Engineered hemoproteins have recently emerged as viable biocatalysts for the asymmetric synthesis of chiral cyclopropanes, which are key carbocyclic motifs found in many pharmaceuticals and bioactive molecules. Recent work in our group led to the development of a myoglobin variant capable of catalyzing the cyclopropanation of aryl olefins in the presence of ethyl diazoacetate with high efficiency and excellent diastereo- and enantioselectivity. Through a combination of computational and mechanistic studies, insights into the mechanism of this reaction and the reactivity of heme-carbenoid intermediate were gained. In addition, the structural determinants responsible for chiral induction and high stereocontrol in this cyclopropanase have been investigated via crystallographic, computational (DFT), and structure-activity analyses, revealing the interplay of steric complementarity and non-covalent interactions between the protein, the heme-carbenoid intermediate, and the olefin substrate in controlling the stereoselectivity of the cyclopropanation reaction. These findings have been exploited to expand the substrate scope of the myoglobin-based carbene transferase and to increase its cyclopropanation activity with a bulky a-diazo-ester.

Mechanistic investigation of stereoselective olefin cyclopropanation catalyzed by an engineered carbene transferase

2019 Fall National Meeting

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