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

Abstract

A method is reported to control the stereoselectivity at C(20) in the syntheses of 20-R-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 CF₃SiMe₃. 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 vs. CF₃SiMe₃ with opposite absolute configurations at C(20). Some individual C(20)-epimers of the fluorinated alcohols 12 were isolated from the reaction mixtures in pure form by trivial crystallization. The reactions of the ketones with RMgX (R ≠ Me) and RLi (R = tertiary or secondary alkyl) resulted in the reduction of the carbonyl function to produce the secondary alcohols 11a,b rather than the tertiary alcohols 12. The additives of the salts were found to affect the composition of the products in the reactions of 9 with alkyl organomagnesium and organolithium reagents.