Chemical Synthesis of the Epimeric (23R)- and (23S)-Fluoro Derivatives of Bile Acids via Horner-Wadsworth-Emmons Reaction

A method for the synthesis of two (23R)- and (23S)-epimeric pairs of 23-fluoro-3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholan-24-oic acid and 23-fluoro-3 alpha,7 alpha-dihydroxy-5 beta-cholan-24-oic acid is described. The key intermediates, 23,24-dinor-22-aldehyde peracetates were prepared from cholic and chenodeoxycholic acids via the 24-nor-22-ene, 24-nor-22 xi,23-epoxy, and 23,24-dinor-22-aldehyde derivatives. The Horner-Wadsworth-Emmons reaction of the 23,24-dinor-22-aldehydes using triethyl 2-fluoro-2-phosphonoacetate in the presence of LiCl and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), and subsequent hydrogenation of the resulting 23 xi-fluoro-22-ene ethyl esters, followed by hydrolysis, gave a mixture of the epimeric (23R)- and (23S)-fluorinated bile acids which were resolved efficiently by preparative RP-HPLC. The stereochemical configuration of the fluorine atom at C-23 in the newly synthesized compounds was confirmed directly by the X-ray crystallographic data. The H-1 and C-13 NMR spectral differences between the (23R)- and (23S)-epimers were also discussed.