On the Structure–Odor Correlation of Muguet Aldehydes: Synthesis of 3‐(4’‐Isobutyl‐2’‐methylphenyl)propanal (Nympheal) and Four Novel Derivatives from a Hagemann’s Ester

Abstract

Lilybelle and Biomuguet are currently the only renewable and biodegradable non‐spermotoxic Lilial replacers. Being non‐aromatic, these lack however some of the green, aquatic aspects of Lilial that are present in the captive odorant Nympheal, 3‐(4‐isobutyl‐2‐methylphenyl)propanal, which is not available from renewable resources. Therefore, the influence of the aromatic nucleus on the odor of four new hydrogenated Nympheal derivatives was investigated, which were all accessible from the isobutyl Hagemann’s ester that was synthesized in 75 % yield from isovaleraldehyde with two equivalents of ethyl acetoacetate. The respective Hagemann’s ester was alkylated with 3‐bromopropanal dimethyl acetal and subjected to decarboxylative saponification, followed by hydride reduction and dehydration through the corresponding mesylate to furnish, after deprotection with formic acid, the corresponding exo‐ and endo‐dihydro‐Nympheal derivative. Full or partial hydrogenation of the central acetal‐protected intermediate provided after deprotection the analogous fully saturated analogue or the cyclohexene derivative. The olfactory properties of these four novel Nympheal derivatives are discussed and rationalized by computational olfactophore models.

Sniffing Out the Sustainable Future: The Renewability Revolution in Fragrance Chemistry**

“…Lilial (165) can be synthesized either by starting from 4-tertbutylbenzaldehyde via aldol condensation with propional [157] or via electrochemical oxidation through the BASF [158] route from 4-tert-butyl toluene, no matter how making 165 non-renewable, the same holds true for Bourgeonal (166, Scheme 20). Although they do biodegrade, what might be an advantage in nature leads to a toxification in the liver with 4-tert-butylcarboxylic acid as sperm toxic metabolite.…”

“…Accordingly, these muguet aromatic aldehydes were classified CMR substances, with Lilial (165) in addition being suspected as an endocrine disruptor, and therefore banned from the EU market in March 2022. [159] To make matters worse, Lilial (165), Bourgeonal (166), their p-isobutyl constitutional isomer Silvial (167) and their pisopropyl isomer Cyclamenaldehyde (168) are skin sensitizers. However, the spermotoxicity of these muguet aldehydes could be blocked by the additional "magic methyl" group in Nympheal (170, marked in green, Scheme 20).…”

“…[161,162,163,164] A potentially renewable synthesis route could be from the Hagemann's ester 169 by decarboxylation, α-alkylation and aromatization. [165] The only two 100/100 sustainable and biodegradable muguet odorants remain Biomuguet (154) and Lilybelle (177). The latter was featured in the white-floral jasmine-osmanthus perfume "Bloomastral" (J. U. S. Parfums, 2021) by Alexandra Carlin.…”