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  • Review Article
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Rethinking amide bond synthesis

Abstract

One of the most important reactions in organic chemistry—amide bond formation—is often overlooked as a contemporary challenge because of the widespread occurrence of amides in modern pharmaceuticals and biologically active compounds. But existing methods are reaching their inherent limits, and concerns about their waste and expense are becoming sharper. Novel chemical approaches to amide formation are therefore being developed. Here we review and summarize a new generation of amide-forming reactions that may contribute to solving these problems. We also consider their potential application to current synthetic challenges, including the development of catalytic amide formation, the synthesis of therapeutic peptides and the preparation of modified peptides and proteins.

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Figure 1: Chemical structure of amides and the conventional chemical method for amide bond synthesis.
Figure 2: Representation of protein and peptide synthesis by biochemical and chemical methods.
Figure 3: Emerging organocatalytic and metal-catalysed methods for amide synthesis.
Figure 4: Metal-catalysed and oxidative methods for amide synthesis.
Figure 5: Emerging reactions for chemoselective amide bond formation with carboxylic acid, thioacid and amine surrogates.
Figure 6: Methods for chemoselective amide forming ligation for peptides, proteins and glycopeptides.
Figure 7: Established and emerging methods for transition-metal-catalysed polyamide synthesis.
Figure 8: Three-dimensional structures of representative examples for cyclic, knotted and N -methylated peptides.

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Acknowledgements

J.W.B. is grateful for the support of diverse agencies for the development of new methods for amide formation, including the Arnold and Mabel Beckman Foundation, the David and Lucille Packard Foundation, Research Corporation for Science Advancement, the US National Institutes of Health (NIH-NIGMS) and the Swiss National Science Foundation (200021-131957). V.R.P. is supported by an ETH Fellowship. We thank all our past and present co-workers who have contributed to the discovery and development of new amide-forming reactions.

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J.W.B. conceived the outline of this Review; J.W.B. and V.R.P. discussed, planned and wrote it.

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Correspondence to Jeffrey W. Bode.

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Pattabiraman, V., Bode, J. Rethinking amide bond synthesis. Nature 480, 471–479 (2011). https://doi.org/10.1038/nature10702

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