Dynamic kinetic resolution of 2-methyl-2-nitrocyclohexanol: Combining the intramolecular nitroaldol (Henry) reaction & lipase-catalysed resolution |
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| Authors: | Aoife M Foley Declan P Gavin Rebecca E Deasy Sinéad E Milner Thomas S Moody Kevin S Eccles Simon E Lawrence Anita R Maguire |
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| Institution: | 1. School of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid-State Pharmaceutical Centre, University College Cork, Cork, Ireland;2. Department of Biocatalysis & Isotope Chemistry, Almac, Craigavon, BT63 5QD, Northern Ireland, United Kingdom;3. Arran Chemical Company Limited, Unit 1, Monksland Industrial Estate, Athlone, Co. Roscommon, Ireland;4. School of Chemistry & School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid-State Pharmaceutical Centre, University College Cork, Cork, Ireland |
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| Abstract: | Efforts to combine the intramolecular nitroaldol reaction with lipase-catalysed resolution of the resulting nitroaldol adduct in a one-pot dynamic kinetic resolution (DKR) are described. Significant challenges were encountered in the combination of the two systems. trans-2-Methyl-2-nitrocyclohexyl acetate (±)-3b was isolated in excellent enantiopurity (>98% ee) via a sequential DKR sequence where the lipase-mediated resolution and base-mediated interconversion of 2-methyl-2-nitrocyclohexanol 2 were effected alternately, demonstrating the feasibility of this approach initially. Further work showed, for the first time, evidence that a DKR-type system is possible for 2. Reaction engineering allowed the design of a sequential one-pot reaction system which furnished the products with excellent enantioselectivity, and good diastereoselectivity. |
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| Keywords: | Biocatalysis Kinetic resolution Henry reaction Dynamic kinetic resolution Lipases |
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