(+)-cis-Verbenol

Method for Improving the Optical Purity of Cis-Verbenol

Vitaly Kovalenko, et al. Chirality, 2019, 31(10), 865-869.

The monoterpene alcohol cis-verbenol has been traditionally used as a flavoring ingredient, a major component of insect pheromones, and a building block for the synthesis of natural products. This work presented an efficient and scalable resolution method to produce optically pure cis-verbenol from a mixture of enantiomers.
The experimental methods involved the conversion of crude verbenol into phthalic mono-ester using phthalic anhydride. The carboxylic function was then employed to form salts with chiral bases, specifically (R)-α-methylbenzylamine and (S)-α-methylbenzylamine, which resulted in diastereomeric products with distinct crystallization behavior.
The crystallization of the salt of mono-ester with (R)-(+)-α-methylbenzylamine was studied, leading to a significant increase in enantiomeric excess after several crystallization runs. The pure salt was obtained with approximately 50% yield from verbenone. The mono-ester was then isolated from the salt using aqueous inorganic acid, and the phthalate group was removed to obtain pure (S)-cis-verbenol with over 99% enantiomeric excess.
Both the (S)- and (R)- enantiomers of cis-verbenol were isolated, with the (R)-enantiomer obtained from the mother liquor after crystallization. The diastereomeric purity of the cis/trans ratio was improved through repeated crystallizations, resulting in a ratio of up to 100:1.