Full Papers
doi.org/10.1002/cctc.202100901
ChemCatChem
Conclusions
Acknowledgements
The selective hydrodefluorination of α-fluoroketones or alde-
hydes is a difficult transformation as these carbonyl compounds
are highly reactive, and apart from the CÀ F bond reduction, the
C=O bond can also be reduced. In fact, most of the reported
catalytic hydrodefluorination protocols rely on the use of
transition metal complexes over fluoroarene or alkenyl sub-
strates under harsh reaction conditions. Recently, we described
a tandem hydrodefluorination–deamination reaction on β-
fluoroamines due to the promiscuous catalytic hydrodefluor-
inase activity shown by TAs. Following this study, we have now
Financial supports from the Spanish Ministry of Economy and
Competitiveness (MEC, Project CTQ2016-75752-R), the Spanish
Ministry of Science and Innovation (MCI, PID2019-109253RBÀ I00)
and the Asturian Regional Government (FC-GRUPIN-IDI/2018/
000181) are gratefully acknowledged. A.C. was funded by grant
BB/P005578/1 from the BBSRC. The University of Graz and the
Field of Excellence BioHealth are acknowledged for financial
support.
applied these enzymes to cleave the CÀ F bond in various α- Conflict of Interest
fluoroketones to give the corresponding defluorinated ketones
with high conversions under very mild conditions and in
aqueous medium. To achieve this goal, a stoichiometric amount
of an amine reagent (e.g., 2-PrNH2) was necessary, affording the
oxidized amine (e.g., acetone), ammonia and hydrogen fluoride
as co-products. This transformation has proven to be chemo-
selective (reducing a CÀ F vs C=O bond) as well as regioselective
(breaking an aliphatic CÀ F vs an aromatic CÀ F bond) and
stereoselective (preferentially defluorinating an enantiomer of a
chiral fluorinated alkyl compound). To improve these processes,
enzyme engineering could be envisaged as a method for
gaining access to more stereoselective hydrodefluorinases for
the synthesis of enantiopure α-fluoro carbonyl derivatives.
The authors declare no conflict of interest.
Keywords: transaminases fluorine chemistry
·
· catalytic
promiscuity · hydrodefluorination · biocatalysis
b) Fluorine in Life Sciences: Pharmaceuticals, Medicinal Diagnosis, and
Agrochemicals, (Eds.: G. Haufe, F. R. Leroux), Elsevier, Amsterdam, 2019;
Barnes-Seeman, J. Beck, C. Springer, Curr. Top. Med. Chem. 2014, 14,
855–864; e) J. Wang, M. Sánchez-Roselló, J. L. Acena, C. Del Pozo, A. E.
Kansy, B. Kuhn, K. Müller, U. Obst-Sander, M. Stahl, ChemBioChem 2004,
5, 637–643.
Experimental Section
General enzymatic hydrodehalogenation protocol: In an Eppen-
dorf tube, the corresponding transaminase [commercial TA (2 mg),
or lyophilized cells overexpressing the TA (10 mg)] was placed, and
then a mixture of phosphate buffer (100 mM, pH 7.5, 1 mM PLP)
with the desired concentration of the amine donor (2-propylamine
or D- or L-alanine, 30–100 mM) and DMSO (12.5 μL, final volume:
0.5 mL) were added. Finally, the corresponding substrate 1–11a
(30 mM) was added into the reaction mixture, and it was shaken at
[6] Recent bibliography: a) W. Chen, C. Bakewell, M. R. Crimmin, Synthesis
[7] For other defluorination processes involving the activation of CÀ F
Bakewell, M. R. Crimmin, Synthesis 2017, 49, 810–821; c) T. Ahrens, J.
°
30 C and 250 rpm for 24 h in an orbital shaker. The reaction was
stopped by addition of a saturated aqueous solution of Na2CO3
(350 μL) and extracted with ethyl acetate (3×350 μL). The organic
layers were separated by centrifugation (14,400 rpm), combined
and dried over Na2SO4. The conversion was measured by GC-FID
(see the Supporting Information for analytical conditions).
Hydrodefluorination of 2a and 6a at semi-preparative scale: In an
Erlenmeyer flask, lyophilized cells of E. coli/CV-TA (for 2a: 210 mg
and for 6a: 180 mg) were placed and then a mixture of phosphate
buffer (100 mM, pH 7.5, 30 mM 2-PrNH2, 1 mM PLP) and MeCN (for
2a: 160 μL, final volume: 6.4 mL and for 6a: 165 μL, final volume:
6.6 mL). Finally, the corresponding substrates 2a and 6a (30 mg,
30 mM) were added into the reaction mixture, and it was shaken at
°
30 C and 250 rpm for 45 h in an orbital shaker. Conversion was
[9] a) J. B. I. Sap, N. J. W. Straathof, T. Knauber, C. F. Meyer, M. Médebielle, L.
Buglioni, C. Genicot, A. A. Trabanco, T. Noël, C. W. am Ende, V.
measured by GC-FID (see the Supporting Information for analytical
conditions). The reaction was extracted with EtOAc (6×6 mL) until
there was no organic product in the aqueous phase (confirmed by
TLC). Organic phases were combined, dried over anhydrous Na2SO4
and the solvent removed under reduced pressure affording
dehalogenated products 2b (24 mg, 90% yield) and 6b (11 mg,
40% yield). 1H-NMR spectra of the obtained products were
compared with samples of the commercially available ketones.
[10] Recent bibliography about enzymatic halogenation: a) M. Voss, S.
Dockrey, A. R. H. Narayan, Tetrahedron 2019, 75, 1115–1121; c) D. S.
ChemCatChem 2021, 13, 1–7
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