbonyl Ene Reactions

“…34 Similarly, reaction of 15 with CH 2 OÁMe 2 AlCl provides a 4:1 mixture of 16 and the cis isomer in only 50% yield, whereas reaction with CH 2 OÁMAPH provides only 16 in 92% yield. 35 Formaldehyde encapasulated in zeolites has also been used for ene reactions with 1,1-di-and trisubstituted double bonds. 36 This reagent shows selectivity for the ring double bond of limonene, whereas CH 2 OÁMe 2 AlCl and CH 2 OÁMAPH are selective for the side chain double bond.…”