A Simple and Efficient Highly Enantioselective Synthesis of r-Ionone and r-Damascone Marcella Bovolenta, Francesca Castronovo, Alessandro Vadala ` , Giuseppe Zanoni, and Giovanni Vidari* Dipartimento di Chimica Organica, Universita ` di Pavia, Via Taramelli 10, 27100 Pavia, Italy vidari@unipv.it Received June 11, 2004 Abstract: An efficient highly enantioselective (ee g99%) synthesis of R-ionone and R-damascone is described. Both enantiomers of title compounds were synthesized through two straightforward pathways diverging from enantiopure (R)- or (S)-R-cyclogeraniol. These versatile building blocks were obtained by regioselective ZrCl 4 -promoted biomimetic cyclization of (6S)- or (6R)-(Z)-6,7-epoxygeraniol, respec- tively, followed by deoxygenation of the so formed secondary alcohol. The chiral information was encoded by a highly regioselecive Sharpless asymmetric dihydroxylation of in- expensive geranyl acetate. Ionones and damascones are established among the most highly valued fragrance constituents as a result of their distinctive fine violet and rose scents. 1,2 Besides their use in the perfumery industry, ionones and dam- ascones are also appreciated synthetic building blocks. 3,4 Both of these C 13 norterpenoids exist in nature as three distinct regioisomers, which differ in the position of the double bond, and are called the R-, -, and γ-isomers. Olfactory evaluation shows that the regioisomeric purity and the absolute stereochemistry of these isomers dramatically determines the fragrance properties, some- times with amazingly pronounced differences between the notes and the odor thresholds even of the two enantiomers. Furthermore, the endocyclic double bond confers particularly characteristic nuances to the fra- grance that can favorably complement the use of other widely used compounds from the same family. For example, whereas -damascone is floral-woody, somewhat tobacco-like, R-damascone smells floral-fruity, green, apple-like with a harsh camphoraceous cork-note. This cork-stopper off-note is due to (R)-(+)-R-damascone 1, whereas the (S)-(-)-isomer 2 is linear, clean, and more intense, besides possessing a pleasant wine-like nuance. 3 As to R-ionone, relative sensitivities for the enantiomers were found to diverge widely for different flavorists; 5-8 however, according to recent results collected by Fuganti et al. on almost enantiopure samples, both stereoisomers show similar odor description, (S)-(-)-R-ionone 3 being slightly more powerful than the (R)-antipode 4. 9 The odor of (S)-(-)-R-ionone is described as floral, woody, with an additional honey aspect. 9 Early enantioselective ap- proaches to R-damascone by Yamada 10 and Ohloff 11 delivered the (R)-(+)-enantiomer 1 in poor to modest ee’s of 17.5% and 66%, respectively. Later, thanks to an efficient method for the enantioselective protonation of enolates, 12 coupled with a fractional crystallization, Fehr and Galindo achieved both R-damascone enantiomers in a very high ee (>98%). 12-15 Despite its elegance, this approach requires, however, very demanding reaction conditions and is therefore of difficult industrial ap- plicability. From (R)- and (S)-R-damascone, Fehr then developed a four-step entry to the corresponding R-ionone enantiomers (ee >98%) through an ingenious enone transposition. 8 Highly enantioselective enzyme-based synthesis of useful precursors of damascones and ionones have been published recently. They are exemplified by the preparation of (S)-R-damascone 2 (ee ca. 100%) by Mori, 16 as well as of (R)-R-ionone 4 (85% ee) by Pfander 17 * To whom correspondence should be addressed. Tel: +39 0382507322. Fax: +39 0382507323. (1) Ohloff, G. Scent and Fragrances: The Fascination of Fragrances and their Chemical Perspectives; Springer-Verlag: Berlin, 1994. (2) Pybus, D. H.; Sell, C. S. The Chemistry of Fragrances; The Royal Society of Chemistry: London, 1999. (3) Fra ´ ter, G.; Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998, 54, 7633-7703. (4) (a) Buchecker, R.; Egli, R.; Regel-Wild, H.; Tscharner, C.; Eugster, C. H.; Uhde, G.; Ohloff, G. Helv. Chim. Acta 1973, 56, 2548- 2563. (b) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Polo, E.; Simoni, D. J. Chem. Soc., Chem. Commun. 1986, 757-758. (c) U ¨ belhart, P.; Baumeler, A.; Haag, A.; Prewo, R.; Bieri, J. H.; Eugster, C. H. Helv. Chim. Acta 1986, 69, 816-834. (d) Colombo, M. I.; Zinczuk, J.; Ruveda, E. A. Tetrahedron 1992, 48, 963-1037. (5) Polak, E. H.; Fombon, A. M.; Tilquin, C.; Punter, P. H. Behav. Brain Res. 1989, 31, 199-206. (6) Werkhoff, P.; Bretschneider, W.; Gu ¨ ntert, M.; Hopp, R.; Surburg, H. Z. Lebensm.-Unters. Forsch. 1991, 192, 111-115. 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Chem. 1995, 48, 145-151. 10.1021/jo049012j CCC: $27.50 © 2004 American Chemical Society J. Org. Chem. 2004, 69, 8959-8962 8959 Published on Web 11/11/2004