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June 28, 2010
Volume 88, Number 26
p. 13

New Route To Amide Formation

Organic Synthesis: Unusual reaction has reactive species with reversed polarities

Stu Borman

Polar Opposite
Polar Opposite In conventional amide formation (top row), the acyl donor is electrophilic, and the amine is nucleophilic. Polarities are reversed in the Johnston group’s umpolung approach (bottom row).
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A new reaction that uses an atypical starting material to create amide linkages could make it easier to prepare peptides and other amide-containing compounds that have been difficult to make until now. The reaction works completely differently from conventional amide syntheses and provides better enantioselectivities in some cases.

Amides are common functional groups in organic and biological compounds. In the lab, they are typically made by combining the acyl group from a carboxylic acid derivative with an amine, with the elimination of water. Synthetic variations have been devised over the years, but now chemistry professor Jeffrey N. Johnston and coworkers at Vanderbilt University report a reaction that uses α-halonitroalkanes as the acyl source and that is distinct from all the others (Nature 2010, 465, 1027).

In traditional amide synthesis using carboxylic acid derivatives, the acyl source is electrophilic and the amine is nucleophilic. In the new reaction, the reactant polarities are reversed (or umpolung, in German): The acyl source is nucleophilic and the amine is electrophilic. In the halonitroalkane, the halogen and nitro groups enhance the acidity of the acyl-carbon-to-be, which becomes deprotonated and thus nucleophilic. And a reagent halogenates the amine, making it electrophilic.

Johnston and coworkers hypothesize that the reaction proceeds via attack of the nitroalkane’s acyl-carbon-to-be on the amine nitrogen to form a tetrahedral intermediate. Water may then react with the intermediate to yield the amide product. The reaction thus appears to occur by addition of water, whereas traditional amide formation involves loss of water.

The researchers demonstrated the capabilities of the umpolung approach by reacting aryl glycine (acyl source) with amino acids (amine sources) to form amides enantio­selectively. Aryl glycine is prone to base-promoted epimerization (enantiomeric conversion) in traditional amide synthesis, making it difficult to control chirality. But the new reaction does not allow epimerization and thus creates aryl glycine-based amides enantioselectively.

The study “is an outstanding example of how rational design of reactions can shift established conceptual paradigms,” says Claudio Palomo, a specialist in C-heteroatom bond formation at the University of the Basque Country, San Sebastián-Donostia, Spain. “The method appears to be quite general—aromatic amines being an exception—and superior in some difficult situations.”

Whether it would compete with conventional solid-phase peptide synthesis is unclear, as is the availability and safety of the required α-bromonitroalkanes, Palomo says. But, he adds, the approach “definitely opens new opportunities on a transformation of magnificent importance and should at least complement known technologies.”

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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