Highly Stereoselective Synthesis of Fused Cyclopropane-γ-Lactams via Biocatalytic Iron-Catalyzed Intramolecular Cyclopropanation
We report the development of an iron-based biocatalytic strategy for the asymmetric synthesis of fused cyclopropane-γ-lactams, which are key structural motifs found in synthetic drugs and bioactive natural products. Using a combination of mutational landscape and iterative site-saturation mutagenesi...
| Published in: | ACS Catalysis |
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| Main Authors: | , , |
| Format: | Text |
| Language: | English |
| Published: |
2020
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| Subjects: | |
| Online Access: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111458/ http://www.ncbi.nlm.nih.gov/pubmed/32257580 https://doi.org/10.1021/acscatal.9b05383 |
| Summary: | We report the development of an iron-based biocatalytic strategy for the asymmetric synthesis of fused cyclopropane-γ-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-γ-lactams as well as β-cyclopropyl amines and cyclopropane-fused pyrrolidines, as valuable building blocks and synthons for medicinal chemistry and natural product synthesis. |
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