Synthesis 2019; 51(11): 2351-2358
DOI: 10.1055/s-0037-1610695
paper
© Georg Thieme Verlag Stuttgart · New York

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

Stephanie J. Mattingly
a  Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada
b  Department of Oncology, University of Alberta, Medical Isotope Cyclotron Facility, 6820 116th Street, Edmonton, AB, T6H 2V8, Canada
,
Frank Wuest*
a  Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada
c  Faculty 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*
b  Department of Oncology, University of Alberta, Medical Isotope Cyclotron Facility, 6820 116th Street, Edmonton, AB, T6H 2V8, Canada
c  Faculty 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
d  Department of Chemistry, 11227 Saskatchewan Drive, University of Alberta, Edmonton, AB, T6G 2N4, Canada
› Author Affiliations
This work was supported by the Natural Science and Engineering Research Council of Canada (NSERC) and the Dianne and Irving Kipnes Foundation.
Further Information

Publication History

Received: 02 January 2019

Accepted after revision: 29 January 2019

Publication Date:
12 March 2019 (eFirst)

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.

Supporting Information

 
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