Side Reactions in Peptide Synthesis

 
 
Academic Press
  • 1. Auflage
  • |
  • erschienen am 1. September 2015
  • |
  • 376 Seiten
 
E-Book | ePUB mit Adobe DRM | Systemvoraussetzungen
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978-0-12-801181-2 (ISBN)
 

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.

  • 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


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.
  • Englisch
  • San Diego
  • |
  • USA
Elsevier Science
  • 15,52 MB
978-0-12-801181-2 (9780128011812)
0128011815 (0128011815)
weitere Ausgaben werden ermittelt
  • Cover
  • Title Page
  • Copyright Page
  • Dedication
  • Contents
  • Preface
  • Chapter 1 - Peptide Fragmentation/Deletion Side Reactions
  • 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
  • References
  • Chapter 2 - ß-Elimination Side Reactions
  • 2.1 - ß-Elimination of Cys sulfhydryl side chain
  • 2.2 - ß-Elimination of phosphorylated Ser/Thr
  • References
  • Chapter 3 - Peptide Global Deprotection/Scavenger-Induced Side Reactions
  • 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
  • References
  • Chapter 4 - Peptide Rearrangement Side Reactions
  • 4.1 - Acid catalyzed acyl NO migration and the subsequent peptide acidolysis
  • 4.2 - Base catalyzed acyl ON migration
  • 4.3 - His-Nim- induced acyl migration
  • References
  • Chapter 5 - Side Reactions Upon Amino Acid/Peptide Carboxyl Activation
  • 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 - d-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-ß-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 Na 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
  • References
  • Chapter 6 - Intramolecular Cyclization Side Reactions
  • 6.1 - Aspartimide formation
  • 6.1.1 - Factors That Influence Aspartimide Formation
  • 6.1.1.1 - Base
  • 6.1.1.2 - Acid
  • 6.1.1.3 - Protecting Groups on Asp Side Chain Carboxyl Group
  • 6.1.1.4 - Solid Support for Peptide Synthesis
  • 6.1.1.5 - Temperature
  • 6.1.1.6 - Solvent
  • 6.1.1.7 - Peptide Sequence
  • 6.1.1.8 - Peptide Conformation
  • 6.1.1.9 - Microwave
  • 6.1.2 - Solutions for Aspartimide Formation
  • 6.1.2.1 - Protecting Groups on ß-Carboxyl Group of Asp
  • 6.1.2.2 - Base
  • 6.1.2.3 - Protection on Backbone Amide and Application of Pseudoproline
  • 6.1.2.4 - N-Hydroxylamine and Phenol Derivatives
  • 6.1.2.5 - Na-Protecting Groups
  • 6.1.2.6 - Fine-Tuning of Asp ß-Carboxyl Activation
  • 6.1.2.7 - Methanolysis of Aspartimide
  • 6.2 - Asn/Gln deamidation and other relevant side reactions
  • 6.2.1 - Mechanism of Asn/Gln Deamidation
  • 6.2.2 - Factors Impacting on Asn/Gln Deamidation
  • 6.2.2.1 - pH Value
  • 6.2.2.2 - Peptide Sequence
  • 6.2.2.3 - Peptide Conformation and Other Factors
  • 6.2.3 - Influences of Asn/Gln Deamidation on Peptide Chemical Synthesis
  • 6.3 - Pyroglutamate formation
  • 6.4 - Hydantoin formation
  • 6.5 - Side reactions on N-terminal Cys(Cam) and N-bromoacetylated peptide
  • References
  • Chapter 7 - Side Reactions on Amino Groups in Peptide Synthesis
  • 7.1 - Na-acetylation side reactions
  • 7.2 - Trifluoroacetylation side reactions
  • 7.3 - Formylation side reactions
  • 7.3.1 - Trp(For)-Induced Peptide Formylation
  • 7.3.2 - Formic Acid-Induced Peptide Formylation
  • 7.3.3 - DMF-Induced Peptide Formylation
  • 7.4 - Peptide N-alkylation side reactions
  • 7.4.1 - Chloromethyl Resin Induced Peptide N-Alkylation Side Reactions
  • 7.4.2 - Peptide N-Alkylation During Deblocking of Na-Urethane Protecting Group
  • 7.4.3 - Peptide N-Alkylation During Global Deprotection
  • 7.4.3.1 - Formaldehyde-Induced Peptide N-Alkylation During Side Chain Global Deprotection
  • 7.4.3.2 - Peptide N-alkylation during Pd(0)-catalyzed N-Alloc deblocking
  • 7.4.4 - N-Alkylation Side Reaction on N-Terminal His via Acetone-Mediated Enamination
  • 7.5 - Side reactions during amino acid Na-protection (Fmoc-OSu induced Fmoc-ß-Ala-OH and Fmoc-ß-Ala-AA-OH dipeptide formation)
  • References
  • Chapter 8 - Side Reactions on Hydroxyl and Carboxyl Groups in Peptide Synthesis
  • 8.1 - Side reactions on Asp/Glu side chain and peptide backbone carboxylate
  • 8.1.1 - Base-Catalyzed Asp/Glu(OBzl) Transesterification Side Reaction During the Loading of Chloromethyl Resin
  • 8.1.2 - Esterification Side Reactions on Asp/Glu During Peptidyl Resin Cleavage and Product Purification
  • 8.2 - Side reactions on Ser/Thr side chain hydroxyl groups
  • 8.2.1 - Alkylation Side Reactions on Ser/Thr Side Chain Hydroxyl Groups
  • 8.2.2 - Acylation Side Reactions on Ser/Thr Side Chain Hydroxyl Groups
  • 8.2.2.1 - Acylation Side Reactions on Ser/Thr Side Chain Hydroxyl Groups During Amino Acid Coupling
  • 8.2.2.2 - Acylation on Ser/Thr ß-Hydroxyl Groups in Acidic Condition
  • 8.2.2.3 - Acylation Side Reactions on Ser/Thr Side Chain Hydroxyl Groups Induced by Acid-Catalyzed Acyl NO Migration
  • 8.2.3 - ß-Elimination Side Reactions on Ser/Thr
  • 8.2.4 - N-Terminal Ser/Thr-Induced Oxazolidone Formation Side Reactions
  • 8.2.5 - Ser/Thr-Induced Retro Aldol Cleavage Side Reaction
  • References
  • Chapter 9 - Peptide Oxidation/Reduction Side Reactions
  • 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
  • References
  • Chapter 10 - Redundant Amino Acid Coupling Side Reactions
  • 10.1 - Dipeptide formation during amino acid Na-Fmoc derivatization
  • 10.2 - Redundant amino acid coupling via premature Fmoc deprotection
  • 10.2.1 - Lys-Ne-Induced Fmoc Premature Cleavage
  • 10.2.2 - Na-Proline-Induced Fmoc Premature Cleavage
  • 10.2.3 - DMF/NMP-Induced Fmoc Premature Cleavage
  • 10.2.4 - Residual Piperidine-Induced Fmoc Premature Cleavage
  • 10.2.5 - DMAP/DIEA-Induced Fmoc Premature Cleavage
  • 10.2.6 - Hydrogenation-Induced Fmoc Premature Cleavage
  • 10.2.7 - Fmoc Deblocking in the Starting Material
  • 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
  • References
  • Chapter 11 - Peptide Racemization
  • 11.1 - Peptide racemization mechanism
  • 11.1.1 - Peptide Racemization via Oxazol-5(4H)-one Formation
  • 11.1.2 - Peptide Racemization via Enolate Formation
  • 11.1.3 - Peptide Racemization via Direct Ha Abstraction
  • 11.1.4 - Peptide Racemization via Aspartimide Formation
  • 11.1.5 - Acid-Catalyzed Peptide Racemization
  • 11.2 - Racemization in peptide synthesis
  • 11.2.1 - Amino Acids with a High Tendency of Racemization in Peptide Synthesis
  • 11.2.1.1 - Histidine
  • 11.2.1.2 - Cysteine
  • 11.2.1.3 - Glycosylated Amino Acid
  • 11.2.1.4 - N-Alkyl Amino Acid and Ca,a-Disubstituted Amino Acid
  • 11.2.1.5 - Aryl Glycine Derivatives
  • 11.2.2 - DMAP-Induced Racemization
  • 11.2.3 - Microwave Irradiation-Induced Racemization
  • 11.2.4 - Racemization During Peptide Segment Condensation
  • 11.3 - Strategies to suppress racemization in peptide synthesis
  • 11.3.1 - Amino Acid Na-Protecting Group
  • 11.3.1.1 - Na-Urethane Protecting Group
  • 11.3.1.2 - Na-Sulfanyl Protecting Group
  • 11.3.1.3 - Na-Sulfonyl Protecting Group
  • 11.3.1.4 - Na-Alkyl Protecting Group
  • 11.3.1.5 - Na,Na-bis Protection Strategy
  • 11.3.1.6 - a-Azido Acid as Synthon of Amino Acid
  • 11.3.2 - Amino Acid Side Chain Protecting Group
  • 11.3.2.1 - Cys Side Chain Protecting Groups
  • 11.3.2.2 - His Side Chain Protecting Groups
  • 11.3.3 - Coupling Reagent
  • 11.3.3.1 - Amino Acid Azides
  • 11.3.3.2 - Amino Acid Halides
  • 11.3.3.3 - Halophosphonium Salts
  • 11.3.3.4 - Uronium Salts
  • 11.3.3.5 - UNCA
  • 11.3.3.6 - Miscellaneous Coupling Reagents
  • 11.3.4 - Coupling Tactics
  • 11.3.4.1 - Pseudoproline
  • 11.3.4.2 - Natural Chemical Ligation
  • 11.3.5 - Solvent
  • 11.3.6 - Base
  • 11.3.7 - Amino Acid Activation Mode
  • 11.3.8 - Temperature
  • 11.3.9 - Cu(II) Salt Additive
  • References
  • Chapter 12 - Side Reactions in Peptide Phosphorylation
  • 12.1 - Formation of H-phosphonate side product
  • 12.2 - Formation of pyrophosphate side product
  • References
  • Chapter 13 - Cys Disulfide-Related Side Reactions in Peptide Synthesis
  • 13.1 - Disulfide scrambling via thiol-disulfide exchange
  • 13.2 - Disulfide degradation and consequent trisulfide and lanthionine formation
  • 13.2.1 - Disulfide Degradation Pattern
  • 13.2.2 - Trisulfide Formation
  • 13.2.3 - Lanthionine Formation
  • References
  • Chapter 14 - Solvent-Induced Side Reactions in Peptide Synthesis
  • 14.1 - DCM-induced side reaction
  • 14.2 - DMF-induced side reaction
  • 14.2.1 - DMF-Induced N-Formylpiperidine Formation
  • 14.2.2 - DMF-Induced Formylation Side Reactions
  • 14.2.3 - DMF-Induced Acid Chloride Formation Side Reactions
  • 14.3 - Methanol/ethanol-induced side reactions
  • 14.3.1 - Methanol-Induced Esterification Side Reactions
  • 14.3.2 - Methanol-Induced N-Alkylation Side Reactions in Catalytic Hydrogenation
  • 14.4 - Acetonitrile-induced side reaction
  • 14.5 - Acetone-induced side reaction
  • 14.6 - MTBE-induced side reaction
  • 14.7 - TFE-induced side reaction
  • References
  • Appendix I - Molecular Weight Deviation of Peptide Impurity
  • Reference
  • Appendix II - List of Abbreviations
  • Subject Index
  • Back Cover

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