Discovery of competing anaerobic and aerobic pathways in umpolung amide synthesis allows for site-selective amide18O-labeling

The mechanism of umpolung amide synthesis was probed by interrogating potential sources for the oxygen of the product amide carbonyl that emanates from the α-bromo nitroalkane substrate. Using a series of 18O-labeled substrates and reagents, evidence is gathered to advance two pathways from the puta...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-01, Vol.109 (1), p.44-46
Main Authors: Shackleford, Jessica P., Shen, Bo, Johnston, Jeffrey N.
Format: Article
Language:English
Subjects:
Amides
Amines
Carbonates
Isotopes
Isotopic labeling
Ligation
Nitrites
Oxygen
Product labeling
Reagents
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Summary:The mechanism of umpolung amide synthesis was probed by interrogating potential sources for the oxygen of the product amide carbonyl that emanates from the α-bromo nitroalkane substrate. Using a series of 18O-labeled substrates and reagents, evidence is gathered to advance two pathways from the putative tetrahedral intermediate. Under anaerobic conditions, a nitro-nitrite isomerization delivers the amide oxygen from nitro oxygen. The same homolytic nitro-carbon fragmentation can be diverted by capture of the carbon radical intermediate with oxygen gas (O2) to deliver the amide oxygen from O2. This understanding was used to develop a straightforward protocol for the preparation of 18O-labeled amides in peptides by simply performing the umpolung amide synthesis reaction under an atmosphere of 18O2.
ISSN:0027-8424