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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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References

    1. Epstein JW, Brabander HJ, Fanshawe WJ, Hofmann CM, McKenzie TC, Safir SR, Osterberg AC, Cosulich DB, and Lovell FM 1-Aryl-3-azabicyclo[3.1.0]hexanes, a new series of nonnarcotic analgesic agents, J. Med. Chem. 1981, 24, 481–490. - PubMed
    1. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N, Burroughs M, Brass CA, Albrecht JK, Esteban R, and Investigators HR −. Boceprevir for previously treated chronic HCV genotype 1 infection, N. Engl. J. Med. 2011, 364, 1207–1217. - PMC - PubMed
    1. Micheli F, Cavanni P, Andreotti D, Arban R, Benedetti R, Bertani B, Bettati M, Bettelini L, Bonanomi G, Braggio S, Carletti R, Checchia A, Corsi M, Fazzolari E, Fontana S, Marchioro C, Merlo-Pich E, Negri M, Oliosi B, Ratti E, Read KD, Roscic M, Sartori I, Spada S, Tedesco G, Tarsi L, Terreni S, Visentini F, Zocchi A, Zonzini L, and Di Fabio R 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane: a new potent and selective triple reuptake inhibitor, J. Med. Chem. 2010, 53, 4989–5001. - PubMed
    1. Gootz TD, Zaniewski R, Haskell S, Schmieder B, Tankovic J, Girard D, Courvalin P, and Polzer RJ Activity of the new fluoroquinolone trovafloxacin (CP-99,219) against DNA gyrase and topoisomerase IV mutants of Streptococcus pneumoniae selected in vitro, Antimicrob. Agents Chemother. 1996, 40, 2691–2697. - PMC - PubMed
    1. Thibodeaux CJ, Chang WC, and Liu HW Enzymatic chemistry of cyclopropane, epoxide, and aziridine biosynthesis, Chem. Rev. 2012, 112, 1681–1709. - PMC - PubMed