Pentafluorinated thevinol scaffold for opioid ligands

Abstract

An addition reaction of Me₃SiCF₂CF₃ to the carbonyl group of thevinal (10), a morphinan derivative, followed by an oxidation of the resulting mixture of the C(20)-epimeric secondary alcohols (20R)-11a and (20S)-11b (15:1) resulted in the first preparation of the pentafluorinated ketone 12. The latter is expected to serve as a starting compound for the preparation of thevinols and orvinols, putative opioid receptor ligands pentafluorinated within their C(20)-centered pharmacophore. It was shown that MeLi and MeMgI, indeed, add to the carbonyl group of ketone 12 to afford the mixture of C(20)-epimeric tertiary alcohols, pentafluoroethylthevinols, with the 20R-isomer predominating. The reduction of ketone 12 with LiAlH₄ also results in the formation of a mixture of the C(20)-epimeric pentafluorothevinols (20R)-11a and (20S)-11b However, the ratio of the epimers (1:8) is opposite to that one obtained from the reaction of aldehyde 10 with Me₃SiCF₂CF₃.