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Bringing Biocatalysis into the Deuteration Toolbox

preprint
submitted on 11.04.2019 and posted on 12.04.2019 by Jack Rowbotham, Oliver Lenz, Holly Reeve, Kylie Vincent

Chemicals labelled with the heavy hydrogen isotope deuterium (2H) have long been used in chemical and biochemical mechanistic studies, spectroscopy, and as analytical tracers. More recently, demonstration of selectively deuterated drug candidates that exhibit advantageous pharmacological traits has spurred innovations in metal-catalysed 2H insertion at targeted sites, but asymmetric deuteration remains a key challenge. Here we demonstrate an easy-to-implement biocatalytic deuteration strategy, achieving high chemo-, enantio- and isotopic selectivity, requiring only 2H2O (D2O) and unlabelled dihydrogen under ambient conditions. The vast library of enzymes established for NADH-dependent C=O, C=C, and C=N bond reductions have yet to appear in the toolbox of commonly employed 2H-labelling techniques due to requirements for suitable deuterated reducing equivalents. By facilitating transfer of deuterium atoms from 2H2O solvent to NAD+, with H2 gas as a clean reductant, we open up biocatalysis for asymmetric reductive deuteration as part of a synthetic pathway or in late stage functionalisation. We demonstrate enantioselective deuteration via ketone and alkene reductions and reductive amination, as well as exquisite chemo-control for deuteration of compounds with multiple unsaturated sites.

Funding

EP/N013514/1

EXC 314‐2, Deutsche Forschungsgemeinschaft

History

Email Address of Submitting Author

kylie.vincent@chem.ox.ac.uk

Institution

Department of Chemistry, University of Oxford

Country

United Kingdom

ORCID For Submitting Author

0000-0001-6444-9382

Declaration of Conflict of Interest

There are no conflicts to declare

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