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Side Reactions in Peptide Synthesis - 1st Edition - ISBN: 9780128010099, 9780128011812

Side Reactions in Peptide Synthesis

1st Edition

Author: Yi Yang
Hardcover ISBN: 9780128010099
eBook ISBN: 9780128011812
Imprint: Academic Press
Published Date: 1st September 2015
Page Count: 376
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Side Reactions in Peptide Synthesis, based on the author’s academic and industrial experience, and backed by a thorough review of the current literature, provides analysis of, and proposes solutions to, the most frequently encountered side reactions during peptide and peptidomimetic synthesis.

This valuable handbook is ideal for research and process chemists working with peptide synthesis in diverse settings across academic, biotech, and pharmaceutical research and development.

While peptide chemistry is increasingly prevalent, common side reactions and their causes are often poorly understood or anticipated, causing unnecessary waste of materials and delay.

Each chapter discusses common side reactions through detailed chemical equations, proposed mechanisms (if any), theoretical background, and finally, a variety of possible solutions to avoid or alleviate the specified side reaction.

Key Features

  • Provides a systematic examination on how to troubleshoot and minimize the most frequent side reactions in peptide synthesis
  • Gives chemists the background information and the practical tools they need to successfully troubleshoot and improve results
  • Includes optimization-oriented analysis of side reactions in peptide synthesis for improved industrial process development in peptidyl API (active pharmaceutical ingredient) production
  • Answers the growing, global need for improved, replicable processes to avoid impurities and maintain the integrity of the end product.
  • Presents a thorough discussion of critical factors in peptide synthesis which are often neglected or underestimated by chemists
  • Covers solid phase and solution phase methodologies, and provides abundant references for further exploration


Pharmaceutical and process chemists at CMO and CRO companies, research/R&D chemists at universities, institutes,

Table of Contents

  • Dedication
  • Preface
  • Chapter 1: Peptide Fragmentation/Deletion Side Reactions
    • Abstract
    • 1.1. Acidolysis of peptides containing N-Ac-N-alkyl-Xaa motif
    • 1.2. Des-Ser/Thr impurities induced by O-acyl isodipeptide Boc-Ser/Thr(Fmoc-Xaa)-OH as building block for peptide synthesis
    • 1.3. Acidolysis of -N-acyl-N-alkyl-Aib-Xaa- bond
    • 1.4. Acidolysis of -Asp-Pro- bond
    • 1.5. Autodegradation of peptide N-terminal H-His-Pro-Xaa- moiety
    • 1.6. Acidolysis of the peptide C-terminal N-Me-Xaa
    • 1.7. Acidolysis of peptides with N-terminal FITC modification
    • 1.8. Acidolysis of thioamide peptide
    • 1.9. Deguanidination side reaction on Arg
    • 1.10. DKP (2,5-diketopiperazine) formation
  • Chapter 2: β-Elimination Side Reactions
    • Abstract
    • 2.1. β-Elimination of Cys sulfhydryl side chain
    • 2.2. β-Elimination of phosphorylated Ser/Thr
  • Chapter 3: Peptide Global Deprotection/Scavenger-Induced Side Reactions
    • Abstract
    • 3.1. Tert-butylation side reaction on Trp during peptide global deprotection
    • 3.2. Trp alkylation by resin linker cations during peptide cleavage/global deprotection
    • 3.3. Formation of Trp-EDT and Trp-EDT-TFA adduct in peptide global deprotection
    • 3.4. Trp dimerization side reaction during peptide global deprotection
    • 3.5. Trp reduction during peptide global deprotection
    • 3.6. Cys alkylation during peptide global deprotection
    • 3.7. Formation of Cys-EDT adducts in peptide global deprotection reaction
    • 3.8. Peptide sulfonation in side chain global deprotection reaction
    • 3.9. Premature Acm cleavage off Cys(Acm) and Acm S→ O migration during peptide global deprotection
    • 3.10. Methionine alkylation during peptide side chain global deprotection with DODT as scavenger
    • 3.11. Thioanisole-induced side reactions in peptide side chain global deprotection
  • Chapter 4: Peptide Rearrangement Side Reactions
    • Abstract
    • 4.1. Acid catalyzed acyl NO migration and the subsequent peptide acidolysis
    • 4.2. Base catalyzed acyl O→N migration
    • 4.3. His-Nim- induced acyl migration
  • Chapter 5: Side Reactions Upon Amino Acid/Peptide Carboxyl Activation
    • Abstract
    • 5.1. Formation of N-acylurea upon peptide/amino acid-carboxyl activation by DIC
    • 5.2. Uronium/Guanidinium salt coupling reagents-induced amino group guanidination side reactions
    • 5.3. δ-lactam formation upon Arg activation reaction
    • 5.4. NCA formation upon Boc/Z-Amino acid activation
    • 5.5. Dehydration of side chain-unprotected Asn/Gln during carboxyl-activation
    • 5.6. Formation of H-β-Ala-OSu from HOSu-carbodiimide reaction during amino acid carboxyl-activation
    • 5.7. Benzotriazinone ring opening and peptide chain termination during carbodiimide/HOOBt mediated coupling reactions
    • 5.8. Peptide chain termination through the formation of peptide N-terminal urea in CDI-mediated coupling reaction
    • 5.9. Guanidino or hydantoin-2-imide formation from carbodiimide and Nα group on amino acid/peptide
    • 5.10. Side reactions-induced by curtius rearrangement on peptide acyl azide
    • 5.11. Formation of pyrrolidinamide-induced by pyrrolidine impurities in phosphonium salt
  • Chapter 6: Intramolecular Cyclization Side Reactions
    • Abstract
    • 6.1. Aspartimide formation
    • 6.2. Asn/Gln deamidation and other relevant side reactions
    • 6.3. Pyroglutamate formation
    • 6.4. Hydantoin formation
    • 6.5. Side reactions on N-terminal Cys(Cam) and N-bromoacetylated peptide
  • Chapter 7: Side Reactions on Amino Groups in Peptide Synthesis
    • Abstract
    • 7.1. Nα-acetylation side reactions
    • 7.2. Trifluoroacetylation side reactions
    • 7.3. Formylation side reactions
    • 7.4. Peptide N-alkylation side reactions
    • 7.5. Side reactions during amino acid Nα-protection (Fmoc-OSu induced Fmoc-β-Ala-OH and Fmoc-β-Ala-AA-OH dipeptide formation)
  • Chapter 8: Side Reactions on Hydroxyl and Carboxyl Groups in Peptide Synthesis
    • Abstract
    • 8.1. Side reactions on Asp/Glu side chain and peptide backbone carboxylate
    • 8.2. Side reactions on Ser/Thr side chain hydroxyl groups
  • Chapter 9: Peptide Oxidation/Reduction Side Reactions
    • Abstract
    • 9.1. Oxidation side reactions on Cys
    • 9.2. Oxidation side reactions on Met
    • 9.3. Oxidation side reactions on Trp
    • 9.4. Oxidation side reactions on other amino acids and AT nonsynthetic steps
    • 9.5. Peptide reduction side reactions
  • Chapter 10: Redundant Amino Acid Coupling Side Reactions
    • Abstract
    • 10.1. Dipeptide formation during amino acid Nα-Fmoc derivatization
    • 10.2. Redundant amino acid coupling via premature Fmoc deprotection
    • 10.3. Redundant amino acid coupling induced by NCA formation
    • 10.4. His-Nim promoted Gly redundant incorporation
    • 10.5. Redundant coupling induced by the undesired amino acid-CTC resin cleavage
    • 10.6. Redundant amino acid coupling induced by insufficient resin rinsing
    • 10.7. Redundant amino acid coupling induced by overacylation side reaction
  • Chapter 11: Peptide Racemization
    • Abstract
    • 11.1. Peptide racemization mechanism
    • 11.2. Racemization in peptide synthesis
    • 11.3. Strategies to suppress racemization in peptide synthesis
  • Chapter 12: Side Reactions in Peptide Phosphorylation
    • Abstract
    • 12.1. Formation of H-phosphonate side product
    • 12.2. Formation of pyrophosphate side product
  • Chapter 13: Cys Disulfide-Related Side Reactions in Peptide Synthesis
    • Abstract
    • 13.1. Disulfide scrambling via thiol-disulfide exchange
    • 13.2. Disulfide degradation and consequent trisulfide and lanthionine formation
  • Chapter 14: Solvent-Induced Side Reactions in Peptide Synthesis
    • Abstract
    • 14.1. DCM-induced side reaction
    • 14.2. DMF-induced side reaction
    • 14.3. Methanol/ethanol-induced side reactions
    • 14.4. Acetonitrile-induced side reaction
    • 14.5. Acetone-induced side reaction
    • 14.6. MTBE-induced side reaction
    • 14.7. TFE-induced side reaction
  • Appendix I: Molecular Weight Deviation of Peptide Impurity
  • Appendix II: List of Abbreviations
  • Subject Index


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© Academic Press 2016
1st September 2015
Academic Press
Hardcover ISBN:
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About the Author

Yi Yang

Yi Yang began researching peptide synthesis in 2003, and obtained his doctoral degree at Bielefeld University, Germany in 2008. Dr. Yang worked for three years at Lonza AG, Visp, Switzerland as R&D and Process Peptide Chemist, participated in multi cGMP peptidyl API production at Lonza, which is regarded as one of the largest peptide contract manufacturing organization (CMO) in the world, serving pharmaceutical companies. He is currently the Senior Research Scientist of Chemical Development, Global Pharmaceutical R&D, Ferring Pharmaceuticals A/S, Copenhagen, Denmark. Dr. Yang’s experience with a wide variety of peptide side reactions, from both practical and theoretical aspects, is ideal for this publication.

Affiliations and Expertise

PhD, Senior Research Scientist, Chemical Development, Global Pharmaceutical R&D, Ferring Pharmaceuticals A/S, Copenhagen, Denmark

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