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.
While investigating the effect of the Cassyrane (rac-3/4) substitution pattern on the odor of dienones, (3E,5E)-5-tertbutylocta-3,5-dien-2-one (34) was discovered as an orris odorant with the lowest threshold reported so far in the ionone family (0.036 ng/L air). Derivatives 35-37, which allowed some insight into the underlying structure-odor relationships, were synthesized by a sequence consisting of copper(I)-catalyzed Grignard reactions with acyl chlorides, cerium-and lanthanum-assisted Grignard reactions of the resulting products with the Grignard reagent 17, prepared from but-3-yn-2-ol, manganese(IV) oxide oxidation of the secondary hydroxy function, elimination of the tertiary hydroxy function via its mesylate, alanate reduction of the ynone moiety to the corresponding allylic alcohol, and concluding manganese(IV) oxide oxidation. Furthermore, the γ,δ-unsaturated 38-41, and the fully hydrogenated analogues 42-45 were synthesized, and evaluated for their olfactory properties.
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