The synthesis of A- and B-ring fluorinated analogues of cholesterol

Abstract

The synthesis of a number of mono- and difluorinated steroids with the potential to act as probes of the metabolism of cholesterol is described. 2α-Fluorocholestan-3-one 7, 4-fluorocholest-5-en-3-one 11 and 6-fluorocholest-4-en-3-one 12 were synthesised from the appropriate silyl enol ethers using 1-fluoropyridinium triflate, and subsequently reduced to the corresponding alcohols, 8, 13 and 14 respectively. A similar approach was used to synthesise 2,2-difluorocholestan-3-ol 16 starting from the monofluoro steroid 7. To synthesise 4,4-difluorocholestan-3β-ol 26, 3β-acetoxycholestan-4-one 25 was generated via an acid catalysed rearrangement of 4,5-epoxycholestan-3-one 20 and treated with DAST. Finally, a difluorocyclopropyl analogue of cholesterol 28 was synthesised using chlorodifluoroacetic acid.