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

Abstract

AbstractAll 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.