10.1002/chem.202001120
Chemistry - A European Journal
FULL PAPER
NMR spectra of the product mixtures also gave evidence for the
formation of intermediates in an acid catalyst-dependent manner.
Overall, we have delivered a clearer understanding of the
kinetics of fluorination of steroidal systems and the subsequent
epimerisation of fluorosteroids. These results highlight the
opportunities for achieving more efficient synthetic routes through
kinetic understanding.
Experimental Section
All experimental details can be found in the Supporting Information, which
contains characterisations of compounds, details of kinetics experiments
and kinetics data. Crystallographic data for the structures has been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publications CCDC-1985095-1985099.
Figure 9. Correlation of kobs values versus [HCl] for the epimerisation of 21-β to
21-α by HCl in acetic acid at 25 °C.
Acknowledgements
N. R. received doctoral funding from the Faculty of Science,
Durham University. A. H. acknowledges doctoral funding from the
European Community’s Seventh Framework Programme
(FP7/2007-2013) and EFPIA companies’ kind contribution for the
Innovative Medicine Initiative under Grant Agreement No. 115360
(Chemical manufacturing methods for the 21st century
pharmaceutical industries, CHEM21). E. J. C. received MChem
funding from Durham University. Dr Juan Aguilar-Malavia and
Kevin Maduka are thanked for their assistance with kinetic NMR
experiments, and Dr Dmitry S. Yufit for performing X-ray
crystallography.
H+
-H+
H+
H
H
H
O
O
O
O
F
21-β
F
27-β
F
F
28
27-α
AcOH
-H+
AcOH
HO
AcO
HO
O
AcO
F
F
F
29-β
29-α
21-α
Keywords: fluorination • kinetics • epimerisation •
Scheme 5. A potential mechanism for epimerisation of 21-β to 21-α. Another
pathway, hemiacylal formation via AcOH (in blue), is proposed.
stereoselectivity • fluorosteroid
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Conclusion
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upon the rate of fluorination.
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The epimerisation of 6β-fluoroprogesterone 21-β to 6α-
fluoroprogesterone 21-α with increasing concentrations of HCl in
acetic acid proved to be more rapid. Additional signals in the 19
F
8
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