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Rethinking amide bond synthesis


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.


  1. 1

    Arthur, G. The Amide Linkage: Selected Structural Aspects in Chemistry, Biochemistry, and Materials Science (Wiley-Interscience, 2000)

    Google Scholar 

  2. 2

    Wieland, T. & Bodanszky, M. The World of Peptides: A Brief History of Peptide Chemistry (Springer, 1991)

    Google Scholar 

  3. 3

    Schmeing, T. M. & Ramakrishnan, V. What recent ribosome structures have revealed about the mechanism of translation. Nature 461, 1234–1242 (2009)

    ADS  CAS  Google Scholar 

  4. 4

    Coin, I., Beyermann, M. & Bienert, M. Solid-phase peptide synthesis: from standard procedures to the synthesis of difficult sequences. Nature Protocols 2, 3247–3256 (2007)

    CAS  PubMed  Google Scholar 

  5. 5

    Constable, D. J. C. et al. Key green chemistry research areas — a perspective from pharmaceutical manufacturers. Green Chem. 9, 411–420 (2007)

    CAS  Google Scholar 

  6. 6

    Roughley, S. D. & Jordan, A. M. The medicinal chemist’s toolbox: an analysis of reactions used in the pursuit of drug candidates. J. Med. Chem. 54, 3451–3479 (2011)

    CAS  PubMed  Google Scholar 

  7. 7

    Merrifield, R. B. Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. J. Am. Chem. Soc. 85, 2149–2154 (1963)Seminal paper describing the concept and utility of solid-phase peptide synthesis.

    CAS  Google Scholar 

  8. 8

    Dawson, P. E., Muir, T. W., Clarklewis, I. & Kent, S. B. H. Synthesis of proteins by native chemical ligation. Science 266, 776–779 (1994)Seminal paper describing the concept of native chemical ligation for protein synthesis.

    ADS  CAS  PubMed  Google Scholar 

  9. 9

    Pentelute, B. L., Gates, Z. P., Dashnau, J. L., Vanderkooi, J. M. & Kent, S. B. H. Mirror image forms of snow flea antifreeze protein prepared by total chemical synthesis have identical antifreeze activities. J. Am. Chem. Soc. 130, 9702–9707 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Mandal, K. et al. Racemic crystallography of synthetic protein enantiomers used to determine the X-ray structure of plectasin by direct methods. Protein Sci. 18, 1146–1154 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Torbeev, V. Y. & Kent, S. B. H. Convergent chemical synthesis and crystal structure of a 203 amino acid “covalent dimer” HIV-1 protease enzyme molecule. Angew. Chem. Int. Edn 46, 1667–1670 (2007)The largest fully chemically synthesized protein using native chemical ligation.

    CAS  Google Scholar 

  12. 12

    Marchildon, K. Polyamides – still strong after seventy years. Macromol. React. Eng. 5, 22–54 (2011)

    CAS  Google Scholar 

  13. 13

    Marcelli, T. Mechanistic insights into direct amide bond formation catalyzed by boronic acids: halogens as Lewis bases. Angew. Chem. Int. Edn 49, 6840–6843 (2010)

    CAS  Google Scholar 

  14. 14

    Ishihara, K. Dehydrative condensation catalyses. Tetrahedron 65, 1085–1109 (2009)

    CAS  Google Scholar 

  15. 15

    Ishihara, K., Ohara, S. & Yamamoto, H. 3,4,5-Trifluorobenzeneboronic acid as an extremely active amidation catalyst. J. Org. Chem. 61, 4196–4197 (1996)The first highly active boronic acid catalyst for amide synthesis.

    CAS  PubMed  Google Scholar 

  16. 16

    Tang, P. Boric acid catalyzed amide formation from carboxylic acids and amines: n-benzyl-4-phenylbutyramide. Org. Synth. 81, 262–268 (2005)

    CAS  Google Scholar 

  17. 17

    Al-Zoubi, R. M., Marion, O. & Hall, D. G. Direct and waste-free amidations and cycloadditions by organocatalytic activation of carboxylic acids at room temperature. Angew. Chem. Int. Edn 47, 2876–2879 (2008)

    CAS  Google Scholar 

  18. 18

    Charville, H., Jackson, D., Hodges, G. & Whiting, A. The thermal and boron-catalysed direct amide formation reactions: mechanistically understudied yet important processes. Chem. Commun. 46, 1813–1823 (2010)

    CAS  Google Scholar 

  19. 19

    Bode, J. W. & Sohn, S. S. N-Heterocyclic carbene-catalyzed redox amidations of α-functionalized aldehydes with amines. J. Am. Chem. Soc. 129, 13798–13799 (2007)Details catalytic, redox neutral amide-forming reactions.

    CAS  PubMed  Google Scholar 

  20. 20

    Chiang, P.-C., Kim, Y. & Bode, J. W. Catalytic amide formation with α-hydroxyenones as acylating reagents. Chem. Commun. 4566–4568 (2009)

  21. 21

    Vora, H. U. & Rovis, T. Nucleophilic carbene and HOAt relay catalysis in an amide bond coupling: an orthogonal peptide bond forming reaction. J. Am. Chem. Soc. 129, 13796–13797 (2007)Details an organocatalytic oxidative method for amide formation.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    De Sarkar, S. & Studer, A. Oxidative amidation and azidation of aldehydes by NHC catalysis. Org. Lett. 12, 1992–1995 (2010)

    CAS  PubMed  Google Scholar 

  23. 23

    Allen, C. L. & Williams, J. M. J. Metal-catalysed approaches to amide bond formation. Chem. Soc. Rev. 40, 3405–3415 (2011)

    CAS  PubMed  Google Scholar 

  24. 24

    Ekoue-Kovi, K. & Wolf, C. One-pot oxidative esterification and amidation of aldehydes. Chem. Eur. J. 14, 6302–6315 (2008)

    CAS  PubMed  Google Scholar 

  25. 25

    Tamaru, Y., Yamada, Y. & Yoshida, Z. Direct oxidative transformation of aldehydes to amides by palladium catalysis. Synthesis 474–476 (1983)

  26. 26

    Yoo, W.-J. & Li, C.-J. Highly efficient oxidative amidation of aldehydes with amine hydrochloride salts. J. Am. Chem. Soc. 128, 13064–13065 (2006)

    CAS  PubMed  Google Scholar 

  27. 27

    Gunanathan, C., Ben-David, Y. & Milstein, D. Direct synthesis of amides from alcohols and amines with liberation of H2 . Science 317, 790–792 (2007)First report of the use of ruthenium catalysts for direct coupling of alcohols and amines for amide synthesis.

    ADS  CAS  PubMed  Google Scholar 

  28. 28

    Nordstrøm, L. U., Vogt, H. & Madsen, R. Amide synthesis from alcohols and amines by the extrusion of dihydrogen. J. Am. Chem. Soc. 130, 17672–17673 (2008)

    PubMed  Google Scholar 

  29. 29

    Muthaiah, S. et al. Direct amide synthesis from either alcohols or aldehydes with amines: activity of Ru(II) hydride and Ru(0) complexes. J. Org. Chem. 75, 3002–3006 (2010)

    CAS  PubMed  Google Scholar 

  30. 30

    Chan, W.-K., Ho, C.-M., Wong, M.-K. & Che, C.-M. Oxidative amide synthesis and N-terminal α-amino group ligation of peptides in aqueous medium. J. Am. Chem. Soc. 128, 14796–14797 (2006)

    CAS  PubMed  Google Scholar 

  31. 31

    Shen, B., Makley, D. M. & Johnston, J. N. Umpolung reactivity in amide and peptide synthesis. Nature 465, 1027–1032 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Li, X. & Danishefsky, S. J. New chemistry with old functional groups: on the reaction of isonitriles with carboxylic acids — A route to various amide types. J. Am. Chem. Soc. 130, 5446–5448 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Wu, X. Y., Stockdill, J. L., Wang, P. & Danishefsky, S. J. Total synthesis of cyclosporine: access to N-methylated peptides via isonitrile coupling reactions. J. Am. Chem. Soc. 132, 4098–4100 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Chatterjee, J., Gilon, C., Hoffman, A. & Kessler, H. N-Methylation of peptides: a new perspective in medicinal chemistry. Acc. Chem. Res. 41, 1331–1342 (2008)

    CAS  PubMed  Google Scholar 

  35. 35

    Blake, J. Peptide segment coupling in aqueous-medium – silver ion activation of the thiolcarboxyl group. Int. J. Pept. Protein Res. 17, 273–274 (1981)

    CAS  PubMed  Google Scholar 

  36. 36

    Rosen, T., Lico, I. M. & Chu, D. T. W. A convenient and highly chemoselective method for the reductive acetylation of azides. J. Org. Chem. 53, 1580–1582 (1988)

    CAS  Google Scholar 

  37. 37

    Messeri, T., Sternbach, D. D. & Tomkinson, N. C. O. A novel deprotection/functionalisation sequence using 2,4-dinitrobenzenesulfonamide: Part 1. Tetrahedr. Lett. 39, 1669–1672 (1998)

    CAS  Google Scholar 

  38. 38

    Messeri, T., Sternbach, D. D. & Tomkinson, N. C. O. A novel deprotection/functionalisation sequence using 2,4-dinitrobenzenesulfonamide: Part 2. Tetrahedr. Lett. 39, 1673–1676 (1998)

    CAS  Google Scholar 

  39. 39

    Shangguan, N., Katukojvala, S., Greenberg, R. & Williams, L. J. The reaction of thio acids with azides: a new mechanism and new synthetic applications. J. Am. Chem. Soc. 125, 7754–7755 (2003)

    CAS  PubMed  Google Scholar 

  40. 40

    Yuan, Y., Chen, J., Wan, Q. A., Wilson, R. M. & Danishefsky, S. J. Toward fully synthetic, homogeneous glycoproteins: advances in chemical ligation. Biopolymers 94, 373–384 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Wang, P. & Danishefsky, S. J. Promising general solution to the problem of ligating peptides and glycopeptides. J. Am. Chem. Soc. 132, 17045–17051 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Rao, Y., Li, X. C. & Danishefsky, S. J. Thio FCMA intermediates as strong acyl donors: a general solution to the formation of complex amide bonds. J. Am. Chem. Soc. 131, 12924–12926 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Talan, R. S., Sanki, A. K. & Sucheck, S. J. Facile synthesis of N-glycosyl amides using a N-glycosyl-2,4-dinitrobenzenesulfonamide and thioacids. Carbohydr. Res. 344, 2048–2050 (2009)

    CAS  PubMed  Google Scholar 

  44. 44

    Crich, D., Sana, K. & Guo, S. Amino acid and peptide synthesis and functionalization by the reaction of thioacids with 2,4-dinitrobenzenesulfonamides. Org. Lett. 9, 4423–4426 (2007)

    CAS  PubMed  Google Scholar 

  45. 45

    Crich, D. & Sasaki, K. Reaction of thioacids with isocyanates and isothiocyanates: a convenient amide ligation process. Org. Lett. 11, 3514–3517 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Stephenson, N. A., Zhu, J., Gellman, S. H. & Stahl, S. S. Catalytic transamidation reactions compatible with tertiary amide metathesis under ambient conditions. J. Am. Chem. Soc. 131, 10003–10008 (2009)

    CAS  PubMed  Google Scholar 

  47. 47

    Rohde, H. & Seitz, O. Ligation-desulfurization: a powerful combination in the synthesis of peptides and glycopeptides. Biopolymers 94, 551–559 (2010)

    CAS  PubMed  Google Scholar 

  48. 48

    Blanco-Canosa, J. B. & Dawson, P. E. An efficient Fmoc-SPPS approach for the generation of thioester peptide precursors for use in native chemical ligation. Angew. Chem. Int. Edn 47, 6851–6855 (2008)

    CAS  Google Scholar 

  49. 49

    Fang, G.-M. et al. Protein chemical synthesis by ligation of peptide hydrazides. Angew. Chem. Int. Edn 50, 7645–7649 (2011)

    CAS  Google Scholar 

  50. 50

    Li, X., Lam, H. Y., Zhang, Y. & Chan, C. K. Salicylaldehyde ester-induced chemoselective peptide ligations: enabling generation of natural peptidic linkages at the serine/threonine sites. Org. Lett. 12, 1724–1727 (2010)

    CAS  PubMed  Google Scholar 

  51. 51

    Staudinger, H. & Meyer, J. Über neue organische phosphorverbindungen III. Phosphinmethylenderivate und phosphinimine. Helv. Chim. Acta 2, 635–646 (1919)

    CAS  Google Scholar 

  52. 52

    Bode, J. W., Fox, R. M. & Baucom, K. D. Chemoselective amide ligations by decarboxylative condensations of N-alkylhydroxylamines and α-ketoacids. Angew. Chem. Int. Edn 45, 1248–1252 (2006)Seminal paper describing the principle and application of the α-ketoacid-hydroxylamine ligation reaction.

    CAS  Google Scholar 

  53. 53

    Saxon, E., Armstrong, J. I. & Bertozzi, C. R. A “traceless” Staudinger ligation for the chemoselective synthesis of amide bonds. Org. Lett. 2, 2141–2143 (2000)Describes the development of the Staudinger reaction for peptide ligation.

    CAS  Google Scholar 

  54. 54

    Nilsson, B. L., Kiessling, L. L. & Raines, R. T. Staudinger ligation: a peptide from a thioester and azide. Org. Lett. 2, 1939–1941 (2000)The development of traceless Staudinger ligation.

    CAS  Google Scholar 

  55. 55

    Nilsson, B. L., Hondal, R. J., Soellner, M. B. & Raines, R. T. Protein assembly by orthogonal chemical ligation methods. J. Am. Chem. Soc. 125, 5268–5269 (2003)

    CAS  PubMed  Google Scholar 

  56. 56

    Köhn, M. & Breinbauer, R. The Staudinger ligation — a gift to chemical biology. Angew. Chem. Int. Edn 43, 3106–3116 (2004)

    Google Scholar 

  57. 57

    Kleineweischede, R. & Hackenberger, C. P. R. Chemoselective peptide cyclization by traceless Staudinger ligation. Angew. Chem. Int. Ed 47, 5984–5988 (2008)

    CAS  Google Scholar 

  58. 58

    Medina, S. I., Wu, J. & Bode, J. W. Nitrone protecting groups for enantiopure N-hydroxyamino acids: synthesis of N-terminal peptide hydroxylamines for chemoselective ligations. Org. Biomol. Chem. 8, 3405–3417 (2010)

    CAS  PubMed  Google Scholar 

  59. 59

    Wu, J., Ruiz-Rodriguez, J., Comstock, J. M., Dong, J. Z. & Bode, J. W. Synthesis of human GLP-1 (7–36) by chemoselective α-ketoacid-hydroxylamine peptide ligation of unprotected fragments. Chem. Sci. 2, 1976–1979 (2011)

    CAS  Google Scholar 

  60. 60

    Arora, J. S., Kaur, N. & Phanstiel, O. Chemoselective N-acylation via condensations of N-(benzoyloxy)amines and α-ketophosphonic acids under aqueous conditions. J. Org. Chem. 73, 6182–6186 (2008)

    CAS  PubMed  Google Scholar 

  61. 61

    Carrillo, N., Davalos, E. A., Russak, J. A. & Bode, J. W. Iterative, aqueous synthesis of β3-oligopeptides without coupling reagents. J. Am. Chem. Soc. 128, 1452–1453 (2006)

    CAS  PubMed  Google Scholar 

  62. 62

    Sanki, A. K., Talan, R. S. & Sucheck, S. J. Synthesis of small glycopeptides by decarboxylative condensation and insight into the reaction mechanism. J. Org. Chem. 74, 1886–1896 (2009)

    CAS  PubMed  Google Scholar 

  63. 63

    Hirano, K., Macmillan, D., Tezuka, K., Tsuji, T. & Kajihara, Y. Design and synthesis of a homogeneous erythropoietin analogue with two human complex-type sialyloligosaccharides: combined use of chemical and bacterial protein expression methods. Angew. Chem. Int. Edn 48, 9557–9560 (2009)

    CAS  Google Scholar 

  64. 64

    Aimoto, S., Mizoguchi, N., Hojo, H. & Yoshimura, S. Development of a facile method for polypeptide-synthesis — synthesis of bovine pancreatic trypsin-inhibitor (BPTI). Bull. Chem. Soc. Jpn 62, 524–531 (1989)The early application of the ‘thioester ligation’ method for protein synthesis.

    CAS  Google Scholar 

  65. 65

    Hojo, H. et al. Chemical synthesis of 23 kDa glycoprotein by repetitive segment condensation: a synthesis of MUC2 basal motif carrying multiple O-GalNac moieties. J. Am. Chem. Soc. 127, 13720–13725 (2005)

    CAS  PubMed  Google Scholar 

  66. 66

    Deming, T. J. Synthetic polypeptides for biomedical applications. Prog. Polym. Sci. 32, 858–875 (2007)

    CAS  Google Scholar 

  67. 67

    Rutledge, R. D. & Wright, D. W. Biomineralization: Peptide-mediated Synthesis of Materials (Wiley & Sons, 2009)

    Google Scholar 

  68. 68

    Ouchi, M., Terashima, T. & Sawamoto, M. Transition metal-catalyzed living radical polymerization: toward perfection in catalysis and precision polymer synthesis. Chem. Rev. 109, 4963–5050 (2009)

    CAS  Google Scholar 

  69. 69

    Deming, T. J. Facile synthesis of block copolypeptides of defined architecture. Nature 390, 386–389 (1997)The first organometal initiators for controlled polyamide synthesis.

    ADS  CAS  PubMed  Google Scholar 

  70. 70

    Kramer, J. R. & Deming, T. J. Glycopolypeptides via living polymerization of glycosylated-L-lysine N-carboxyanhydrides. J. Am. Chem. Soc. 132, 15068–15071 (2010)

    CAS  PubMed  Google Scholar 

  71. 71

    Sun, H., Zhang, J., Liu, Q., Yu, L. & Zhao, J. Metal-catalyzed copolymerization of imines and CO: a non-amino acid route to polypeptides. Angew. Chem. Int. Edn 46, 6068–6072 (2007)

    CAS  Google Scholar 

  72. 72

    Bray, B. L. Large-scale manufacture of peptide therapeutics by chemical synthesis. Nature Rev. Drug Discov. 2, 587–593 (2003)

    CAS  Google Scholar 

  73. 73

    Vlieghe, P., Lisowski, V., Martinez, J. & Khrestchatisky, M. Synthetic therapeutic peptides: science and market. Drug Discov. Today 15, 40–56 (2010)

    CAS  PubMed  Google Scholar 

  74. 74

    Marx, V. Roche's fuzeon challenge. Chem. Eng. News 83, 16–17 (2005)

    Google Scholar 

  75. 75

    Ireland, D. C., Clark, R. J., Daly, N. L. & Craik, D. J. Isolation, sequencing, and structure‚ activity relationships of cyclotides. J. Nat. Prod. 73, 1610–1622 (2010)

    CAS  PubMed  Google Scholar 

  76. 76

    Clark, R. J. et al. The engineering of an orally active conotoxin for the treatment of neuropathic pain. Angew. Chem. Int. Edn 49, 6545–6548 (2010)

    CAS  Google Scholar 

  77. 77

    Rodriguez, H., Suarez, M. & Albericio, F. A convenient microwave-enhanced solid-phase synthesis of short chain N-methyl-rich peptides. J. Pept. Sci. 16, 136–140 (2010)

    CAS  PubMed  Google Scholar 

  78. 78

    Rebuffat, S. F. et al. Molecular knots as templates for protein engineering: the story of lasso peptides. J. Pept. Sci. 16, 38 (2010)

    Google Scholar 

  79. 79

    Vincent, P. A. & Morero, R. D. The structure and biological aspects of peptide antibiotic microcin J25. Curr. Med. Chem. 16, 538–549 (2009)

    CAS  PubMed  Google Scholar 

  80. 80

    Knappe, T. A., Linne, U., Robbel, L. & Marahiel, M. A. Insights into the biosynthesis and stability of the lasso peptide capistruin. Chem. Biol. 16, 1290–1298 (2009)

    CAS  PubMed  Google Scholar 

  81. 81

    Kawulka, K. E. et al. Structure of subtilosin A, a cyclic antimicrobial peptide from Bacillus subtilis with unusual sulfur to α-carbon cross-links: formation and reduction of α-thio-α-amino acid derivatives. Biochemistry 43, 3385–3395 (2004)

    CAS  PubMed  Google Scholar 

  82. 82

    Rea, M. C. et al. Thuricin CD, a posttranslationally modified bacteriocin with a narrow spectrum of activity against Clostridium difficile. Proc. Natl Acad. Sci. USA 107, 9352–9357 (2010)

    ADS  CAS  PubMed  Google Scholar 

  83. 83

    Rosengren, K. J. et al. Microcin J25 has a threaded sidechain-to-backbone ring structure and not a head-to-tail cyclized backbone. J. Am. Chem. Soc. 125, 12464–12474 (2003)

    CAS  PubMed  Google Scholar 

  84. 84

    Kumar, K. S. A., Spasser, L., Erlich, L. A., Bavikar, S. N. & Brik, A. Total chemical synthesis of di-ubiquitin chains. Angew. Chem. Int. Edn 49, 9126–9131 (2010)

    CAS  Google Scholar 

  85. 85

    Virdee, S., Ye, Y., Nguyen, D. P., Komander, D. & Chin, J. W. Engineered diubiquitin synthesis reveals Lys29-isopeptide specificity of an OTU deubiquitinase. Nature Chem. Biol. 6, 750–757 (2010)

    CAS  Google Scholar 

  86. 86

    Yang, R., Pasunooti, K. K., Li, F., Liu, X.-W. & Liu, C.-F. Synthesis of K48-linked diubiquitin using dual native chemical ligation at lysine. Chem. Commun. 46, 7199–7201 (2010)

    CAS  Google Scholar 

  87. 87

    Tam, J. P., Yu, Q. & Yang, J.-L. Tandem ligation of unprotected peptides through thiaprolyl and cysteinyl bonds in water. J. Am. Chem. Soc. 123, 2487–2494 (2001)

    CAS  PubMed  Google Scholar 

  88. 88

    Bang, D., Pentelute, B. L. & Kent, S. B. H. Kinetically controlled ligation for the convergent chemical synthesis of proteins. Angew. Chem. Int. Edn 45, 3985–3988 (2006)

    CAS  Google Scholar 

  89. 89

    Zeng, H. & Guan, Z. Direct synthesis of polyamides via catalytic dehydrogenation of diols and diamines. J. Am. Chem. Soc. 133, 1159–1161 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Ryadnov, M. G. & Woolfson, D. N. Self-assembled templates for polypeptide synthesis. J. Am. Chem. Soc. 129, 14074–14081 (2007)

    CAS  PubMed  Google Scholar 

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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.

Corresponding author

Correspondence to Jeffrey W. Bode.

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Pattabiraman, V., Bode, J. Rethinking amide bond synthesis. Nature 480, 471–479 (2011).

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