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.

The diastereoisomeric 18-110~-and 19-norambrox ((6~)-and (6~)-dodecahqdro-3a,6,9a-trimethyInaphtho[2,1-b]furans resp.) as well as the corresponding 18,19-dinor-derivatives (dodecahydro-3a,9a-dimethylnaphtho[2, I-blfurans) have been synthesized and subjected to sensory evaluation. Threshold data and odor determination give an enlarged insight into the structure-activity relationship (SAR) in ambrox-type ambergris fragrances. As a general conclusion, the accumulation of axial CH, groups in the tricyclic ethers 1-12 leads to the strongest receptor affinity.The release of ambergris scent is strongly related to structural elements of the labdane skeleton, ambrox (1)') being the typical example. In the olfactory recognition process, which has been defined by the 'triaxial rule', the stereochemistry of the CH, groups at C(8) and C(10) in 1 plays an important role in the hydrophobic interaction with the hypothetical receptor site [l]. To assess the significance of the geminal CH, groups at C(4) for the specific ambergris odor sensation the diastereoisomeric tricyclic ethers 1-3 and the six nor-ethers 4-9, belonging to the same enantiomeric series, were synthesized. The 18,19-dinor-ethers l(r12, in racemic form, were also included in the investigation.All compounds mentioned in the Figure had distinct odors of varying quality and strength. Surprisingly, (-)-9-epiambrox (2) possessed the strongest odor and the lowest threshold concentration of the total series (0.15 ppb). (-)-Ambrox (1) as well as the two 18-nor-derivatives 4 and 5 showed only a small qualitative deviation. Thus, the sensory result obtained from the racernate of 4 [2] [3] can be confirmed.

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.

No abstract

Stereochemistry-odor relationships in the 1 -decalone series and their oxa-analogs. -Summary. The olfactory relationships of ( -)-(9S,lOS)-5,5,9-trimethyl-tra~zzs-l-decalone (Za), 6 diasterioisomers in the ll-nordriman-9-one series (2b-g), and 20 racemic 2-oxabicyclo[4.4.0]decanes are reported and correlated with the 'Triaxial Rule of Odor Sensation'. This rule also is applied to the two internal C(13) acetals derived from (+)-diliydro-y-ionone as well as to two epiineric C(18) ethers in the labdane series. Syntheses are described for most of the compounds examined.Ambrariechstoffe [l] weisen eine strenge Strukturbeziehung zum trans-Dekalinringsystem [2] auf. Das olfaktorische Rezeptorsystem tritt dabei mit dem Stimulans in eine dreidimensionale Wechselwirkung. Mindestens drei molekulare Punkte, in einem definierten Abstand voneinander angeordnet (Fig.), sind fur die AusIosung Ziel der vorliegenden Arbeit ist es, die Grenzen dieser Gesetzmassigkeiten kennenzulernen, um somit den Anwendungsbereich dieser Regel erweitern zu konnen. Ausgangspunkt der Untersuchung war die Beobachtung, dass zur triaxialen Weclisel- 2) 3)Zur Definition des Begriffes Ambrariechstoffe vgl. Schlussbetrachtungen in [33. Angaben iiber die Stereochemie der Estergruppe fehlen. Vcrbindungen der allgemeinen Formel 1 und 2 liegen gemeinsam das scsquiterpenoide Geriist des Drimans zugrunde.