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Abstract A chemobiocatalytic strategy for the highly stereoselective synthesis of nitrile‐substituted cyclopropanes is reported. The present approach relies on an asymmetric olefin cyclopropanation reaction catalyzed by an engineered myoglobin in the presence of ex situ generated diazoacetonitrile within a compartmentalized reaction system. This method enabled the efficient transformation of a broad range of olefin substrates at a preparative scale with up to 99.9 % de and ee and up to 5600 turnovers. The enzymatic product could be further elaborated to afford a variety of functionalized chiral cyclopropanes. This work expands the range of synthetically valuable, abiotic transformations accessible through biocatalysis and paves the way to the practical and safe exploitation of diazoacetonitrile in biocatalytic carbene transfer reactions.
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Highly stereoselective and enantiodivergent synthesis of cyclopropylphosphonates with engineered carbene transferases
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 (1 R ,2 S ) and (1 S ,2 R ) 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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- Award ID(s):
- 1929237
- PAR ID:
- 10354885
- Date Published:
- Journal Name:
- Chemical Science
- Volume:
- 13
- Issue:
- 29
- ISSN:
- 2041-6520
- Page Range / eLocation ID:
- 8550 to 8556
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/d2sc01965e
