Enantioselective, ketoreductase-based entry into pharmaceutical building blocks: ethanol as tunable nicotinamide reductant.
The use of NADH- and NADPH-dependent ketoreductases to access enantioenriched pharmaceutical building blocks is reported. Seven structurally diverse synthons are obtained, including those for atomoxetine (KRED 132), talampanel (RS1-ADH and CPADH), Dolastatin (KRED 132), and fluoxetine (KRED 108/132). Ethanol may be used as stoichiometric reductant, regenerating both nicotinamide cofactors, particularly under four-electron redox conditions. Its favorable thermodynamic and economic profile, coupled with its advantageous dual cosolvent role, suggests a new application for biomass-derived ethanol.
Broussy
Sylvain
S
Department of Chemistry, University of Nebraska, Lincoln, Nebraska 68588-0304, USA.
Cheloha
Ross W
RW
Berkowitz
David B
DB
D000426:Alcohol Dehydrogenase / Q000378:metabolism*; D000818:Animals; D000431:Ethanol / Q000378:metabolism*; D006801:Humans; D007659:Ketones / Q000378:metabolism; D009536:Niacinamide / Q000378:metabolism*; D019163:Reducing Agents / Q000378:metabolism*; D013237:Stereoisomerism; D013379:Substrate Specificity
D007659:Ketones; D019163:Reducing Agents; D009536:Niacinamide; D000431:Ethanol; D000426:Alcohol Dehydrogenase