Constructing conformationally constrained macrobicyclic musks.
To investigate the structure-odor correlation of musks, (12R)-12-methyl-13-tridecanolide (1), a macrocyclic musk, and 13-tridecanolide, its non-musky demethyl analogue, were conformationally constrained by introduction of methylene bridges between C-3 and C-8 or C-9. These [7.5.1]- and [8.4.1]-macrobicycles were synthesized starting from bicyclo[5.3.1]undec-8-en-9-one (3) and bicyclo[4.3.1]dec-7-en-8-one (8), respectively, by a sequence consisting of catalytic hydrogenation, alpha-alkylation with a TBS-protected (tert-butyldimethylsilyl) hydroxy halide, acid-catalyzed cyclization, oxidative cleavage of the formed enol ether double bond, and subsequent reduction of the carbonyl group via its tosylhydrazone. The compound (1R,6R,9R)-(+)-6-methyl-4-oxa-bicyclo[7.5.1]pentadecan-3-one (22) was found to possess the most pronounced musk odor, and this was rationalized by a superposition analysis with the polycyclic aromatic musk odorant (4S,7R)-Galaxolide (2). In its (1S,6R,9S)-(+)-stereoisomer 23 as well as in (1S,6R, 10R)-(+)-6-methyl-4-oxabicyclo[8.4.1]-pentadecan-3-one (18) the (6R)-methyl group seems to hinder the interaction with the musk receptor, while the demethyl compounds 7 and 12 showed only very faint odors.
Kraft
P
P
Givaudan Dübendorf Ltd., Fragrance Research, Switzerland. philip.kraft@givaudan.com
Cadalbert
R
R
D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis*; D003500:Cyclization; D005229:Fatty Acids, Monounsaturated / Q000138:chemical synthesis*; D008958:Models, Molecular; D008968:Molecular Conformation; D009812:Odorants; D013329:Structure-Activity Relationship
C439403:6-methyl-4-oxabicyclo(7.5.1)pentadecan-3-one; D001643:Bridged Bicyclo Compounds; D005229:Fatty Acids, Monounsaturated; C008563:musk