Structural modifications of testosterone and 19‐nortestosterone have led to the synthesis of over 60 androstane and estrane derivatives whose sensory evaluation has allowed molecular parameters to be established for release of a ‘steroid‐type’ scent. Odor perception with O‐containing compounds in both classes has been found to be regioselective. Osmophoric groups at C(3) were found to be the most active and specific. Functionality at C(2) is accompanied to a large extent by anosmic defects, and O‐containing substituents at C(1) and C(4) appear to affect the receptor membrane in exceptional cases. A further characteristic of the ‘steroid‐type’ scent is diastereoselectivity. The odor intensity of axial 2‐ and 3‐hydroxysteroids is far greater than that of the equatorial epimers, and epimeric hydroxy‐groups in the 1‐, 4‐, and 5‐positions lead to almost complete absence of odor. In addition, only steroids with ‘normal’ ring junctions and configuration were found to be odorants, whereas compounds with cis‐junctions between rings A and B, or C and D, were found to be practically inactive, Steroids therefore folow the ‘triaxial rule of odor sensation’. The most remarkable feature of our findings with steroid odorants is enantioselectivity . Whereas with C 19 ‐steroids of the ‘natural’ enantiomeric series the perception threshold is extremely low (<6 ppb), the corresponding ‘unnatural’ enantiomers have been found essentially odorless by a panel of 30 persons. This appears to be the first reported instance of a total enantioselective response to an odorant.

We describe in detail a direct, stereoselective synthesis of (-)-cubebol based on a Pt-, Au-, or Cu-catalyzed cycloisomerization in which control of the configuration of the propargylic center is essential for the facial selectivity. In addition, we show that cycloisomerization reactions of enantioenriched propargyl pivalates occur with substantial chirality transfer. We confirm a mechanism by means of cyclization followed by an [1,2]-acyl migration for the Pt- and the Au-catalyzed cycloisomerization. So far, no evidence supports that the Cu-catalyzed cycloisomerization follows the same reaction course.

We synthesized or re-synthesized a large series of 2H-1,5-benzodioxepin-3(4H)-ones 9 (Scheme 1), 4,5-dihydro-1-benzoxepin-3(2H)-ones 10 (Schemes 3 and 4) and 5,6,8,9-tetrahydro-7H-benzocyclohepten-7-ones 11 (Schemes 5 and 6), since the lead compound for the olfactory note of perfumes based on marine accords is a well-known benzodioxepinone named Calone 1951 (9b). We meticulously described the odor profile of each synthesized compound and discussed relevant structure -odor relationships (Tables 1 -3). In particular, we revealed a correlation between the conformation of the seven-membered ring and the activities of these compounds (Table 4 and Fig. 3). We also clarified the effect of the position and the size of the alkyl substituent at the aromatic ring.

Diastereoselective Odor Perception of Alcohols in the Ionone Series The characteristic odor of the diastereoisomers 1 and 2 of 1‐(2,2,6‐trimethylcyclohexyl)‐3‐hexanol is configuration dependent, the trans‐alcohol 1 being identified as the sensorily active component. Structure modification of model 1/2, for example substitution on C(2), C(13), and C(14) (ionon numbering) by CH3 groups, introduction of double bonds in the 3‐ or 4‐position, and isosteric substitution of C(7) by an O‐atom, leads to analogues revealing an unequivocal relation between stereochemistry and odor. The specific odor of alcohol 1 is generally released when all substituents are in an equatorial position; the resulting analogy with the molecular size and shape of odoriferous steroids suggests that the release of the particular scent can be correlated with a steroid‐resembling receptor event.