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. 2020 Feb 7;10(3):2308-2313.
doi: 10.1021/acscatal.9b05383. Epub 2020 Jan 14.

Highly Stereoselective Synthesis of Fused Cyclopropane-γ-Lactams via Biocatalytic Iron-Catalyzed Intramolecular Cyclopropanation

Xinkun Ren  1 , Ajay L Chandgude  1 , Rudi Fasan  1
Affiliations

Highly Stereoselective Synthesis of Fused Cyclopropane-γ-Lactams via Biocatalytic Iron-Catalyzed Intramolecular Cyclopropanation

Xinkun Ren et al. ACS Catal. .

Abstract

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.

Keywords: Myoglobin; carbene transfer; cyclopropanation; lactams; protein engineering.

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Conflict of interest statement

Notes The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Drugs and bioactive natural products containing cyclopropyl-fused lactam and pyrrolidine moieties
Figure 2.
Figure 2.
Overview of biocatalyst evolution process.
Scheme 1.
Scheme 1.
Biosynthetic vs. (chemo)biocatalytic synthesis of cyclopropyl-fused lactam/pyrrolidine scaffolds.
Scheme 2.
Scheme 2.
Chemoenzymatic synthesis of β-cyclopropyl amines and cyclopropyl-fused pyrrolidines
See this image and copyright information in PMC

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