Synthesis of deuterium labeled perillyl alcohol and dual C-13 and deuterium labeled perillic acid, major metabolites of d-limonene

Article abstract of DOI:10.1002/(SICI)1099-1344(199705)39:5<369::AID-JLCR983>3.0.CO;2-F

Dual C-13 and deuterium labeled perillic acid [(1,1-dideuterio-1-¹³C-2-methyl)ethenyl]-1-cyclohexene-1-carboxylic acid (6) and deuterated perillyl alcohol, [(2,2-dideuterio-1-methyl)-ethenyl[-1-deuteriohydroxymethyl-1-cyclohexene(9) were synthesized from commercially available (4S)-(-)-perillaldehyde (1). Compound 1 was first protected with ethylene glycol to yield the ethylene ketal followed by oxidation with OsO₄/NalO₄ to cleave the terminal double bond t afford the key intermediate ketone, 4-acetyl-1-cyclohexene-1-carboxaldehyde ethylene ketal (3). 3 was then converted to the labeled perillyl aldehyde by Wittig reaction with prepared Ph₃¹³CD₃l or Ph₃PCD₃l followed by deprotection to give the labeled perillaldehydes, [(2,2-dideuterio-2-¹³C-1-methyl)-ethenyl]-1-cyclohexene-1-carboxaldehyde (8). 5 was further oxidized by freshly prepared Ag₂O to give the desired compound 6. 8 was reduced by LiAID₄ to afford the desired compound 9. The same synthetic procedure may be adopted to synthesize the radioactive isotope labeled perillic acid and perillyl alcohol.