Enantioselectivity of Isomerization of n-Humulone to trans- and cis-n-Isohumulones.

The enantiomeric composition of products obtained from isomerization of n-humulone 1a to trans- and cis-n-isohumulones 2a and 3a, respectively, was determined by chiral HPLC analysis of the isolated trans and cis isomers. Enantiomers of humulone 1 were readily resolved on a Whelk-O1 chiral stationary phase (CSP), whereas the isomeric isohumulones 2 and 3 were separated on a carbohydrate-based IC-3 CSP. Magnesium-catalyzed isomerization of n-humulone under basic conditions gave mixtures of trans- and cis-n-isohumulones exhibiting an increasing preference for the cis isomer at lower temperatures. At either 10 °C in CH2Cl2/H2O or reflux in methanol-water, the trans-(-) (4S,5S)-2a isomer was obtained in greater than 95% ee, while diastereomeric cis-3a exhibited 88% ee of the (+)-(4S,5R) enantiomer. Precision continuous flow photochemical isomerization using 395 nm LEDs provided trans-(-)-2a in greater than 95% ee in an isolated yield of 93%. However, photochemical isomerization with 365 nm LEDs gave a mixture of isomers consisting of 46% ee for the trans-(-)-2a and greater than 95% ee for the cis-(-)-(4R,5S)-3a enantiomer. The photochemically obtained (-)-3a isomer has the opposite absolute configuration compared to thermal isomerization. An oxadi-π-methane rearrangement is proposed to account for the formation of isohumulone isomers under photochemical conditions.