Chapter
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
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
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
4.1 - Acid catalyzed acyl N→O 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
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 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
Chapter 6 - Intramolecular Cyclization Side Reactions
6.1 - Aspartimide formation
6.1.1 - Factors That Influence Aspartimide Formation
6.1.1.3 - Protecting Groups on Asp Side Chain Carboxyl Group
6.1.1.4 - Solid Support for Peptide Synthesis
6.1.1.7 - Peptide Sequence
6.1.1.8 - Peptide Conformation
6.1.2 - Solutions for Aspartimide Formation
6.1.2.1 - Protecting Groups on β-Carboxyl Group of Asp
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 β-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
6.2.2.2 - 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
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-β-Ala-OH and Fmoc-β-Ala-AA-OH dipeptide formation)
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 β-Hydroxyl Groups in Acidic Condition
8.2.2.3 - Acylation Side Reactions on Ser/Thr Side Chain Hydroxyl Groups Induced by Acid-Catalyzed Acyl N→O Migration
8.2.3 - β-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
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
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-Nε-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
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
11.2.1.3 - 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 - α-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
11.3.3.6 - Miscellaneous Coupling Reagents
11.3.4 - Coupling Tactics
11.3.4.2 - Natural Chemical Ligation
11.3.7 - Amino Acid Activation Mode
11.3.9 - Cu(II) Salt Additive
Chapter 12 - Side Reactions in Peptide Phosphorylation
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
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
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
Appendix I - Molecular Weight Deviation of Peptide Impurity
Appendix II - List of Abbreviations
Side Reactions in Peptide Synthesis
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