Stereoselective C–C bond formation catalysed by engineered carboxymethylproline synthases
Author: ["Refaat B. Hamed","J. Ruben Gomez-Castellanos","Armin Thalhammer","Daniel Harding","Christian Ducho","Timothy D. W. Claridge","Christopher J. Schofield"]
Publication: Nature Chemistry
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Abstract
The reaction of enol(ate)s with electrophiles is used extensively in organic synthesis for stereoselective C–C bond formation. Protein-based catalysts have had comparatively limited application for the stereoselective formation of C–C bonds of choice via enolate chemistry. We describe protein engineering studies on 5-carboxymethylproline synthases, members of the crotonase superfamily, aimed at enabling stereoselective C–C bond formation leading to N-heterocycles via control of trisubstituted enolate intermediates. Active site substitutions, including at the oxyanion binding site, enable the production of substituted N-heterocycles in high diastereomeric excesses via stereocontrolled enolate formation and reaction. The results reveal the potential of the ubiquitous crotonase superfamily as adaptable catalysts for the control of enolate chemistry. The reaction of enols and enolates with electrophiles is used extensively in synthesis. Here, protein engineering — substituting amino acid residues in an enzyme active site — is used to produce biocatalysts for the control of enolate chemistry. The adapted enzymes enable stereoselective C–C bond formation yielding N-heterocycles in high diastereomeric excess by the reaction of trisubstituted-enolates.
Cite this article
Hamed, R., Gomez-Castellanos, J., Thalhammer, A. et al. Stereoselective C–C bond formation catalysed by engineered carboxymethylproline synthases. Nature Chem 3, 365–371 (2011). https://doi.org/10.1038/nchem.1011
