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Umpolung reactivity in amide and peptide synthesis

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Abstract

The amide bond is one of nature’s most common functional and structural elements, as the backbones of all natural peptides and proteins are composed of amide bonds. Amides are also present in many therapeutic small molecules. The construction of amide bonds using available methods relies principally on dehydrative approaches, although oxidative and radical-based methods are representative alternatives. In nearly every example, carbon and nitrogen bear electrophilic and nucleophilic character, respectively, during the carbon–nitrogen bond-forming step. Here we show that activation of amines and nitroalkanes with an electrophilic iodine source can lead directly to amide products. Preliminary observations support a mechanism in which the polarities of the two reactants are reversed (German, umpolung) during carbon–nitrogen bond formation relative to traditional approaches. The use of nitroalkanes as acyl anion equivalents provides a conceptually innovative approach to amide and peptide synthesis, and one that might ultimately provide for efficient peptide synthesis that is fully reliant on enantioselective methods.

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Figure 1
Figure 2: Amide and peptide synthesis.
Figure 3
Figure 4
Figure 5: Stereoselective peptide synthesis.
Figure 6: Enantioselective peptide synthesis.

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Acknowledgements

This work was supported by the Vanderbilt Institute of Chemical Biology, and in part (catalyst preparation and development) by the NIH (GM084333 and Chemistry-Biology Interface training grant T32 GM065086 in support of D.M.M.).

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Authors and Affiliations

  1. Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235-1822, USA,

    Bo Shen, Dawn M. Makley & Jeffrey N. Johnston

  2. Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235-1822, USA,

    Bo Shen, Dawn M. Makley & Jeffrey N. Johnston

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  1. Bo Shen
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  2. Dawn M. Makley
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  3. Jeffrey N. Johnston
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Contributions

The reaction was conceptualized and reduced to practice by B.S. and J.N.J. Experiments were performed by B.S. (mechanism and scope) and D.M.M. (scope). The manuscript was prepared by J.N.J. with input from all coauthors.

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Correspondence to Jeffrey N. Johnston.

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The authors declare no competing financial interests.

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Shen, B., Makley, D. & Johnston, J. Umpolung reactivity in amide and peptide synthesis. Nature 465, 1027–1032 (2010). https://doi.org/10.1038/nature09125

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