多肽合成副反应 英文【2025|PDF|Epub|mobi|kindle电子书版本百度云盘下载】

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1 Peptide Fragmentation/Deletion Side Reactions1

1.1 Acidolysis of Peptides Containing N-Ac-N-alkyl-Xaa Motif1

1.2 Des-Ser/Thr Impurities Induced by O-acyl Isodipeptide BocSer/Thr（Fmoc-Xaa）-OH as Building Block for Peptide Synthesis3

1.3 Acidolysis of-N-acyl-N-alkyl-Aib-Xaa-Bond6

1.4 Acidolysis of-Asp-Pro-Bond9

1.5 Autodegradation of Peptide N-Terminal H-His-Pro-Xaa-Moiety10

1.6 Acidolysis of the Peptide C-Terminal N-Me-Xaa11

1.7 Acidolysis of Peptides with N-Terminal FITC Modification12

1.8 Acidolysis of Thioamide Peptide14

1.9 Deguanidination Side Reaction on Arg18

1.10 DKP（2，5-Diketopiperazine）Formation22

References28

2 β-Elimination Side Reactions33

2.1 β-Elimination of Cys Sulfhydryl Side Chain33

2.2 β-Elimination of Phosphorylated Ser/Thr37

References41

3 Peptide Global Deprotection/Scavenger-Induced Side Reactions44

3.1 Tert-Butylation Side Reaction on Trp During Peptide Global Deprotection44

3.2 Trp Alkylation by Resin Linker Cations During Peptide Cleavage/Global Deprotection47

3.3 Formation of Trp-EDT and Trp-EDT-TFA Adduct in Peptide Global Deprotection53

3.4 Trp Dimerization Side Reaction During Peptide Global Deprotection55

3.5 Trp Reduction During Peptide Global Deprotection57

3.6 Cys Alkylation During Peptide Global Deprotection58

3.7 Formation of Cys-EDT Adducts in Peptide Global Deprotection Reaction59

3.8 Peptide Sulfonation in Side Chain Global Deprotection Reaction63

3.9 Premature Acm Cleavage Off Cys（Acm）and Acm S→O Migration During Peptide Global Deprotection67

3.10 Methionine Alkylation During Peptide Side Chain Global Deprotection with DODT as Scavenger69

3.11 Thioanisole-Induced Side Reactions in Peptide Side Chain Global Deprotection71

References73

4 Peptide Rearrangement Side Reactions77

4.1 Acid Catalyzed Acyl N→O Migration and the Subsequent Peptide Acidolysis77

4.2 Base Catalyzed Acyl O→N Migration80

4.3 His-Nim-Induced Acyl Migration86

References93

5 Side Reactions Upon Amino Acid/Peptide Carboxyl Activation95

5.1 Formation of N-Acylurea Upon Peptide/Amino Acid-Carboxyl Activation by DIC95

5.2 Uronium/Guanidinium Salt Coupling Reagents-Induced Amino Group Guanidination Side Reactions97

5.3 δ-Lactam Formation Upon Arg Activation Reaction100

5.4 NCA Formation Upon Boc/Z-Amino Acid Activation102

5.5 Dehydration of Side Chain-Unprotected Ash/Gln During Carboxyl-Activation103

5.6 Formation of H-β-Ala-OSu from HOSu-Carbodiimide Reaction During Amino Acid Carboxyl-Activation105

5.7 Benzotriazinone Ring Opening and Peptide Chain Termination During Carbodiimide/HOOBt Mediated Coupling Reactions107

5.8 Peptide Chain Termination Through the Formation of Peptide N-Terminal Urea in CDI-Mediated Coupling Reaction108

5.9 Guanidino or Hydantoin-2-Imide Formation from Carbodiimide and Nα Group on Amino Acid/Peptide110

5.10 Side Reactions-Induced by Curtius Rearrangement on Peptide Acyl Azide110

5.11 Formation of Pyrrolidinamide-Induced by Pyrrolidine Impurities in Phosphonium Salt115

References116

6 Intramolecular Cyclization Side Reactions119

6.1 Aspartimide Formation119

6.1.1 Factors That Influence Aspartimide Formation121

6.1.2 Solutions for Aspartimide Formation127

6.2 Asn/Gln Deamidation and Other Relevant Side Reactions137

6.2.1 Mechanism of Asn/Gln Deamidation137

6.2.2 Factors Impacting on Asn/Gln Deamidation140

6.2.3 Influences of Asn/Gln Deamidation on Peptide Chemical Synthesis142

6.3 Pyroglutamate Formation144

6.4 Hydantoin Formation147

6.5 Side Reactions on N-Terminal Cys（Cam）and N-Bromoacetylated Peptide153

References156

7 Side Reactions on Amino Groups in Peptide Synthesis163

7.1 Nα-Acetylation Side Reactions163

7.2 Trifluoroacetylation Side Reactions166

7.3 Formylation Side Reactions171

7.3.1 Trp（For）-Induced Peptide Formylation172

7.3.2 Formic Acid-Induced Peptide Formylation173

7.3.3 DMF-Induced Peptide Formylation175

7.4 Peptide N-Alkylation Side Reactions179

7.4.1 Chloromethyl Resin Induced Peptide N-Alkylation Side Reactions179

7.4.2 Peptide N-Alkylation During Deblocking of Nα-Urethane Protecting Group180

7.4.3 Peptide N-Alkylation During Global Deprotection183

7.4.4 N-Alkylation Side Reaction on N-Terminal His via Acetone-Mediated Enamination195

7.5 Side Reactions During Amino Acid Nα-Protection（Fmoc-OSu Induced Fmoc-β-Ala-OH and Fmoc-β-Ala-AA-OH Dipeptide Formation）196

References198

8 Side Reactions on Hydroxyl and Carboxyl Groups in Peptide Synthesis203

8.1 Side Reactions on Asp/Glu Side Chain and Peptide Backbone Carboxylate203

8.1.1 Base-Catalyzed Asp/Glu（OBzl）Transesterification Side Reaction During the Loading of Chloromethyl Resin203

8.1.2 Esterification Side Reactions on Asp/Glu Du ring Peptidyl Resin Cleavage and Product Purification204

8.2 Side Reactions on Ser/Thr Side Chain Hydroxyl Groups207

8.2.1 Alkylation Side Reactions on Ser/Thr Side Chain Hydroxyl Groups207

8.2.2 Acylation Side Reactions on Ser/Thr Side Chain Hydroxyl Groups208

8.2.3 β-Elimination Side Reactions on Ser/Thr210

8.2.4 N-Terminal Ser/Thr-Induced Oxazolidone Formation Side Reactions212

8.2.5 Ser/Thr-Induced Retro Aldol Cleavage Side Reaction214

References215

9 Peptide Oxidation/Reduction Side Reactions217

9.1 Oxidation Side Reactions on Cvs217

9.2 Oxidation Side Reactions on Met223

9.3 Oxidation Side Reactions on Trp227

9.4 Oxidation Side Reactions on Other Amino Acids and at Nonsynthetic Steps228

9.5 Peptide Reduction Side Reactions230

References231

10 Redundant Amino Acid Coupling Side Reactions235

10.1 Dipeptide Formation During Amino Acid Nα-Fmoc Derivatization235

10.2 Redundant Amino Acid Coupling via Premature Fmoc Deprotection238

10.2.1 Lvs-Nε-Induced Fmoc Premature Cleavage239

10.2.2 Nα-Proline-Induced Fmoc Premature Cleavage242

10.2.3 DMF/NMP-Induced Fmoc Premature Cleavage245

10.2.4 Residual Piperidine-Induced Fmoc Premature Cleavage246

10.2.5 DMAP/DIEA-Induced Fmoc Premature Cleavage247

10.2.6 Hydrogenation-Induced Fmoc Premature Cleavage248

10.2.7 Fmoc Deblocking in the Starting Material248

10.3 Redundant Amino Acid Coupling Induced by NCA Formation249

10.4 His-Nim Promoted Gly Redundant Incorporation250

10.5 Redundant Coupling Induced by the Undesired Amino Acid-CTC Resin Cleavage250

10.6 Redundant Amino Acid Coupling Induced by Insufficient Resin Rinsing252

10.7 Redundant Amino Acid Coupling Induced by Overacylation Side Reaction253

References254

11 Peptide Racemization257

11.1 Peptide Racemization Mechanism257

11.1.1 Peptide Racemization via Oxazol-5（4H）-one Formation257

11.1.2 Peptide Racemization via Enolate Formation258

11.1.3 Peptide Racemization via Direct Hα Abstraction259

11.1.4 Peptide Racemization via Aspartimide Formation260

11.1.5 Acid-Catalyzed Peptide Racemization260

11.2 Racemization in Peptide Synthesis261

11.2.1 Amino Acids with a High Tendency of Racemization in Peptide Synthesis261

11.2.2 DMAP-Induced Racemization267

11.2.3 Microwave Irradiation-Induced Racemization268

11.2.4 Racemization During Peptide Segment Condensation268

11.3 Strategies to Suppress Racemization in Peptide Synthesis269

11.3.1 Amino Acid Nα-Protecting Group269

11.3.2 Amino Acid Side Chain Protecting Group274

11.3.3 Coupling Reagent276

11.3.4 Coupling Tactics282

11.3.5 Solvent285

11.3.6 Base285

11.3.7 Amino Acid Activation Mode286

11.3.8 Temperature287

11 3.9 Cu（Ⅱ）Salt Additive287

References288

12 Side Reactions in Peptide Phosphorylation293

12.1 Formation of H-Phosphonate Side Product293

12.2 Formation of Pyrophosphate Side Product296

References297

13 Cys Disulfide-Related Side Reactions in Peptide Synthesis299

13.1 Disulfide Scrambling via Thiol-Disulfide Exchange299

13.2 Disulfide Degradation and Consequent Trisulfide and Lanthionine Formation302

13.2.1 Disulfide Degradation Pattern302

13.2.2 Trisulfide Formation303

13.2.3 Lanthionine Formation308

References309

14 Solvent-Induced Side Reactions in Peptide Synthesis311

14.1 DCM-Induced Side Reaction311

14.2 DMF-Induced Side Reaction312

14.2.1 DMF-Induced N-Formylpiperidine Formation312

14.2.2 DMF-Induced Formylation Side Reactions313

14.2.3 DMF-Induced Acid Chloride Formation Side Reactions313

14.3 Methanol/Ethanol-Induced Side Reactions315

14.3.1 Methanol-Induced Esterification Side Reactions315

14.3.2 Methanol-Induced N-Alkylation Side Reactions in Catalytic Hydrogenation315

14.4 Acetonitrile-Induced Side Reaction316

14.5 Acetone-Induced Side Reaction317

14.6 MTBE-Induced Side Reaction319

14.7 TFE-Induced Side Reaction319

References320

Appendix Ⅰ Molecular Weight Deviation of Peptide Impurity323

Appendix Ⅱ List of Abbreviations347

Subject Index353