A Promiscuous De Novo Retro‐Aldolase Catalyzes Asymmetric Michael Additions via Schiff Base Intermediates

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Abstract
Recent advances in computational design have enabled the development of primitive enzymes for a range of mechanistically distinct reactions. Here we show that the rudimentary active sites of these catalysts can give rise to useful chemical promiscuity. Specifically, RA95.5‐8, designed and evolved as a retro‐aldolase, also promotes asymmetric Michael additions of carbanions to unsaturated ketones with high rates and selectivities. The reactions proceed by amine catalysis, as indicated by mutagenesis and X‐ray data. The inherent flexibility and tunability of this catalyst should make it a versatile platform for further optimization and/or mechanistic diversification by directed evolution.
Funding Information
  • Swiss National Science Foundation (SNSF)
  • ETH Zurich
  • Spanish Ministerio de Educación, Cultura y Deporte
  • Marie Curie Action (IEF-2011-299400)

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