Journal
ACS CATALYSIS
Volume 10, Issue 3, Pages 2308-2313Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.9b05383
Keywords
myoglobin; carbene transfer; cyclopropanation; protein engineering; lactams
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Funding
- U.S. National Institute of Health [GM098628]
- Sunivo LLC (USA)
- U.S. National Science Foundation [CHE-0946653, CHE-1725028]
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We report the development of an iron-based biocatalytic strategy for the asymmetric synthesis of fused cyclopropane-gamma-lactams, which are key structural motifs found in synthetic drugs and bioactive natural products. Using a combination of mutational landscape and iterative site-saturation mutagenesis, sperm whale myoglobin was evolved into a biocatalyst capable of promoting the cyclization Of a diverse range of allyl diazoacetamide substrates into the corresponding bicyclic lactams in high yields and with high enantioselectivity (up to 99% ee). These biocatalytic transformations can be performed in whole cells and could be leveraged to enable the efficient (chemo)enzymatic construction of chiral cyclopropane-gamma-lactams as well as beta-cyclopropyl amines and cyclopropane-fused pyrrolidines, as valuable building blocks and synthons for medicinal chemistry and natural product synthesis.
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