Biocatalytic Asymmetric Cyclopropanations via Enzyme-Bound Iminium Ion Intermediates
Andreas Kunzendorf1, Guangcai Xu1, Mohammad Saifuddin1,2
1Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
Abstract:
Cyclopropane rings are an important structural motif frequently found in many natural products and pharmaceuticals. Commonly, biocatalytic methodologies for the asymmetric synthesis of cyclopropanes rely on repurposed or artificial heme enzymes. Here, we engineered an unusual cofactor-independent cyclopropanation enzyme based on a promiscuous tautomerase for the enantioselective synthesis of various cyclopropanes via the nucleophilic addition of diethyl 2-chloromalonate to α,β-unsaturated aldehydes. The engineered enzyme promotes formation of the two new carbon-carbon bonds with excellent stereocontrol over both stereocenters, affording the desired cyclopropanes with high diastereo- and enantiopurity (d.r. up to 25:1; e.r. up to 99:1). Our results highlight the usefulness of promiscuous enzymes for expanding the biocatalytic repertoire for non-natural reactions.
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