Woody pretzels: spirocycles from vetiver to patchouli and Georgywood.
This review, including new experimental results, is the summary of a talk at the RSC/SCI conference 'flavours & fragrances 2007' in London, Imperial College, 24-26 September, 2007. Though the third dimension of the receptor models of J. E. Amoore rarely was exceeding 4 A, the world of woody odorants such as (+)-cedrol (3; cedarwood), (-)-khusimone (4; vetiver), and (-)-patchoulol (5; patchouli) is anything but flat. Any tricyclic skeleton with a zero-bridge contains a spirocyclic ring system determining its 3D structure, so spirocycles (spira, Lat. pretzel) are the fastest access to the third dimension. In the vetiver family, a spirocyclic mimic 9 of (-)-khusimone (4) was first discovered by chance by Büchi in 1976, and also by chance, we obtained another system, 12, with a characteristic vetiver smell by tandem-Rupe-Nazarov reaction of alkyne diols. A 5-A distance between a quaternary C-atom and a carbonyl group (or alternative HB acceptor) with an alpha-methyl or methylene branching is proposed to be the key to their vetiver odor. Upon scale-up of one of these odorants, 24, we discovered a very powerful (0.067 ng/l) impurity with a most typical patchouli scent: the spirocyclic, sterically crowded hydroxy ketone 33--a most unusual structure for a patchouli odorant. Several spirocyclic hydroxy ketone analogs, also with inverted ring systems such as in 70 and 84, provided new insights into the structure-odor correlation of this family. A superposition analysis indicated the carbonyl function of the hydroxy ketone to overlay on the geminal dimethyl motive of (-)-patchoulol. And indeed, the corresponding hydroxy ketone of patchoulol, 59, synthesized in 13 steps from Cyclal C (63), also emanated a patchouli odor. Finally, the synthesis and olfactory properties of twelve rigid spirocyclic analogs, 95-97, 99-102, and 106-110, of Georgywood (91) are presented that highlight stereochemical requirements for woody odorants and raise doubts about an alpha-helical binding motive postulated by Hong and Corey.
Kraft
Philip
P
Givaudan Schweiz AG, Fragrance Research, Uberlandstrasse 138, CH-8600 Dübendorf.
D049930:Chrysopogon / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000737:chemistry*; D009812:Odorants / Q000032:analysis*; D010476:Perfume / Q000138:chemical synthesis / Q000737:chemistry; D012717:Sesquiterpenes / Q000737:chemistry*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry
D009281:Naphthalenes; D010476:Perfume; D012717:Sesquiterpenes; D013141:Spiro Compounds; C509294:georgyone; C052983:patchouli alcohol