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Umpolung reactivity in amide and peptide synthesis
Open accessAbstract
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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Metadata
- Authors
- Shen, B., Makley, D. M., & Johnston, J. N.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Johnston, Jeffrey N.
- ORCID
- Johnston, Jeffrey N.
- Venue
- Nature
- Published
- 2010-06
- Volume
- 465
- Issue
- 7301
- Pages
- 1027-1032
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2945247
- OpenAlex
- W2094137451
- Cited by
- 318
- References
- 48
- Citations by year
- 2026: 8 · 2025: 21 · 2024: 13 · 2023: 10 · 2022: 11 · 2021: 13 · 2020: 14 · 2019: 14 · 2018: 23 · 2017: 23 · 2016: 25 · 2015: 33 · 2014: 28 · 2013: 21 · 2012: 30
- FWCI
- 10.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Vanderbilt University
- National Institute of General Medical Sciences (T32GM065086, R01GM063557, GM084333, R01GM084333)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Physical Sciences › Chemistry › Organic Chemistry › Advanced Synthetic Organic Chemistry
- Physical Sciences › Chemistry › Organic Chemistry › Asymmetric Synthesis and Catalysis
- Keywords
- umpolung, amide synthesis, peptide synthesis, nitroalkanes, amines, acyl anion equivalents, asymmetric synthesis, C–N bond formation
- MeSH terms
- Alkanes, Amides, Amines, Carbon, Ethane, Glycine, Models, Chemical, Nitro Compounds, Nitrogen, Peptides
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