Chiral cyclopropanols
are highly desirable building blocks for
medicinal chemistry, but the stereoselective synthesis of these molecules
remains challenging. Here, a novel strategy is reported for the diastereo-
and enantioselective synthesis of cyclopropanol derivatives via the
biocatalytic asymmetric cyclopropanation of vinyl esters with ethyl
diazoacetate (EDA). A dehaloperoxidase enzyme fromAmphitrite
ornatawas repurposed to catalyze this challenging cyclopropanation
reaction, and its activity and stereoselectivity were optimized via
protein engineering. Using this system, a broad range of electron-deficient
vinyl esters were efficiently converted to the desired cyclopropanation
products with up to 99.5:0.5 diastereomeric and enantiomeric ratios.
In addition, the engineered dehaloperoxidase-based biocatalyst is
able to catalyze a variety of other abiological carbene transfer reactions,
including N–H/S–H carbene insertion with EDA as well
as cyclopropanation with diazoacetonitrile, thus adding to the multifunctionality
of this enzyme and defining it as a valuable new scaffold for the
development of novel carbene transferases.