Enantiomerically pure (3S)-3a and -3b, the olfactory active forms of 1-(2,2,6-trimethylcyclohexyl)hexan-3-ol, components of the commercial woody odorant Timberol , are obtained by lipase-PS-mediated enantioselective acetylation of the allylic alcohols 6 and 7 and of the saturated alcohol 3. These materials, as mixtures of diastereoisomers, provided (3R)-configured transformation products. However, whereas in the conversion of 6 and 7 there is no diastereoselection, 3 provided the acetate of (1'S,3R,6'R)-3c much more rapidly than that of the diastereoisomer (1'R,3R,6'S)-3d (Scheme 3). Inversion of the configuration at C(3) of the side chain of the olfactory inactive (3R)-materials obtained as acetates in the enzymic treatment of 6, 7, and 3 also provided, eventually, the desired olfactory active (3S)-products.
Introduction. ± The structure-odour relationship is the subject of active current research interests [1] [2] [3a]. A relevant example of the evolution of the knowledge of the structural factors governing the still largely obscure phenomenon of olfaction through chemical synthesis is 1-(2,2,6-trimethylcyclohexyl)hexan-3-ol (1). The material was first put on the market nearly 20 years ago as Timberol by Dragoco [4], a fragrance synthetic with fixative properties. The product, showing a powdery-woody odour with animal, steroid-type undertones, was soon introduced as a key component in many formulations of commercial success [2]. Subsequent studies indicated that the commercial product was mainly composed of the two racemic ring cis/trans diastereoisomers 2 (64%) and 3 (13%), respectively, and, most importantly, that the woody animal note was mainly due to the trans diastereoisomer-3 [5], with the substituents at C(1') and C(6') of the cyclohexane moiety both in equatorial positions. The observed 2 (cis)/3 (trans) ratio of Timberol originates from the industrial synthesis, i.e., the catalytic hydrogenation of the ionone homologue 4 (in mixture with the D 5 -isomer).
The odour-active 1',6'-equatorially disubstituted material 3 was subsequently prepared as a 1 : 1 mixture of the two racemic diastereoisomers 3a,c and 3b,d, and commercialized by Firmenich with the brand name of Norlimbanol . This synthesis was based on the reduction of the dihydroionone analogue 5 possessing the desired 1',6'trans substitution due to the synthetic sequence starting from the trans-dihydrocyclocitral ( trans-2,2,6-trimethylcyclohexanecarboxaldehyde).
The single enantiomers 3a ± d, which are the components of Norlimbanol , were later prepared, starting from the C 10 and C 5 chiral pool components [6] (R)-and (S)dihydrocyclocitral and l-and d-norleucine. Intermediates in the convergent synthesis of 3a ± d were the enantiomers of the alcohol prepared by reduction of transdihydrocyclocitral, and propyloxirane. The coupling of the two fragments was achieved