Synthesis of 4, 4-difluoro analogs of retinol and retinoic acid.

Oxidation of retinol at the C-4 position is a major metabolic route to biologically inactive excretory products. Thus, the replacement of hydrogen with fluorine at C-4 might well modify the rate of metabolism, biological activity, and pharmacological activity of vitamin A, 4,4-Difluororetinyl acetate and related analogs were consequently synthesized by the following procedure. Retinoic acid (1), upon methylation to methyl retinoate (2), was oxidized with manganese dioxide to methyl 4-oxoretinoate (3). Methyl 4,4-difluororetinoate (4), prepared from methyl 4-oxoretinoate (3) by reaction with diethylaminosulfurtrifluoride (DAST), was further converted to 4,4-difluororetinoic acid (5), 4,4-difluororetinol (6), 4,4-difluororetinyl acetate (7), and 4,4-difluororetinyl palmitate (8). 4,4-Difluororetinyl acetate was also prepared directly from 4-oxoretinyl acetate (9) by reaction with DAST. The purified, often crystalline, analogs were characterized by UV absorption, mass spectrometry, and 1H-NMR and 19F-NMR spectra.