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Oxidative diversification of amino acids and peptides by small-molecule iron catalysis

Nature volume 537, pages 214–219 (2016)Cite this article

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Abstract

Secondary metabolites synthesized by non-ribosomal peptide synthetases display diverse and complex topologies and possess a range of biological activities1,2. Much of this diversity derives from a synthetic strategy that entails pre-3 and post-assembly2 oxidation of both the chiral amino acid building blocks and the assembled peptide scaffolds. The vancomycin biosynthetic pathway is an excellent example of the range of oxidative transformations that can be performed by the iron-containing enzymes involved in its biosynthesis4. However, because of the challenges associated with using such oxidative enzymes to carry out chemical transformations in vitro, chemical syntheses guided by these principles have not been fully realized in the laboratory5. Here we report that two small-molecule iron catalysts are capable of facilitating the targeted C–H oxidative modification of amino acids and peptides with preservation of α-centre chirality. Oxidation of proline to 5-hydroxyproline furnishes a versatile intermediate that can be transformed to rigid arylated derivatives or flexible linear carboxylic acids, alcohols, olefins and amines in both monomer and peptide settings. The value of this C–H oxidation strategy is demonstrated in its capacity for generating diversity: four ‘chiral pool’ amino acids are transformed to twenty-one chiral unnatural amino acids representing seven distinct functional group arrays; late-stage C–H functionalizations of a single proline-containing tripeptide furnish eight tripeptides, each having different unnatural amino acids. Additionally, a macrocyclic peptide containing a proline turn element is transformed via late-stage C–H oxidation to one containing a linear unnatural amino acid.

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Figure 1: NRPS-inspired strategy for iron-catalysed C–H oxidative functionalization of amino acids and peptides.
Figure 2: Four amino acids transformed to twenty-one chiral UAAs via small-molecule iron-catalysed C–H hydroxylations.
Figure 3: Direct oxidative modification of N-terminal, C-terminal and internal proline residues in peptides by small-molecule iron-catalysed C–H hydroxylation.
Figure 4: Small-molecule iron-catalysed oxidative diversification of tripeptides and macrocycles.

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Data deposits

The crystal data have been deposited in The Cambridge Crystallographic Data Centre (http://www.ccdc.cam.ac.uk) under accession numbers 1478939, 1478940, and 1478941.

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Acknowledgements

Financial support for this work was provided by the NIH/National Institute of General Medical Sciences (GM112492) and a grant from Pfizer to study the modification of natural products and medicinal compounds. T.J.O. is a Springborn Graduate Fellow. We thank L. Zhu for assistance with nuclear magnetic resonance spectroscopy, D. Gray and J. Bertke for X-ray crystallographic studies, A. I. Greenwood and J. Zhao for calculations on product (−)-10, W. A. van der Donk for use of his HPLC instrument, X. Yang and X. Zhao for assistance with Marfey’s reagent for chiral amino acid analysis of tripeptide (−)-53, C. Jiang for preliminary studies of amino acid oxidations, and G. S. Snapper for substrate synthesis.

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Author notes

  1. Thomas J. Osberger and Donald C. Rogness: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, Roger Adams Laboratory, University of Illinois, Urbana, 61801, Illinois, USA

    Thomas J. Osberger, Donald C. Rogness & M. Christina White

  2. Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, 06340, Connecticut, USA

    Jeffrey T. Kohrt

  3. Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, 02139, Massachusetts, USA

    Antonia F. Stepan

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  1. Thomas J. Osberger
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Contributions

T.J.O. and D.C.R. conducted the experiments and analysed the data. M.C.W. and T.J.O. wrote the manuscript. M.C.W., J.T.K., A.F.S., T.J.O. and D.C.R. designed the project. All authors provided comments on the experiments and manuscript during its preparation.

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Correspondence to M. Christina White.

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The authors declare no competing financial interests.

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Osberger, T., Rogness, D., Kohrt, J. et al. Oxidative diversification of amino acids and peptides by small-molecule iron catalysis. Nature 537, 214–219 (2016). https://doi.org/10.1038/nature18941

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