Ambrox through the Looking Glass: Chemoenzymatic Synthesis and GC-Olfactometric Analysis of 15 Ambrox Stereoisomers

Abstract

All eight theoretical stereoisomers of (10S)-Ambrox have been synthesized by enzymatic polycyclization of the four geometric isomers of homofarnesol with selected squalene hopene cyclases. This includes the highly strained (+)-(8S,9S)-Ambrox, an isomer historically considered unlikely to exist. The enantiomeric (10R)-series has been prepared by a combination of diastereoselective synthesis and preparative chiral HPLC. Thus, for the first time, the synthesis and sensory properties of all but one stereoisomers of Ambrox are presented. The results solve a long standing peradventure: the commercial product (−)-Ambrox exhibits by far the strongest odour, the previously described 9-epi-Ambrox is 26 times weaker. The enantiomer difference between (−)-and (+)-Ambrox was also found much higher than in previous reports (1000 vs. 8 times). The (8R)-configuration was identified as the single most important structural feature for high odour strength.