Synthesis of 2-Fluoroacetoacetic Acid and 4-Fluoro-3-hydroxy­butyric Acid

Stephanie J. Mattingly; Frank Wuest; Ralf Schirrmacher

doi:10.1055/s-0037-1610695

Synthesis, Table of Contents

Synthesis 2019; 51(11): 2351-2358
DOI: 10.1055/s-0037-1610695

paper

Synthesis of 2-Fluoroacetoacetic Acid and 4-Fluoro-3-hydroxybutyric Acid

Stephanie J. Mattingly

^aDepartment of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada

^bDepartment of Oncology, University of Alberta, Medical Isotope Cyclotron Facility, 6820 116th Street, Edmonton, AB, T6H 2V8, Canada

,

Frank Wuest*

^aDepartment of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada

^cFaculty of Pharmacy and Pharmaceutical Sciences, 2-35, Medical Sciences Building, University of Alberta, 8613 114th Street, Edmonton, AB, T6G 2H7, Canada Email: wuest@ualberta.ca Email: schirrma@ualberta.ca

,

Ralf Schirrmacher*

^bDepartment of Oncology, University of Alberta, Medical Isotope Cyclotron Facility, 6820 116th Street, Edmonton, AB, T6H 2V8, Canada

^cFaculty of Pharmacy and Pharmaceutical Sciences, 2-35, Medical Sciences Building, University of Alberta, 8613 114th Street, Edmonton, AB, T6G 2H7, Canada Email: wuest@ualberta.ca Email: schirrma@ualberta.ca

^dDepartment of Chemistry, 11227 Saskatchewan Drive, University of Alberta, Edmonton, AB, T6G 2N4, Canada

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Abstract

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Abstract

The butyric acid scaffold is the base structure of several human metabolites that serve diverse and prominent biochemical roles including as oxidative sources of cellular energy and as substrates for biosynthesis. Derivatization of metabolites through incorporation of fluorine often alters bioactivity and can facilitate detection and analysis by nuclear magnetic resonance or positron emission tomography depending upon the fluorine isotope employed. We describe the synthesis of two new fluorinated butyric acids (and three related esters) that are derivatives of the metabolites acetoacetic acid and 3-hydroxybutyric acid. 4-Fluoro-3-hydroxybutyric acid is prepared from epoxy ester precursors via ring opening by triethylamine trihydrofluoride. 2-Fluoroacetoacetic acid is prepared by electrophilic fluorination of an acid-labile β-keto ester. The gradual pH-dependent decarboxylation of 2-fluoroacetoacetic acid is investigated by ¹⁹F NMR spectroscopy.

Key words

fluorination - ketone bodies - acetoacetate - acetoacetic acid - 3-oxobutanoic acid - 3-hydroxybutanoic acid - β-hydroxybutyrate

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References

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Supplementary Material

Supporting Information

Synthesis of 2-Fluoroacetoacetic Acid and 4-Fluoro-3-hydroxy­butyric Acid

Synthesis of 2-Fluoroacetoacetic Acid and 4-Fluoro-3-hydroxybutyric Acid