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

• Published in: ACS Catalysis
• Main Authors: Ren, Xinkun, Chandgude, Ajay L., Fasan, Rudi
• Format: Text
• Language: English
• Published: 2020
• Subjects: Article; Sperm whale
• 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

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.