Search for New Linear Musks Devoid of a 2,2-Dimethyl-1,4-dioxabutane Unit: Synthesis and Olfactory Properties of 5-Substituted (3E)-Hex-3-enoates on the Way to Carba-Helvetolide and Carba-Serenolide
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Media type:
E-Article
Title:
Search for New Linear Musks Devoid of a 2,2-Dimethyl-1,4-dioxabutane Unit: Synthesis and Olfactory Properties of 5-Substituted (3E)-Hex-3-enoates on the Way to Carba-Helvetolide and Carba-Serenolide
Contributor:
Nguyen, Kim;
Sutter, Pascal;
Kraft, Philip
Description:
<jats:p>Since the nucleophilic opening of isobutylene oxide competes with the formation of polyethers, the 2,2-dimethyl-1,4-dioxabutane moiety constitutes the most important cost driver in the synthesis of linear musks. Therefore, musk motifs devoid of this structural element would be highly attractive. Based on molecular modeling considerations, 5-methyl-substituted (3E)-configured alk-3-enoic esters accessible by deconjugative Knoevenagel reaction with malonic acid in the presence of piperidinium acetate with citronellal and Florhydral as substrates, were synthesized but showed disappointing olfactory properties, as did inverted ester motifs or dimethyl carbinols. Moving closer to carba-Serenolide structures, isobutyronitrile was added to m-isopropenylcumene. DIBAL-H with subsequent alanate reduction provided 4-(3-isopropylphenyl)-2,2-dimethylpentan-1-ol, which was either directly esterified, or esterified after Birch reduction and full hydrogenation. While these target structures were all odorless, (2E)-4-(3,3-dimethylcyclohexyl)pent-2-en-1-yl cyclopropanecarboxylate turned out to be a decent musk odorant (4.1 ng/L air). This proved the concept of an (E)-configured double bond in the middle of anticipated horseshoe-shaped conformers, but casted doubt on the non-importance of the ether oxygens in Helvetolide and Serenolide. Therefore, carba-Helvetolide and carba-Serenolide were synthesized from 3,3-dimethylcyclohexanone, and indeed turned out to be completely odorless. So polar interactions play a crucial role in the receptor interaction of these linear musks beyond merely favoring horseshoe-shaped conformers.</jats:p>