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. 2009 Jan 15;11(2):305-8.
doi: 10.1021/ol802464g.

Enantioselective, ketoreductase-based entry into pharmaceutical building blocks: ethanol as tunable nicotinamide reductant

Sylvain Broussy  1 , Ross W Cheloha, David B Berkowitz
Affiliations

Enantioselective, ketoreductase-based entry into pharmaceutical building blocks: ethanol as tunable nicotinamide reductant

Sylvain Broussy et al. Org Lett. .

Abstract

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.

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Figures

Figure 1
Figure 1
Thermodynamics of nicotinamide cofactor regeneration – Tunability of the ethanol reductant.
Figure 2
Figure 2
Comparison of the KRED-132-mediated reduction of ketone 9 with NADPH (@ 2 mol %) regeneration using LKADH (50 mM KPO4 in D2O, pD 7.5; 300 rpm, 30 °C, 3 h), both with (panel A) and without (panel B) YAlDH (see Supporting Information for details). Note the increased conversion and AcOH production under four electron reduction conditions.
Table 1
Table 1
Asymmetric Ketoreductase-Mediated Access to Pharmaceutical Building Blocks
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