C(21)-Di- and monofluorinated scaffold for thevinol/orvinol-based opioid receptor ligands.

Defluorination of the readily available 21,21,21-trifluorothevinone (7) with Mg + MeSiCl allows the preparation of 21,21-difluorothevinone (10) and 21-fluorothevinone (11), which can be used as the starting compounds for syntheses of 21,21-difluoro- and 21-fluoro-substituted relatives of thevinols and orvinols. Taken together, thevinols and orvinols are well known to constitute a family of the highly potent 4,5α-epoxy-18,19--(etheno/ethano)morphinan-type opioid receptor ligands. Alternatively, 10 and 18,19-dihydro-21,21-difluorothevinone (13) have been synthesized by the addition of MeSiCHF to the carbonyl function of thevinal (12) and dihydrothevinal (18) followed by oxidation of the intermediate C(21)-difluorinated secondary alcohols.

C(21)-fluorinated thevinol scaffold for opioid ligands. 21,21,21-Trifluoro-6-O-nororvinols: Design, synthesis and analgesic activity.

Thevinols and their 3-O-demethylated relatives, orvinols, are derivatives of the Diels-Alder adduct of natural alkaloid thebaine with methyl vinyl ketone. Taken together, thevinols and orvinols constitute an important family of opioid receptor (OR) ligands playing an important role in both the OR mediated antinociception and OR antagonism. Herein, we disclose for the first time the OR activity of orvinols fluorinated within the pharmocophore associated with C(20) and its surrounding along with a dependence of the activity profile on the substituent at N(17).

Control of the diastereoselectivity at C(20) in the formation of C(21)-fluorinated thevinols.

A method is reported to control the stereoselectivity at C(20) in the syntheses of 20--21,21,21-trifluorothevinols (12), the opioid ligands incorporating fluorine atoms within the pharmacophore associated with the surroundings of the C(20) carbon atom. The C(20)-alcohols 12 can be prepared either by reaction of 21,21,21-trifluorothevinone (9) with RM (R = alkyl; M = Li, MgX) or by reaction of thevinone (2) and related non-fluorinated ketones with CFSiMe. In general, alcohols 12 were formed as mixtures of the C(20)-epimers, with the major epimers of the alcohols obtained from the aforementioned reactions exploiting RLi CFSiMe with opposite absolute configurations at C(20).

Fluorinated and [F]fluorinated morphinan based opioid ligands.

It is well documented in the literature that opioid receptors modulate a large number of physiological functions (pain perception, breathing, mood, gastrointestinal motility, etc.). Natural opiates and 4,5α-epoxymorphinan derivatives obtained by their chemical modifications, which are frequently referred to as semi-synthetic opioids, are among the most important types of opioid ligands.