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. 2010 Jun 24;465(7301):1027-32.
doi: 10.1038/nature09125.

Umpolung reactivity in amide and peptide synthesis

Bo Shen  1 , Dawn M Makley, Jeffrey N Johnston
Affiliations

Umpolung reactivity in amide and peptide synthesis

Bo Shen et al. Nature. .

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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Figures

Figure 1
Figure 1
Comparison of Component Polarization in Conventional Condensative Amide Synthesis and α-Bromo Nitroalkane-Amine Coupling
Figure 2
Figure 2
Amide and Peptide Synthesis
Figure 3
Figure 3
Mechanistic Hypothesis for Amide Synthesis from an α-Bromo Nitroalkane and Amine
Figure 4
Figure 4
Experiments Designed to Probe Intermediacy of Possible Carbonyl Electrophiles [Ph = phenyl, NIS = N-iodo succinimide, THF = tetrahydrofuran]
Figure 5
Figure 5
Stereoselective Peptide Synthesis [Boc = tert-butoxy carbonyl, Ph = phenyl, NIS = N-iodo succinimide, THF = tetrahydrofuran]
Figure 6
Figure 6
Enantioselective Peptide Synthesis: A Carbonyl Dianion Synthon Approach
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Comment in

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