The synthesis of isotopically labeled retinoids

Retinyl acetate (4a) has been prepared with a tritium label at the C‐11 and C‐12 positions by partial reduction of oxenin (1) with tritium gas followed by acetylation and rearrangement. Specific activities of up to 40 curies/mmole have been attained. By alkaline hydrolysis, retinol (5) has been obtained and derivatized as one of several retinyl esters or has been oxidized to all‐trans retinoic acid (6) having equally high specific tritium activities. From beta ionone (12), 13‐cis retinoic acid (10) has been elaborated in a variety of isotopically labeled forms. A key reaction in the sequence, the Wittig coupling of the triphenylphosphonium derivative of vinyl beta ionol (15a‐c) and the butenolide, 5‐hydroxy‐4‐methyl‐2(5H)‐furanone (8), provides access to 13‐cis retinoic acid and its 4‐oxo metabolite labeled with either isotopic hydrogen or carbon.