Stereodivergent Intramolecular Cyclopropanation Enabled by Engineered Carbene Transferases.

ABSTRACT: We report the development of engineered myoglobin biocatalysts for executing asymmetric intramolecular cyclopropanations resulting in cyclopropane-fused ?-lactones, which are key motifs found in many bioactive molecules. Using this strategy, a broad range of allyl diazoacetate substrates were efficiently cyclized in high yields with up to 99% enantiomeric excess. Upon remodeling of the active site via protein engineering, myoglobin variants with stereodivergent selectivity were also obtained. In combination with whole-cell transformations, these biocatalysts enabled the gram-scale assembly of a key intermediate useful for the synthesis of the insecticide permethrin and other natural products. The enzymatically produced cyclopropyl-?-lactones can be further elaborated to furnish a variety of enantiopure trisubstituted cyclopropanes. This work introduces a first example of biocatalytic intramolecular cyclopropanation and provides an attractive strategy for the stereodivergent preparation of fused cyclopropyl-?-lactones of high value for medicinal chemistry and the synthesis of natural products.

SUBMITTER: Chandgude AL 

PROVIDER: S-EPMC6561828 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature