Umpolung reactivity in amide and peptide synthesis

Shen, Bo; Makley, Dawn M.; Johnston, Jeffrey N.

doi:10.1038/nature09125

Cited by 318Chemical Synthesis and AnalysisAdvanced Synthetic Organic ChemistryAsymmetric Synthesis and Catalysis

Umpolung reactivity in amide and peptide synthesis

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Shen, Bo, Makley, Dawn M., Johnston, Jeffrey N.·2010·Nature

DOI 10.1038/nature09125PMC PMC2945247

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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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Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide
Merrifield, R. B. (1963) · Journal of the American Chemical Society · doi:10.1021/ja00897a025 · Cited by 7,645 · see citing works
Synthesis of Proteins by Native Chemical Ligation
Dawson, P. E., Muir, T. W., Clark‐Lewis, I., & Kent, S. B. H. (1994) · Science · doi:10.1126/science.7973629 · Cited by 4,142 · see citing works
Cell Surface Engineering by a Modified Staudinger Reaction
Saxon, E., & Bertozzi, C. R. (2000) · Science · doi:10.1126/science.287.5460.2007 · Cited by 2,463 · see citing works
Amide bond formation: beyond the myth of coupling reagents
Valeur, E., & Bradley, M. (2008) · Chemical Society Reviews · doi:10.1039/b701677h · Cited by 2,209 · see citing works
Solid Phase Peptide Synthesis
Stewart, J. M. (1976) · Journal of Macromolecular Science Part A - Chemistry · doi:10.1080/00222337608068099 · Cited by 1,770 · see citing works
The Nitro Group in Organic Synthesis
Ono, N. (2001) · Wiley eBooks · doi:10.1002/0471224480 · Cited by 1,622 · see citing works
Direct Synthesis of Amides from Alcohols and Amines with Liberation of H 2
Gunanathan, C., Ben‐David, Y., & Milstein, D. (2007) · Science · doi:10.1126/science.1145295 · Cited by 1,290 · see citing works
Methods of Reactivity Umpolung
Seebàch, D. (1979) · Angewandte Chemie International Edition in English · doi:10.1002/anie.197902393 · Cited by 1,244 · see citing works
Umpolung of the Reactivity of Carbonyl Compounds Through Sulfur-Containing Reagents
Gröbel, B., & Seebàch, D. (1977) · Synthesis · doi:10.1055/s-1977-24412 · Cited by 708 · see citing works
A “Traceless” Staudinger Ligation for the Chemoselective Synthesis of Amide Bonds
Saxon, E., Armstrong, J. I., & Bertozzi, C. R. (2000) · Organic Letters · doi:10.1021/ol006054v · Cited by 681 · see citing works
The Staudinger Ligation—A Gift to Chemical Biology
Köhn, M., & Breinbauer, R. (2004) · Angewandte Chemie International Edition · doi:10.1002/anie.200401744 · Cited by 585 · see citing works
Generation and synthetic applications of 2-lithio-1,3-dithianes
Seebàch, D., & Corey, E. J. (1975) · The Journal of Organic Chemistry · doi:10.1021/jo00890a018 · Cited by 579 · see citing works
Staudinger Ligation: A Peptide from a Thioester and Azide
Nilsson, B. L., Kiessling, L. L., & Raines, R. T. (2000) · Organic Letters · doi:10.1021/ol0060174 · Cited by 533 · see citing works
Amide Synthesis from Alcohols and Amines by the Extrusion of Dihydrogen
Nordstrøm, L. U., Vogt, H., & Madsen, R. (2008) · Journal of the American Chemical Society · doi:10.1021/ja808129p · Cited by 519 · see citing works
Recent Advances in the Catalytic Asymmetric Nitroaldol (Henry) Reaction
Palomo, C., Oiarbide, M., & Laso, A. (2007) · European Journal of Organic Chemistry · doi:10.1002/ejoc.200700021 · Cited by 503 · see citing works
The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K
Gauthier, J. Y., Chauret, N., Cromlish, W. A., Desmarais, S., Duong, L. T., Falgueyret, J., Kimmel, D. B., Lamontagne, S., Léger, S., LeRiche, T., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2007.12.047 · Cited by 479 · see citing works
Copper-Catalyzed Hydrative Amide Synthesis with Terminal Alkyne, Sulfonyl Azide, and Water
Cho, S. H., Yoo, E. J., Bae, I., & Chang, S. (2005) · Journal of the American Chemical Society · doi:10.1021/ja056399e · Cited by 448 · see citing works
Highly Efficient Oxidative Amidation of Aldehydes with Amine Hydrochloride Salts
Yoo, W., & Li, C. (2006) · Journal of the American Chemical Society · doi:10.1021/ja064315b · Cited by 442 · see citing works
Recent synthetic developments in the nitro to carbonyl conversion (Nef reaction)
Ballini, R., & Petrini, M. (2003) · Tetrahedron · doi:10.1016/j.tet.2003.11.016 · Cited by 438 · see citing works
Chemoselective Amide Ligations by Decarboxylative Condensations of N ‐Alkylhydroxylamines and α‐Ketoacids
Bode, J. W., Fox, R. M., & Baucom, K. D. (2006) · Angewandte Chemie International Edition · doi:10.1002/anie.200503991 · Cited by 433 · see citing works
Chiral Proton Catalysis: A Catalytic Enantioselective Direct Aza-Henry Reaction
Nugent, B. M., Yoder, R. A., & Johnston, J. N. (2004) · Journal of the American Chemical Society · doi:10.1021/ja031906i · Cited by 359 · see citing works
Self-citation
Asymmetric synthesis of arylglycines
Williams, R. M., & Hendrix, J. A. (1992) · Chemical Reviews · doi:10.1021/cr00013a007 · Cited by 338 · see citing works
Investigating Cellular Metabolism of Synthetic Azidosugars with the Staudinger Ligation
Saxon, E., Luchansky, S. J., Hang, H. C., Yu, C., Lee, S. C., & Bertozzi, C. R. (2002) · Journal of the American Chemical Society · doi:10.1021/ja027748x · Cited by 309 · see citing works
Unveiling Reliable Catalysts for the Asymmetric Nitroaldol (Henry) Reaction
Palomo, C., Oiarbide, M., & Mielgo, A. (2004) · Angewandte Chemie International Edition · doi:10.1002/anie.200460506 · Cited by 297 · see citing works
Electrophilic amination of carbanions
Erdık, E., & Ay, M. (1989) · Chemical Reviews · doi:10.1021/cr00098a014 · Cited by 294 · see citing works
Practical Synthesis of Amides from In Situ Generated Copper( I ) Acetylides and Sulfonyl Azides
Cassidy, M. P., Raushel, J., & Fokin, V. V. (2006) · Angewandte Chemie International Edition · doi:10.1002/anie.200503805 · Cited by 282 · see citing works
Solid Phase Peptide Synthesis. II. The Synthesis of Bradykinin
Merrifield, R. B. (1964) · Journal of the American Chemical Society · doi:10.1021/ja01056a056 · Cited by 247 · see citing works
Catalytic Enantioselective Aza‐Henry Reactions
Marqués‐López, E., Merino, P., Tejero, T., & Herrera, R. P. (2009) · European Journal of Organic Chemistry · doi:10.1002/ejoc.200801097 · Cited by 204 · see citing works
Asymmetric Catalytic Aza‐Henry Reactions Leading to 1,2‐Diamines and 1,2‐Diaminocarboxylic Acids
Westermann, B. (2003) · Angewandte Chemie International Edition · doi:10.1002/anie.200390071 · Cited by 197 · see citing works
Chemistry of N-bromamines and N-chloramines
Kovacic, P., Lowery, M. K., & Field, K. W. (1970) · Chemical Reviews · doi:10.1021/cr60268a002 · Cited by 192 · see citing works
Oxidative Amide Synthesis and N-Terminal α-Amino Group Ligation of Peptides in Aqueous Medium
Chan, W., Ho, C., Wong, M., & Che, C. (2006) · Journal of the American Chemical Society · doi:10.1021/ja064479s · Cited by 181 · see citing works
A Diastereo- and Enantioselective Synthesis of α-Substituted syn-α,β-Diamino Acids
Singh, A., & Johnston, J. N. (2008) · Journal of the American Chemical Society · doi:10.1021/ja8011808 · Cited by 158 · see citing works
Self-citation
Direct Oxidative Amidation of Aldehydes with Anilines under Mechanical Milling Conditions
Gao, J. Y., & Wang, G. (2008) · The Journal of Organic Chemistry · doi:10.1021/jo800075t · Cited by 149 · see citing works
New Chemistry with Old Functional Groups: On the Reaction of Isonitriles with Carboxylic Acids—A Route to Various Amide Types
Li, X., & Danishefsky, S. J. (2008) · Journal of the American Chemical Society · doi:10.1021/ja800612r · Cited by 147 · see citing works
Chiral Proton Catalysis: Enantioselective Brønsted Acid Catalyzed Additions of Nitroacetic Acid Derivatives as Glycine Equivalents
Singh, A., Yoder, R. A., Shen, B., & Johnston, J. N. (2007) · Journal of the American Chemical Society · doi:10.1021/ja068073r · Cited by 146 · see citing works
Self-citation
N-Heterocyclic Carbene (NHC)-Catalyzed Direct Amidation of Aldehydes with Nitroso Compounds
Wong, F. T., Patra, P. K., Seayad, J., Zhang, Y., & Ying, J. Y. (2008) · Organic Letters · doi:10.1021/ol8004276 · Cited by 108 · see citing works
Bifunctional Asymmetric Catalysis: Amplification of Brønsted Basicity Can Orthogonally Increase the Reactivity of a Chiral Brønsted Acid
Davis, T. A., Wilt, J. C., & Johnston, J. N. (2010) · Journal of the American Chemical Society · doi:10.1021/ja908814h · Cited by 108 · see citing works
Self-citation
Design and Synthesis of Tri-Ring P3 Benzamide-Containing Aminonitriles as Potent, Selective, Orally Effective Inhibitors of Cathepsin K
Palmer, J. T., Bryant, C., Wang, D.-X., Davis, D. E., Setti, E. L., Rydzewski, R. M., Venkatraman, S., Tian, Z., Burrill, L. C., Mendonca, R. V., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm058198r · Cited by 95 · see citing works
A diastereo- and enantioselective synthesis of α-substituted anti-α,β-diaminophosphonic acid derivatives
Wilt, J. C., Pink, M., & Johnston, J. N. (2008) · Chemical Communications · doi:10.1039/b808393b · Cited by 86 · see citing works
Self-citation
Emerging methods in amide- and peptide-bond formation.
Bode, J. W. (2006) · PubMed · Cited by 77 · see citing works
A Formal Enantioselective Acetate Mannich Reaction: The Nitro Functional Group as a Traceless Agent for Activation and Enantiocontrol in the Synthesis of β-Amino Acids
Shen, B., & Johnston, J. N. (2008) · Organic Letters · doi:10.1021/ol801797h · Cited by 73 · see citing works
Self-citation
Practical and efficient synthesis of N-halo compounds
Zhong, Y., Zhou, H., Gauthier, D. R., Lee, J., Askin, D., Dolling, U., & Volante, R. P. (2005) · Tetrahedron Letters · doi:10.1016/j.tetlet.2004.12.088 · Cited by 42 · see citing works
Biomimetic Synthesis of Macrolide/Ketolide Metabolites through a Selective N-Demethylation Reaction
Stenmark, H. G., Brazzale, A., & Ma, Z. (2000) · The Journal of Organic Chemistry · doi:10.1021/jo000055j · Cited by 40 · see citing works
A Tuneable Method for N-Debenzylation of Benzylamino Alcohols
Grayson, E. J., & Davis, B. G. (2005) · Organic Letters · doi:10.1021/ol050624f · Cited by 37 · see citing works
The N ef Reaction
Pinnick, H. W. (1990) · Organic reactions · doi:10.1002/0471264180.or038.03 · Cited by 33 · see citing works
Selective C–N bond oxidation: demethylation of N-methyl group in N-arylmethyl-N-methyl-α-amino esters utilizing N-iodosuccinimide (NIS)
Katoh, T., Watanabe, T., Nishitani, M., Ozeki, M., Kajimoto, T., & Node, M. (2007) · Tetrahedron Letters · doi:10.1016/j.tetlet.2007.11.162 · Cited by 22 · see citing works
The synthesis of bradykinin
Boissonnas, R. A. (1962) · Biochemical Pharmacology · doi:10.1016/0006-2952(62)90214-9 · Cited by 11 · see citing works

Flagged first, then by citations

1 of the 48 references couldn’t be matched to a known paper.

Sorted by citations

Rethinking amide bond synthesis
Pattabiraman, V. R., & Bode, J. W. (2011) · Nature · doi:10.1038/nature10702 · Cited by 2,172 · see citing works
Nonclassical Routes for Amide Bond Formation
de Figueiredo, R. M., Suppo, J., & Campagne, J. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.6b00237 · Cited by 987 · see citing works
Nitro-Mannich Reaction
Noble, A., & Anderson, J. C. (2013) · Chemical Reviews · doi:10.1021/cr300272t · Cited by 369 · see citing works
Industrial-scale manufacturing of pharmaceutical-grade bioactive peptides
Agyei, D., & Danquah, M. K. (2011) · Biotechnology Advances · doi:10.1016/j.biotechadv.2011.01.001 · Cited by 356 · see citing works
A Dual Lewis Base Activation Strategy for Enantioselective Carbene-Catalyzed Annulations
Izquierdo, J., Orue, A., & Scheidt, K. A. (2013) · Journal of the American Chemical Society · doi:10.1021/ja405833m · Cited by 333 · see citing works
Amide Bond Formation Strategies: Latest Advances on a Dateless Transformation
Massolo, E., Pirola, M., & Benaglia, M. (2020) · European Journal of Organic Chemistry · doi:10.1002/ejoc.202000080 · Cited by 296 · see citing works
Vanadium complexes: Recent progress in oxidation catalysis
Sutradhar, M., Martins, L. M. D. R. S., da Silva, M. F. C. G., & Pombeiro, A. J. L. (2015) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2015.01.020 · Cited by 280 · see citing works
Ynamides as Racemization-Free Coupling Reagents for Amide and Peptide Synthesis
Hu, L., Xu, S., Zhao, Z., Yang, Y., Peng, Z., Yang, M., Wang, C., & Zhao, J. (2016) · Journal of the American Chemical Society · doi:10.1021/jacs.6b07230 · Cited by 267 · see citing works
Highly efficient amide synthesis from alcohols and amines by virtue of a water-soluble gold/DNA catalyst.
Wang, Y., Zhu, D., Tang, L., Wang, S.-J., & Wang, Z.-Y. (2011) · Angewandte Chemie · doi:10.1002/anie.201102374 · Cited by 200 · see citing works
Direct Amidation of Carboxylic Acids Catalyzed by ortho-Iodo Arylboronic Acids: Catalyst Optimization, Scope, and Preliminary Mechanistic Study Supporting a Peculiar Halogen Acceleration Effect
Gernigon, N., Al‐Zoubi, R. M., & Hall, D. G. (2012) · The Journal of Organic Chemistry · doi:10.1021/jo3013258 · Cited by 228 · see citing works
Direct Amide Coupling of Non‐activated Carboxylic Acids and Amines Catalysed by Zirconium(IV) Chloride
Lundberg, H., Tinnis, F., & Adolfsson, H. (2012) · Chemistry - A European Journal · doi:10.1002/chem.201104055 · Cited by 201 · see citing works
Achiral Counterion Control of Enantioselectivity in a Brønsted Acid-Catalyzed Iodolactonization
Dobish, M. C., & Johnston, J. N. (2012) · Journal of the American Chemical Society · doi:10.1021/ja301858r · Cited by 196 · see citing works
Self-citation
Marine Algae-Derived Bioactive Peptides for Human Nutrition and Health
Fan, X., Bai, L., Zhu, L., Li, Y., & Zhang, X. (2014) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf502420h · Cited by 172 · see citing works
Modification of N-Terminal α-Amino Groups of Peptides and Proteins Using Ketenes
Chan, A. O., Ho, C., Chong, H.-C., Leung, Y., Huang, J., Wong, M., & Che, C. (2012) · Journal of the American Chemical Society · doi:10.1021/ja208009r · Cited by 169 · see citing works
The Nitro to Carbonyl Conversion (Nef Reaction): New Perspectives for a Classical Transformation
Ballini, R., & Petrini, M. (2015) · Advanced Synthesis & Catalysis · doi:10.1002/adsc.201500008 · Cited by 166 · see citing works
Iron‐Catalyzed Efficient Synthesis of Amides from Aldehydes and Amine Hydrochloride Salts
Ghosh, S. C., Ngiam, J. S. Y., Chai, C. L. L., Seayad, A. M., Dang, T. T., & Chen, A. (2012) · Advanced Synthesis & Catalysis · doi:10.1002/adsc.201200020 · Cited by 155 · see citing works
Amide‐Forming Ligation of Acyltrifluoroborates and Hydroxylamines in Water
Dumas, A. M., Molander, G. A., & Bode, J. W. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201201077 · Cited by 154 · see citing works
Squaramide-Catalyzed Enantioselective Michael Addition of Masked Acyl Cyanides to Substituted Enones
Yang, K. S., Nibbs, A. E., Türkmen, Y. E., & Rawal, V. H. (2013) · Journal of the American Chemical Society · doi:10.1021/ja409012q · Cited by 143 · see citing works
Amide Synthesis by Nickel/Photoredox‐Catalyzed Direct Carbamoylation of (Hetero)Aryl Bromides
Alandini, N., Buzzetti, L., Favi, G., Schulte, T., Candish, L., Collins, K. D., & Melchiorre, P. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202000224 · Cited by 141 · see citing works
Rethinking food-derived bioactive peptides for antimicrobial and immunomodulatory activities
Agyei, D., & Danquah, M. K. (2011) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2011.08.010 · Cited by 131 · see citing works
Borate esters as convenient reagents for direct amidation of carboxylic acids and transamidation of primary amides
Starkov, P., & Sheppard, T. D. (2010) · Organic & Biomolecular Chemistry · doi:10.1039/c0ob01069c · Cited by 128 · see citing works
Catalytic, enantioselective synthesis of stilbene cis-diamines: A concise preparation of (−)-Nutlin-3, a potent p53/MDM2 inhibitor
Davis, T. A., & Johnston, J. N. (2011) · Chemical Science · doi:10.1039/c1sc00061f · Cited by 124 · see citing works
Self-citation
One-Pot Synthesis of Amides from Aldehydes and Amines via C–H Bond Activation
Cadoni, R., Porcheddu, A., Giacomelli, G., & Luca, L. D. (2012) · Organic Letters · doi:10.1021/ol302175v · Cited by 124 · see citing works
Facile Synthesis of Sterically Hindered and Electron‐Deficient Secondary Amides from Isocyanates
Schäfer, G., Matthey, C., & Bode, J. W. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201204481 · Cited by 120 · see citing works
Facile Amide Bond Formation from Carboxylic Acids and Isocyanates
Sasaki, K., & Crich, D. (2011) · Organic Letters · doi:10.1021/ol200531k · Cited by 120 · see citing works
Chemical Protein Synthesis by Chemoselective α‐Ketoacid–Hydroxylamine (KAHA) Ligations with 5‐Oxaproline
Pattabiraman, V. R., Ogunkoya, A. O., & Bode, J. W. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201200907 · Cited by 119 · see citing works
Chemoselective Acylation of Primary Amines and Amides with Potassium Acyltrifluoroborates under Acidic Conditions
Gálvez, A. O., Schaack, C., Noda, H., & Bode, J. W. (2017) · Journal of the American Chemical Society · doi:10.1021/jacs.7b00059 · Cited by 109 · see citing works
Direct Amidation of Esters by Ball Milling**
Nicholson, W. I., Barreteau, F., Leitch, J. A., Payne, R., Priestley, I., Godineau, E., Battilocchio, C., & Browne, D. L. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202106412 · Cited by 108 · see citing works
Direct One‐Pot Reductive N‐Alkylation of Nitroarenes by using Alcohols with Supported Gold Catalysts
Tang, C., He, L., Liu, Y., Cao, Y., He, H., & Fan, K. (2011) · Chemistry - A European Journal · doi:10.1002/chem.201100393 · Cited by 105 · see citing works
A protocol for amide bond formation with electron deficient amines and sterically hindered substrates
Due‐Hansen, M. E., Pandey, S. K., Christiansen, E., Andersen, R., Hansen, S. V. F., & Ulven, T. (2015) · Organic & Biomolecular Chemistry · doi:10.1039/c5ob02129d · Cited by 96 · see citing works
MnO2/graphene oxide: a highly active catalyst for amide synthesis from alcohols and ammonia in aqueous media
Nie, R., Shi, J., Xia, S., Lian, S., Chen, P., Hou, Z., & Xiao, F. (2012) · Journal of Materials Chemistry · doi:10.1039/c2jm34652d · Cited by 95 · see citing works
Enantioselective β-Protonation by a Cooperative Catalysis Strategy
Wang, M. H., Cohen, D. T., Schwamb, C. B., Mishra, R. K., & Scheidt, K. A. (2015) · Journal of the American Chemical Society · doi:10.1021/jacs.5b02887 · Cited by 95 · see citing works
Rh(I)-Catalyzed Hydroamidation of Olefins via Selective Activation of N–H Bonds in Aliphatic Amines
Dong, K., Fang, X., Jackstell, R., Laurenczy, G., Li, Y., & Beller, M. (2015) · Journal of the American Chemical Society · doi:10.1021/jacs.5b02218 · Cited by 93 · see citing works
Gold-catalyzed amide synthesis from aldehydes and amines in aqueous medium
Li, G., Kung, K. K., & Wong, M. (2012) · Chemical Communications · doi:10.1039/c2cc17689k · Cited by 91 · see citing works
Rational Design of an Organocatalyst for Peptide Bond Formation
Handoko, H., Satishkumar, S., Panigrahi, N. R., & Arora, P. S. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.9b07742 · Cited by 86 · see citing works
Catalytic Ring Expansion of Cyclic Hemiaminals for the Synthesis of Medium‐Ring Lactams
Zhao, W., Qian, H., Li, Z., & Sun, J. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201504926 · Cited by 85 · see citing works
Ruthenium-Catalyzed Tertiary Amine Formation from Nitroarenes and Alcohols
Feng, C., Liu, Y., Peng, S., Shuai, Q., Deng, G., & LI, C. ‐. (2010) · Organic Letters · doi:10.1021/ol1020527 · Cited by 85 · see citing works
Fast Amide Couplings in Water: Extraction, Column Chromatography, and Crystallization Not Required
Sharma, S., Buchbinder, N. W., Braje, W. M., & Handa, S. (2020) · Organic Letters · doi:10.1021/acs.orglett.0c01676 · Cited by 83 · see citing works
Aldehyde Capture Ligation for Synthesis of Native Peptide Bonds
Raj, M., Wu, H., Blosser, S. L., Vittoria, M. A., & Arora, P. S. (2015) · Journal of the American Chemical Society · doi:10.1021/jacs.5b03538 · Cited by 81 · see citing works
Peroxide-Mediated Transition-Metal-Free Direct Amidation of Alcohols with Nitroarenes
Xiao, F., Liu, Y., Tang, C., & Deng, G. (2012) · Organic Letters · doi:10.1021/ol203211k · Cited by 79 · see citing works
Allenone-Mediated Racemization/Epimerization-Free Peptide Bond Formation and Its Application in Peptide Synthesis
Wang, Z., Wang, X., Wang, P., & Zhao, J. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c04614 · Cited by 78 · see citing works
Efficient synthesis of primary and secondary amides via reacting esters with alkali metal amidoboranes
Guo, Y., Wang, R., Kang, J., Ma, Y., Xu, C., Li, J., & Chen, X. (2021) · Nature Communications · doi:10.1038/s41467-021-25836-5 · Cited by 77 · see citing works
Promising General Solution to the Problem of Ligating Peptides and Glycopeptides
Wang, P., & Danishefsky, S. J. (2010) · Journal of the American Chemical Society · doi:10.1021/ja1084628 · Cited by 75 · see citing works
Practical synthesis of amides from alkynyl bromides, amines, and water
Chen, Z., Jiang, H., Pan, X., & He, Z. (2011) · Tetrahedron · doi:10.1016/j.tet.2011.06.045 · Cited by 75 · see citing works
A versatile biosynthetic approach to amide bond formation
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Direct Amidation of Amino Acid Derivatives Catalyzed by Arylboronic Acids: Applications in Dipeptide Synthesis
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Clickable coupling of carboxylic acids and amines at room temperature mediated by SO 2 F 2 : a significant breakthrough for the construction of amides and peptide linkages
Wang, S., Zhao, C., Zhang, X., & Qin, H. (2019) · Organic & Biomolecular Chemistry · doi:10.1039/c9ob00699k · Cited by 71 · see citing works
Hypervalent iodine catalyzed transamidation of carboxamides with amines
Vanjari, R., Allam, B. K., & Singh, K. N. (2012) · RSC Advances · doi:10.1039/c2ra22459c · Cited by 72 · see citing works
Mechanistic Investigation of the Ruthenium–N‐Heterocyclic‐Carbene‐Catalyzed Amidation of Amines with Alcohols
Makarov, I. S., Fristrup, P., & Madsen, R. (2012) · Chemistry - A European Journal · doi:10.1002/chem.201202400 · Cited by 71 · see citing works
Selective radical amination of aldehydic C(sp 2 )–H bonds with fluoroaryl azides via Co( ii )-based metalloradical catalysis: synthesis of N-fluoroaryl amides from aldehydes under neutral and nonoxidative conditions
Jin, L., Lu, H., Cui, Y. C., Lizardi, C. L., Arzua, T., Wojtas, Ł., Cui, X., & Zhang, X. P. (2014) · Chemical Science · doi:10.1039/c4sc00697f · Cited by 71 · see citing works
Chiral Brønsted Base-Promoted Nitroalkane Alkylation: Enantioselective Synthesis of sec-Alkyl-3-Substituted Indoles
Dobish, M. C., & Johnston, J. N. (2010) · Organic Letters · doi:10.1021/ol1025712 · Cited by 70 · see citing works
Self-citation
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Fu, Z., Lee, J., Kang, B., & Hong, S. H. (2012) · Organic Letters · doi:10.1021/ol302915g · Cited by 69 · see citing works
Visible light photoredox catalysed amidation of carboxylic acids with amines
Srivastava, V., Singh, P. K., & Singh, P. P. (2018) · Tetrahedron Letters · doi:10.1016/j.tetlet.2018.11.050 · Cited by 68 · see citing works
AIBN-initiated metal free amidation of aldehydes using N-chloroamines
Vanjari, R., Guntreddi, T., & Singh, K. N. (2013) · Green Chemistry · doi:10.1039/c3gc41548a · Cited by 67 · see citing works
An Efficient Synthesis of Fluorinated Azaheterocycles by Aminocyclization of Alkenes
Huang, H., Lacy, T. C., Błachut, B., Ortiz, G. X. J., & Wang, Q. (2013) · Organic Letters · doi:10.1021/ol4003866 · Cited by 67 · see citing works
Enantioselective Synthesis of α-Oxy Amides via Umpolung Amide Synthesis
Leighty, M. W., Shen, B., & Johnston, J. N. (2012) · Journal of the American Chemical Society · doi:10.1021/ja306225u · Cited by 67 · see citing works
Self-citation
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Wu, J., & Panek, J. S. (2011) · The Journal of Organic Chemistry · doi:10.1021/jo202119p · Cited by 67 · see citing works
Base-catalyzed synthesis of aryl amides from aryl azides and aldehydes
Xie, S., Zhang, Y., Ramström, O., & Yan, M. (2015) · Chemical Science · doi:10.1039/c5sc03510d · Cited by 65 · see citing works
Choline chloride based eutectic solvent: an efficient and reusable solvent system for the synthesis of primary amides from aldehydes and from nitriles
Patil, U. B., Singh, A. S., & Nagarkar, J. M. (2013) · RSC Advances · doi:10.1039/c3ra43552k · Cited by 65 · see citing works
Copper-catalyzed highly efficient oxidative amidation of aldehydes with 2-aminopyridines in an aqueous micellar system
Patel, O. P., Anand, D., Maurya, R. K., & Yadav, P. P. (2015) · Green Chemistry · doi:10.1039/c5gc00628g · Cited by 65 · see citing works
Insertion of Arynes into N-Halo Bonds: A Direct Approach to o-Haloaminoarenes
Hendrick, C. E., McDonald, S. L., & Wang, Q. (2013) · Organic Letters · doi:10.1021/ol401518c · Cited by 65 · see citing works
Diphenylsilane as a coupling reagent for amide bond formation
Sayes, M., & Charette, A. B. (2017) · Green Chemistry · doi:10.1039/c7gc02643a · Cited by 64 · see citing works
Umpolung strategies for the functionalization of peptides and proteins
White, A. M., Palombi, I. R., & Malins, L. R. (2022) · Chemical Science · doi:10.1039/d1sc06133j · Cited by 63 · see citing works
Highly Efficient Amide Synthesis from Alcohols and Amines by Virtue of a Water‐Soluble Gold/DNA Catalyst
Wang, Y., Zhu, D., Tang, L. J., Wang, S., & Wang, Z. (2011) · Angewandte Chemie · doi:10.1002/ange.201102374 · Cited by 63 · see citing works
Oxidative Amidation of Nitroalkanes with Amine Nucleophiles using Molecular Oxygen and Iodine
Li, J., Lear, M. J., Kawamoto, Y., Umemiya, S., Wong, A. R., Kwon, E., Sato, I., & Hayashi, Y. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201505192 · Cited by 63 · see citing works
Biotechnological production of mono- and diamines using bacteria: recent progress, applications, and perspectives
Wendisch, V. F., Mindt, M., & Pérez‐García, F. (2018) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-018-8890-z · Cited by 63 · see citing works
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Davis, T. A., Vilgelm, A. E., Richmond, A. J., & Johnston, J. N. (2013) · The Journal of Organic Chemistry · doi:10.1021/jo401321a · Cited by 62 · see citing works
Self-citation
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Li, J., Lear, M. J., & Hayashi, Y. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201603399 · Cited by 65 · see citing works
Decrease in speech pause times with treatment of endogenous depression.
Greden, J. F., & Carroll, B. J. (1980) · PubMed · Cited by 62 · see citing works
Oxidation of amine α-carbon to amide: a review on direct methods to access the amide functionality
Nagaraaj, P., & Vijayakumar, V. (2019) · Organic Chemistry Frontiers · doi:10.1039/c9qo00387h · Cited by 61 · see citing works
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Dumas, A. M., Molander, G. A., & Bode, J. W. (2012) · Angewandte Chemie · doi:10.1002/ange.201201077 · Cited by 59 · see citing works
Diboronic Acid Anhydride-Catalyzed Direct Peptide Bond Formation Enabled by Hydroxy-Directed Dehydrative Condensation
Koshizuka, M., Makino, K., & Shimada, N. (2020) · Organic Letters · doi:10.1021/acs.orglett.0c03252 · Cited by 57 · see citing works
Inverse Peptide Synthesis via Activated α‐Aminoesters
Suppo, J., Subra, G., Bergès, M., de Figueiredo, R. M., & Campagne, J. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201402147 · Cited by 58 · see citing works
A New Wave of Amide Bond Formations for Peptide Synthesis
Hollanders, C., Maes, B. U. W., & Ballet, S. (2019) · Synthesis · doi:10.1055/s-0037-1611773 · Cited by 56 · see citing works
N‐Heterocyclic Carbene‐Catalyzed Oxidative Amidation of Aldehydes with Amines
Alanthadka, A., & Maheswari, C. U. (2015) · Advanced Synthesis & Catalysis · doi:10.1002/adsc.201400739 · Cited by 55 · see citing works
Direct oxidative amidation between methylarenes and amines in water
Wang, T., Yuan, L., Zhao, Z., Shao, A., Gao, M., Huang, Y., Xiong, F., Zhang, H., & Zhao, J. (2015) · Green Chemistry · doi:10.1039/c5gc00299k · Cited by 55 · see citing works
Modularly Evolved 2-AminoDMAP/Squaramides as Highly Active Bifunctional Organocatalysts in Michael Addition
Işık, M., Ünver, M. Y., & Tanyeli, C. (2014) · The Journal of Organic Chemistry · doi:10.1021/jo5022597 · Cited by 55 · see citing works
Metal-free pinnick-type oxidative amidation of aldehydes
Goh, K. S., & Tan, C. (2012) · RSC Advances · doi:10.1039/c2ra20773g · Cited by 53 · see citing works
Synthesis of α-Amino Acid Derivatives and Peptides via Enantioselective Addition of Masked Acyl Cyanides to Imines
Yang, K. S., & Rawal, V. H. (2014) · Journal of the American Chemical Society · doi:10.1021/ja510135t · Cited by 52 · see citing works
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Danneman, M. W., Hong, K. B., & Johnston, J. N. (2015) · Organic Letters · doi:10.1021/acs.orglett.5b01177 · Cited by 52 · see citing works
Self-citation
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Ye, Z., Adhikari, S., Xia, Y., & Dai, M. (2018) · Nature Communications · doi:10.1038/s41467-018-03085-3 · Cited by 52 · see citing works
Copper‐Catalyzed Aerobic Oxidative Inert CC and CN Bond Cleavage: A New Strategy for the Synthesis of Tertiary Amides
Chen, X., Chen, T., Li, Q., Zhou, Y., Han, L., & Yin, S. (2014) · Chemistry - A European Journal · doi:10.1002/chem.201403144 · Cited by 51 · see citing works
Chiral proton catalysis of secondary nitroalkane additions to azomethine: synthesis of a potent GlyT1 inhibitor
Davis, T. A., Danneman, M. W., & Johnston, J. N. (2012) · Chemical Communications · doi:10.1039/c2cc32225k · Cited by 51 · see citing works
Self-citation
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Yang, S., Yan, H., Ren, X., Shi, X., Li, J., Wang, Y., & Huang, G. (2013) · Tetrahedron · doi:10.1016/j.tet.2013.05.072 · Cited by 50 · see citing works
Direct amidation from alcohols and amines through a tandem oxidation process catalyzed by heterogeneous-polymer-incarcerated gold nanoparticles under aerobic conditions.
Soulé, J.-F., Miyamura, H., & Kobayashi, S. (2013) · Chemistry - An Asian Journal · doi:10.1002/asia.201300733 · Cited by 37 · see citing works
Organocatalytic, Diastereo- and Enantioselective Synthesis of Nonsymmetric cis -Stilbene Diamines: A Platform for the Preparation of Single-Enantiomer cis -Imidazolines for Protein–Protein Inhibition
Vara, B., Mayasundari, A., Tellis, J. C., Danneman, M. W., Arredondo, V., Davis, T. A., Min, J., Finch, K. E., Guy, R. K., & Johnston, J. N. (2014) · The Journal of Organic Chemistry · doi:10.1021/jo501003r · Cited by 50 · see citing works
Self-citation
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Aspin, S. J., Taillemaud, S., Cyr, P., & Charette, A. B. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201606120 · Cited by 50 · see citing works
Copper(II)-Mediated O -Arylation of Protected Serines and Threonines
Khatib, M. E., & Molander, G. A. (2014) · Organic Letters · doi:10.1021/ol5024689 · Cited by 49 · see citing works
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Schwieter, K. E., & Johnston, J. N. (2015) · Chemical Science · doi:10.1039/c5sc00064e · Cited by 48 · see citing works
Self-citation
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Self-citation
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Pérez‐García, F., Jorge, J. M. P., Dreyszas, A., Risse, J. M., & Wendisch, V. F. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.02589 · Cited by 47 · see citing works
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Tokumaru, K., & Johnston, J. N. (2017) · Chemical Science · doi:10.1039/c7sc00195a · Cited by 47 · see citing works
Self-citation
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Ni, S., Huang, G., Yong-hui, C., Wright, J. S., Li, M., & Dang, L. (2021) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2021.214255 · Cited by 46 · see citing works
Copper-catalyzed efficient direct amidation of 2-methylquinolines with amines
Xie, H., Liao, Y., Chen, S., Chen, Y., & Deng, G. (2015) · Organic & Biomolecular Chemistry · doi:10.1039/c5ob00915d · Cited by 45 · see citing works
Umpolung Amide Synthesis Using Substoichiometric N -Iodosuccinimide (NIS) and Oxygen as a Terminal Oxidant
Schwieter, K. E., Shen, B., Shackleford, J. P., Leighty, M. W., & Johnston, J. N. (2014) · Organic Letters · doi:10.1021/ol502089v · Cited by 45 · see citing works
Self-citation
COMU: scope and limitations of the latest innovation in peptide acyl transfer reagents
Subirós‐Funosas, R., Nieto‐Rodriguez, L., Jensen, K. J., & Alberício, F. (2013) · Journal of Peptide Science · doi:10.1002/psc.2517 · Cited by 44 · see citing works
Synthesis of human GLP-1 (7–36) by chemoselective α-ketoacid–hydroxylamine peptide ligation of unprotected fragments
Wu, J. H., Ruiz‐Rodríguez, J., Comstock, J. M., Dong, J. Z., & Bode, J. W. (2011) · Chemical Science · doi:10.1039/c1sc00398d · Cited by 44 · see citing works
nBu4NI-catalyzed unexpected amide bond formation between aldehydes and aromatic tertiary amines
Mai, W., Song, G., Yuan, J., Yang, L., Sun, G., Xiao, Y., Mao, P., & Qu, L. (2013) · RSC Advances · doi:10.1039/c3ra40298c · Cited by 44 · see citing works
General base-tuned unorthodox synthesis of amides and ketoesters with water
Khamarui, S., Maiti, R., & Maiti, D. K. (2014) · Chemical Communications · doi:10.1039/c4cc07961b · Cited by 44 · see citing works
Direct Synthesis of Amides from Coupling of Alcohols and Amines Catalyzed by Ruthenium(II) Thiocarboxamide Complexes under Aerobic Conditions
Sindhuja, E., Ramesh, R., Balaji, S., & Liu, Y. (2014) · Organometallics · doi:10.1021/om500556b · Cited by 44 · see citing works

Authors: Shen, B., Makley, D. M., & Johnston, J. N.
Affiliations: Vanderbilt University (US)
Corresponding author: Johnston, Jeffrey N.
ORCID: Johnston, Jeffrey N.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2010-06
Volume: 465
Issue: 7301
Pages: 1027-1032
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature09125
PMC: PMC2945247
OpenAlex: W2094137451
Cited by: 318
References: 48
Citations by year: 2026: 8 · 2025: 21 · 2024: 13 · 2023: 10 · 2022: 11 · 2021: 13 · 2020: 14 · 2019: 14 · 2018: 23 · 2017: 23 · 2016: 25 · 2015: 33 · 2014: 28 · 2013: 21 · 2012: 30
FWCI: 10.56
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Vanderbilt University
National Institute of General Medical Sciences (T32GM065086, R01GM063557, GM084333, R01GM084333)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Physical Sciences › Chemistry › Organic Chemistry › Advanced Synthetic Organic Chemistry
Physical Sciences › Chemistry › Organic Chemistry › Asymmetric Synthesis and Catalysis
Keywords: umpolung, amide synthesis, peptide synthesis, nitroalkanes, amines, acyl anion equivalents, asymmetric synthesis, C–N bond formation
MeSH terms: Alkanes, Amides, Amines, Carbon, Ethane, Glycine, Models, Chemical, Nitro Compounds, Nitrogen, Peptides

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Umpolung reactivity in amide and peptide synthesis

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