Synthesis and Properties of Conformationally Constrained Analogues of Floral‐Type Odorants

Abstract

The twelve bridged analogues 8 ± 19 of floral-type odorants related to cyclamenaldehyde (1) were synthesized (Schemes 1 ± 5) to investigate the relationship between the structural and conformational features of these compounds and their odor properties. Comparison of the data from sensory evaluation and molecular modeling suggests that the side chain of both the unconstrained and the constrained active analogues is not extended (anti) but rather folded (gauche) in the −bioactive× conformation. However, it is mainly the nature of the substituents at the a position of the aldehyde function that critically influences the odor quality and strength. These studies provide new information that should aid ongoing efforts to develop models of odorantÀreceptor interactions.1. Introduction. ± A commercially significant class of floral-type odorants is represented by 3-, which all exhibit a desirable lily-of-the-valley (−muguet×) tonality. Though many other compounds with different functional groups (alcohols, hydroxyaldehydes, acetals) belong to this class of odorants, in the present work, we will focus on aldehydes related to compounds 1 ± 3. StructureÀodor relationships in this class of odorants, among others, have been reviewed [4]. A computational model for lily-of-the-valley-scented compounds, based on AM1 calculations, was proposed by Pelzer et al. [5], which distinguished between two structural fragments bearing either a carbonyl or a hydroxy functional group. More recently, conformational analysis of a series of −muguet×-type odorants was used to design and synthesize candidates anticipated to possess a lily-of-the-valley odor [6]. Interest in this group of compounds has also been stimulated by the demonstration that a mixture of Lilial ¾ (2) and Lyral ¾ 4 ) (4) [7], a compound related to hydroxycitronellal (5) and that also exhibits a characteristic −muguet× odor, was able to stimulate a heterologously expressed rat olfactory receptor protein, OR5, and to generate secondmessenger responses at submicromolar concentrations [8]. Shortly after, computer-

Structure–Activity Relationships in the Domain of Odorants Having Marine Notes

“…2,3-Dihydro-5-isopropyl-1-benzofuran-2carbaldehyde 25c has very nice watermelon, aldehydic, green, oyster, and ozone notes. All of these compounds (25a-c and 33a-d) can adopt a conformation (with an energy penalty below 1 kcal) in which the carbonyl is slightly out of the plane of the benzenic ring (1.2 Å) and compatible with both models (our ozone-watery model and the previous Lilial ® model [29] ). [29,34] It seems that here we are at the crossroads between lily-ofthe-valley and marine-ozone-watery ingredients, which also means that the receptor for both should not be very different.…”

“…[28] The olfactophore model comprises the three key elements of Calone 1951 ® : A hydrophobic part (green), a benzenic ring (orange), and a hydrogen-bond acceptor (red). [29] The main difference is the position of the hydrogen-bond acceptor element. This model is closely related to a previous olfactophore model of the Lilial ® analogues published by Winter and coworkers in 2004.…”

Synthesis and Odor Properties of Substituted Indane‐2‐carboxaldehydes. Discovery of a New Floral (Muguet) Fragrance Alcohol

“…-Previous studies [1] on conformationally constrained analogues of floral-type perfumery materials such as 1 -3, have led to the discovery of new interesting odorants [2], among which compounds 4 and 5 were quite intriguing. Indeed, whereas compound 4 had an odor characterized as 'watery, metallic, aldehydic, green, somewhat fatty, vaguely phenolic', compound 5 was evaluated as typically 'floral, green, 'muguet', Bourgeonal ® , powerful, tenacious' [1]. This result and related ones pointed to the importance of the steric constraints imposed by the receptor environment in the proximity of the ligand functional group.…”