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

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Lipids

Abstract

A method for the synthesis of two (23R)- and (23S)-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 (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 1H and 13C NMR spectral differences between the (23R)- and (23S)-epimers were also discussed.

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Abbreviations

MMO:

4-Methylmorpholine N-oxide

DBU:

1,8-Diazabicyclo[5,4,0]undec-7-ene

NMR:

Nuclear magnetic resonance

HPLC:

High-performance liquid chromatography

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Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Sciences and Technology of Japan (to T.I., 21550091) for 2012-2014.

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Authors and Affiliations

  1. Department of Chemistry, College of Humanities and Sciences, Nihon University, Sakurajousui, Setagaya, Tokyo, 156-8550, Japan

    Kaoru Omura, Yuuki Adachi, Yuuki Kobayashi, Shoutaro Sekiguchi, Biao Zhou & Takashi Iida

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  1. Kaoru Omura
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  2. Yuuki Adachi
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  3. Yuuki Kobayashi
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  4. Shoutaro Sekiguchi
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  5. Biao Zhou
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  6. Takashi Iida
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Correspondence to Takashi Iida.

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Omura, K., Adachi, Y., Kobayashi, Y. et al. Chemical Synthesis of the Epimeric (23R)- and (23S)-Fluoro Derivatives of Bile Acids via Horner–Wadsworth–Emmons Reaction. Lipids 50, 919–926 (2015). https://doi.org/10.1007/s11745-015-4050-8

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  • DOI: https://doi.org/10.1007/s11745-015-4050-8

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