The iconic ambra odorant (-)-Ambrox ((-)-1) features a truncated labdanoid skeleton with 4 chiral centers. Despite the long history and commercial importance of this ingredient, knowledge about structure-odour relationship among the stereoisomers was incomplete. We have now addressed the long-standing challenge of preparation and olfactory assessment of all 16 stereoisomers.^[1] 

Our strategy comprised the preparation of all geometric isomers of homofarnesol and their cyclization using selected squalene hopene cyclases.^[2] This led to the successful preparation of all eight (10S) stereoisomers of Ambrox with >99.9% e.e.. The mildness and stereospecificity of the SHC mediated polycyclizations are illustrated by the challenging conversion of the (3Z,7Z)-isomer 9d to (-)-8 and (+)-6 (Figure 1a).^[1] For the enantiomeric (10R)-series, we relied on enantiomer separation and isolation by chiral preparative HPLC of racemic samples prepared by semi-synthesis.

Figure 1. a) SHC mediated cyclization of Z,Z-homofarnesol. b) Receptor activation results of selected Ambrox stereoisomers.

The final products were evaluated by GC-olfactometry (GCO) with experienced panelists and in vitro receptor screening with the human olfactory receptors (hORs) OR7A17 (“woody receptor”, broadly tuned to woody smelling odorants) and OR7E24 (“ambra receptor”, narrowly tuned to Ambrox-like smelling odorants) (Figure 1b).^[3] The results draw a unique picture of dynamic range and odour modulation solely dictated by stereochemistry.

[1]  F. Flachsmann, N. Aeberli, S. Dossenbach, L. Hortencio, H. Koch, G. Brunner, B. Spenger, E. Eichhorn, A. Fonzo, R. Berweger, D. Lelièvre, Helv. Chim. Acta 2024, 107, e202400016.
[2]  a) E. Eichhorn, B. Schilling, A. Bombrun, F. Schroeder, Chimia 2024, 78, 468.
[3]  R. Emter, C. Merillat, F. Buchli, F. Flachsmann, A. Natsch, Curr. Biol. 2025, 35, 5252.