The industrial synthesis of (−)-menthol

(−)-Menthol, with its cooling odour and taste, is one of the best-selling aroma chemicals. The Japanese company Takasago has made it since 1983 from myrcene, a cheap terpene, using an asymmetric isomerization discovered by Noyori, Hidemasa Takaya and Sei Otsuka. Addition of diethylamine to myrcene gives N,N-diethylgeranylamine.

A rhodium complex of (S)-BINAP shifts the allylic double bond and converts the allylic amine into the enamine of (R)-citronellal, which is hydrolysed to the aldehyde in 98% ee, higher than natural citronellal. Zinc bromide catalyses an intramolecular ene reaction that closes the ring and forms (−)-isopulegol with all three stereocentres correct, and hydrogenation of the double bond gives (−)-menthol, with all three substituents equatorial.