j. Soc. Cosmet. Chem., 48, 107-116 (March/April 1997) (,)-a-Carene as a key compound in syntheses of 6,6-dimethylbicyclo[a.l.O]hexane derivatives with olfactory properties STANISLAW LOCHYi•ISKI, Institute of Organic Chemistry, Biochemistry and Biotechnology, Technical University of Wroctaw, Wyb. Wyspiadskiego 27, 50-370 Wroctaw, Poland. Accepted j•r publication April 30, 1997. Synopsis The synthesis of new 6,6-dimethylbicyclo[3.1.0]hexane derivatives with various substituents at the C-3 position are described. Alcohols, esters, ketones, and nitriles possess interesting olfactory properties. Odor characteristics and the odor-structure relationship are presented. INTRODUCTION (+)-3-Carene (1), a major constituent of Polish turpentine, is a natural, inexpensive, easily available raw material. During several years of study of the stereochemistry and chemical transformations of the carane system, some simple preparative methods for the syntheses of various compounds with olfactory properties were elaborated. Previous- ly (2-5), we described syntheses of compounds 2 and 3 (Scheme 1), in which the carane system was preserved and futher compounds formed from the intermolecular rearrangement of the gem-dimethylbicyclo[4.1.O]heptane system into the gem-di- methylcyclohexadienone (4) and derivatives. Other functionalization of carane gave the gem-dimethylbicyclo[3.1.O]hexane system, substituted at C-2 and C-3 positions, namely derivatives of ketones 5 and 6. In this paper, I present a series of new compounds containing the 6,6-dimethylbicyclo[3.1.0]hexane system, with various substituents at the C-3 position obtained using compound 6 as a key substance. RESULTS AND DISCUSSION The starting material, trans-3-acetyl-6,6-dimethylbicyclo[3.1.O]hexane (6), was ob- tained from (+)-3-carene via (-)-3,4-dibromocarane as described earlier (6). The struc- ture of ketone 6 allowed us to carry out various synthetic operations the aim of which was to modify the side chain substituted at C-3. Two reactions are most useful: (a) the Grignard and Witrig reactions with the furher one carried out in a classical manner or (b) a Wadsworth-Emmons modification (7). The full synthetic scheme is outlined below. This paper was presented as a preliminary communication in 1993. See ref. (1). 107

108 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS OH ,OH Scheme 1 In the first step, ketone 6 was converted by means of the Grignard reaction into the appropriate tertiary alcohols 7, 8, or 9. Reduction of 6 with LiA1H 4 was followed by esterification with acetyl chloride afforded acetate, 10. The reaction of 6 with W• (diethyl ethoxycarbonyl methylphosphonate) gave a mixture of (E) and (Z) isomers (4:1 ratio) of o•,[3-unsaturated esters (11a,b). The hydrogenation of this mixture afforded ester 12 (8), which after reduction with lithium aluminium hydride and oxidation with pyridinium chlorochromate (PCC) (9) afforded the aidehyde 13. This unstable crude aldehyde is readily oxidizable in air. Its reaction with allyl- magnesium bromide gave secondary alcohol 14. By the application of the stereoselective Wittig-Horner reaction with W 3 (acetonylidenetriphenylphosphate), aldehyde 13 was converted into (E) isomer of o•,[3-unsaturated ketone 15a. The reaction of 6 with W 2 (diethyl cyanomethylphosphonate) gave a mixture of unsaturated nitrile 16a,b and lB,y-unsaturated nitrile 17. The ratio of both forms and lB,•/) depended on the solvent that was used in the reaction. If a mixture of DMF and 1,4-dioxane (2:1) was used, o•,•-unsaturated nitriles 16a,b in the ratio of 3:1 were obtained. The mixture of (E) and (Z) isomers provided saturated nitrile (18) by means of hydrogenation in the presence of Raney-nickel. Using a pure dimethylforamide (DMF) as a solvent, the migration of a double bond to the position [3,•/(in 90% yield) was observed (Scheme 2). Finally, ketone 6 was converted into aidehyde 19 by the three-step procedure: degra- dation by the haloform reaction with sodium hypobromite, followed by reduction with LiA1H4, and finally oxidation with PCC. Aldehyde 19 (readily oxidizable in air) was an intermediate for elongation of the side chain at the C-3 position, using all the above- described reactions. Thus the Grignard reaction with allylmagnesium bromide afforded secondary alcohol 20, while the reaction with W2 in DMF gave a mixture of (E) and (Z) isomers of o•,[3-unsaturated nitriles 2 la,b in the ratio of 1:1. Aldehyde 19 in the reaction