Journal
CHEMICAL SCIENCE
Volume 13, Issue 29, Pages 8550-8556Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d2sc01965e
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Funding
- U.S. National Institute of Health [S10OD030302]
- U.S. National Science Foundation [CHE0946653, CHE-1725028]
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This study reports a highly stereoselective strategy for olefin cyclopropanation using a phosphonyl diazo reagent as the carbene precursor, and develops efficient biocatalysts using a "substrate walking" protein engineering strategy. This method enables the efficient transformation of a broad range of vinylarene substrates, with high diastereomeric and enantiomeric selectivity.
Organophosphonate compounds have represented a rich source of biologically active compounds, including enzyme inhibitors, antibiotics, and antimalarial agents. Here, we report the development of a highly stereoselective strategy for olefin cyclopropanation in the presence of a phosphonyl diazo reagent as carbene precursor. In combination with a 'substrate walking' protein engineering strategy, two sets of efficient and enantiodivergent myoglobin-based biocatalysts were developed for the synthesis of both (1R,2S) and (1S,2R) enantiomeric forms of the desired cyclopropylphosphonate ester products. This methodology enables the efficient transformation of a broad range of vinylarene substrates at a preparative scale (i.e. gram scale) with up to 99% de and ee. Mechanistic studies provide insights into factors that contribute to make this reaction inherently more challenging than hemoprotein-catalyzed olefin cyclopropanation with ethyl diazoacetate investigated previously. This work expands the range of synthetically useful, enzyme-catalyzed transformations and paves the way to the development of metalloprotein catalysts for abiological carbene transfer reactions involving non-canonical carbene donor reagents.
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