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Chemical Synthesis of the Epimeric (23 R )‐ and (23 S )‐Fluoro Derivatives of Bile Acids via Horner–Wadsworth–Emmons Reaction
Author(s) -
Omura Kaoru,
Adachi Yuuki,
Kobayashi Yuuki,
Sekiguchi Shoutaro,
Zhou Biao,
Iida Takashi
Publication year - 2015
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/s11745-015-4050-8
Subject(s) - chemistry , clinical chemistry , lipidology , organic chemistry , medicinal chemistry , stereochemistry , biochemistry
Abstract A method for the synthesis of two (23 R )‐ and (23 S )‐epimeric pairs of 23‐fluoro‐3α,7α,12α‐trihydroxy‐5β‐cholan‐24‐oic acid and 23‐fluoro‐3α,7α‐dihydroxy‐5β‐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‐22ξ,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 23ξ‐fluoro‐22‐ene ethyl esters, followed by hydrolysis, gave a mixture of the epimeric (23 R )‐ and (23 S )‐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 1 H and 13 C NMR spectral differences between the (23 R )‐ and (23 S )‐epimers were also discussed.