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

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-cyclo-hexene (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 to 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 Ph3P13CD3l or Ph3PCD3l followed by deprotection to give the labeled perillaldehydes, [(2,2-dideuterio-2-13C-1-methyl)ethenyl]-1-cyclohexene-1-carboxaldehyde (5) or [(2,2-dideuterio-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 LiAlD4 to afford the desired compound 9. The same synthetic procedure may be adopted to synthesize the radioactive isotope labeled perillic acid and perillyl alcohol. © 1997 John Wiley & Sons, Ltd.