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Chapter 1: Fundamentals of Peptide Synthesis 22 Sections 20 Figures 1-01. Chemical and stereochemical nature of amino acids 1-02. Ionic nature of amino acids 1-03. Charged groups in peptides at neutral pH 1-04. Side-chain effects in other amino acids 1-05. General approach to protection and amide-bond formation 1-06. N-Acyl and urethane-forming N-substituents 1-07. Amide-bond formation and the side reaction of oxazolone formation 1-08. Oxazolone formation and nomenclature 1-09. Coupling, 2-alkyl-5(4H)-oxazolone formation and generation of diastereoisomers from activated peptides 1-10. Coupling of N-alkoxycarbonylamino acids without generation of diastereoisomers. Chirally stable 2-alkoxy-5(4H)-oxazolones 1-11. Effects of the nature of the substituents on the amino and carboxyl groups of the residues that are coupled to produce a peptide 1-12. Introduction to carbodiimides and substituted ureas 1-13. Carbodiimide-mediated reactions of N-alkoxycarbonylamino acids 1-14. Carbodiimide-mediated reactions of N-acylamino acids and peptides 1-15. Preformed symmetrical anhydrides of N-alkoxycarbonylamino acids 1-16. Purified symmetrical anhydrides of N-alkoxycarbonylamino acids obtained using a soluble carbodiimide 1-17. Purified 2-alkyl-5(4H)-oxazolones from N-acylamino and N-protected glycylamino acids 1-18. 2-Alkoxy-5(4H)-oxazolones as intermediates in reactions of N-alkoxycarbonylamino acids 1-19. Revision of the central tenet of peptide synthesis 1-20. Strategies for the synthesis of enantiomerically pure peptides 1-21. Abbreviated designations of substituted amino acids and peptides 1-22. The literature and books on peptide synthesis Chapter 2: Methods for the Formation of Peptide Bonds 27 Sections 28 Figures 2-01. Coupling reagents and methods and activated forms 2-02. Peptide-bond formation from carbodiimide-mediated reactions of N-alkoxycarbonylamino acids 2-03. Factors affecting the course of events in carbodiimide-mediated reactions of N-alkoxycarbonylamino acids 2-04. Intermediates and their fate in carbodiimide-mediated reactions of N-alkoxycarbonylamino acids 2-05. Peptide-bond formation from preformed symmetrical anhydrides of N-alkoxycarbonylamino acids 2-06. Peptide-bond formation from mixed anhydrides of N-alkoxycarbonylamino acids 2-07. Alkyl chloroformates and their nomenclature 2-08. Purified mixed anhydrides of N-alkoxycarbonylamino acids and their decomposition to 2-alkoxy-5(4H)-oxazolones 2-09. Peptide-bond formation from activated esters of N-alkoxycarbonylamino acids 2-10. Anchimeric assistance in the aminolysis of activated esters 2-11. On the role of auxiliary nucleophiles. Generation of activated esters 2-12. 1-Hydroxybenzotriazole as an addditive that suppresses N-acylurea formation by protonation of the O-acylisourea 2-13. Peptide-bond formation from azides of N-alkoxycarbonylamino acids 2-14. Peptide-bond formation from chlorides of N-alkoxycarbonylamino acids. N-9-Fluorenylmethoxycarbonylamino-acid chlorides 2-15. Peptide-bond formation from 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-mediated reactions of N-alkoxycarbonylamino acids 2-16. Coupling reagents comprised of an additive linked to a charged atom bearing dialkylamino-substituents and a non-nucleophilic counter-ion 2-17. Peptide-bond formation from benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP)-mediated reactions of N-alkoxycarbonylamino acids. 2-18. Peptide-bond formation from O-benzotriazolyl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU)- and tetrafluoroborate (TBTU)-mediated reactions of N-alkoxycarbonylamino acids 2-19. Pyrrolidino instead of dimethylamino substitutents for the environmental acceptability of phosphonium and carbenium salt-based reagents 2-20. Intermediates and their fate in benzotriazol-1-yl-oxyphosphonium and carbenium salt-mediated reactions 2-21. Couplings using phosphonium and uronium salt-based reagents with 1-hydroxybenzotriazole as additive 2-22. Some tertiary amines used as bases in peptide synthesis 2-23. The applicability of peptide-bond forming reactions to the coupling of Na-protected peptides is dictated by the requirement to avoid epimerization. 5(4H)-Oxazolones from activated peptides 2-24. Methods for coupling Na-protected peptide segments 2-25. On the role of 1-hydroxybenzotriazole as an epimerization suppressant in carbodiimide-mediated reactions 2-26. More on additives. 2-27. An aid to deciphering the constitution of coupling reagents from their abbreviations Chapter 3: Protectors and Methods of Deprotection 20 Sections 26 Figures 3-01. The nature and properties desired of protected amino acids 3-02. Alcohols from which protectors derive and their abbreviated designations 3-03. Deprotection by reduction: hydrogenolysis 3-04. Deprotection by reduction: metal-mediated reactions 3-05. Deprotection by acidolysis: benzyl-based protectors 3-06. Deprotection by acidolysis: tert-butyl-based protectors 3-07. Alkylation due to carbenium ion formation during acidolysis 3-08. Deprotection by acid-catalyzed hydrolysis 3-09. Deprotection by base-catalyzed hydrolysis 3-10. Deprotection by beta-elimination 3-11. Deprotection by beta-elimination: 9-fluorenylmethyl-based protectors 3-12. Deprotection by nucleophilic substitution by hydrazine or alkyl thiols 3-13. Deprotection by palladium-catalyzed allyl transfer 3-14. Protection of amino groups: acylation and dimer formation 3-15. Protection of amino groups: acylation without dimer formation 3-16. Protection of amino groups: tert-butoxycarbonylation 3-17. Protection of carboxyl groups: esterification 3-18. Protection of carboxyl, hydroxyl and sulfhydryl groups: tert-butylation and alkylation 3-19. Protectors sensitized or stabilized to acidolysis 3-20. Protecting group combinations Chapter 4: Chirality in Peptide Synthesis 24 Sections 21 Figures 4-01. Mechanisms of stereomutation: acid-catalyzed enolization 4-02. Mechanisms of stereomutation: base-catalyzed enolization 4-03. Enantiomerization and its avoidance during couplings of Na-alkoxycarbonyl-L-histidine 4-04. Mechanisms of stereomutation: base-catalyzed enolization of oxazolones formed from activated peptides 4-05. Mechanisms of stereomutation: base-induced enolization of oxazolones formed from activated N-alkoxycarbonylamino acids 4-06. Stereomutation and asymmetric induction 4-07. Terminology for designating stereomutation 4-08. Evidence of strereochemical inhomogeneity in synthesized products 4-09. Tests employed to acquire information on stereomutation 4-10. Detection and quantitation of epimeric peptides by nuclear magnetic resonance spectroscopy 4-11. Detection and quantitation of epimeric peptides by high-performance liquid chromatography 4-12. External factors that exert an influence on the extent of stereomutation during coupling 4-13. Constitutional factors that define the extent of stereomutation during coupling: configurations of the reacting residues 4-14. Constitutional factors that define the extent of stereomutation during coupling: the N-substituent of the activated residue or the penultimate residue 4-15. Constitutional factors that define the extent of stereomutation during coupling: the aminolyzing residue and its carboxy substituent 4-16. Constitutional factors that define the extent of stereomutation during coupling: the nature of the activated residue 4-17. Reactions of activated forms of N-alkoxycarbonylamino acids in the presence of tertiary amine 4-18. Implications of oxazolone formation in the couplings of N-alkoxycarbonylamino acids in the presence of tertiary amines 4-19. Enantiomerization in 4-dimethylaminopyridine-assisted reactions of N-alkoxycarbonylamino acids 4-20. Enantiomerization during reactions of activated N-alkoxycarbonylamino acids with amino-acid anions 4-21. Possible origins of diastereomeric impurities in synthesized products 4-22. Options for minimizing epimerization during the coupling of segments 4-23. Methods for determining enantiomeric content 4-24. Determination of enantiomers by analysis of diastereoisomers formed by reaction with a chiral reagent Chapter 5: Solid-Phase Synthesis 24 Sections 23 Figures 5-01. The idea of solid-phase synthesis 5-02. Solid-phase synthesis as developed by Merrifield 5-03. Vessels and equipment for solid-phase synthesis 5-04. A typical protocol for solid-phase synthesis 5-05. Features and requirements of solid-phase synthesis 5-06. Options and considerations for solid-phase synthesis 5-07. Polystyrene resins and solvation in solid-phase synthesis 5-08. Polydimethylacrylamide resin 5-09. Polyethyleneglycol-polystyrene graft polymers 5-10. Terminology and options for anchoring the first residue 5-11. Types of target peptides and anchoring linkages 5-12. Protecting group combinations for solid-phase synthesis 5-13. Features of synthesis using Boc/Bzl chemistry 5-14. Features of synthesis using Fmoc/tBu chemistry 5-15. Coupling reagents and methods for solid-phase synthesis 5-16. Merrifield resin for synthesis of peptides using Boc/Bzl chemistry 5-17. Phenylacetamidomethyl (PAM) resin for synthesis of peptides using Boc/Bzl chemistry 5-18. Benzhydrylamine resin for synthesis of peptide amides using Boc/Bzl chemistry 5-19. Resins and linkers for synthesis of peptides using Fmoc/tBu chemistry 5-20. Resins and linkers for synthesis of peptide amides using Fmoc/tBu chemistry 5-21. Resins and linkers for synthesis of protected peptide acids and amides 5-22. Esterification of Fmoc-amino acids to hydroxyl groups of linker-resins 5-23. 2-Chlorotrityl chloride resin for synthesis using Fmoc/tBu chemistry 5-24. Synthesis of cyclic peptides on solid supports Chapter 6: Reactivity, Protection and Side Reactions 24 Sections 31 Figures 6-01. Protection strategies and implications thereof 6-02. Constitutional factors affecting the reactivity of functional groups 6-03. Constitutional factors affecting the stability of protectors 6-04. The e-amino group of lysine 6-05. The hydroxyl groups of serine and threonine 6-06. Acid-induced O-acylation of side-chain hydroxyls and the O-to-N acyl shift 6-07. The hydroxyl group of tyrosine 6-08. The methylsulfanyl group of methionine 6-09. The indole group of tryptophan 6-10. The imidazole group of histidine 6-11. The guanidino group of arginine 6-12. The carboxyl groups of aspartic and glutamic acids 6-13. Imide formation from substituted dicarboxylic-acid residues 6-14. The carboxamido groups of asparagine and glutamine 6-15. Dehydration of carboxamido groups to cyano groups during activation 6-16. Pyroglutamyl formation from glutamyl and glutaminyl residues 6-17. The sulfhydryl group of cysteine and the synthesis of peptides containing cystine 6-18. Disulfide interchange and its avoidance during the synthesis of peptides containing cystine 6-19. Piperazine-2,5-dione formation from esters of dipeptides 6-20. N-Alkylation during palladium-catalyzed hydrogenolytic deprotection and its synthetic application 6-21. Catalytic transfer hydrogenation and the hydrogenolytic deprotection of sulfur-containing peptides 6-22. Mechanisms of acidolysis and the role of nucleophiles 6-23. Minimization of side reactions during acidolysis 6-24. Trifunctional amino acids with two different protectors Chapter 7: Ventilation of Activated Forms and Coupling Methods 26 Sections 37 Figures 7-01. Notes on carbodiimides and their use 7-02. Cupric ion as additive that eliminates epimerization in carbodiimide-mediated reactions 7-03. Mixed anhydrides: properties and their use 7-04. Secondary reactions of mixed anhydrides: urethane formation 7-05. Decomposition of mixed anhydrides: 2-alkoxy-5(4H)-oxazolone formation and disproportionation 7-06. Activated esters: reactivity 7-07. Preparation of activated esters using carbodiimides and secondary reactions associated therewith 7-08. Other methods for the preparation of activated esters of N-alkoxycarbonylamino acids 7-09. Activated esters: properties and specific uses 7-10. Methods for the preparation of activated esters of protected peptides including alkylthio esters 7-11. Synthesis using N-9-fluorenylmethoxycarbonylamino-acid chlorides 7-12. Synthesis using N-alkoxycarbonylamino-acid fluorides 7-13. Amino-acid N-carboxyanhydrides: preparation and aminolysis 7-14. N-Alkoxycarbonylamino-acid N-carboxyanhydrides 7-15. Decomposition during the activation of Boc-amino acids and consequent dimerization 7-16. Acyl azides and the use of protected hydrazides 7-17. O-Acyl and N-acyl, N'-oxide forms of 1-hydroxybenzotriazole adducts and the uronium and guanidinium forms of coupling reagents 7-18. Phosphonium and uronium/aminium/guanidinium salt-based reagents: properties and their use 7-19. Newer coupling reagents 7-20. To preactivate or not to preactivate. Should that be the question? 7-21. Aminolysis of activated residues by unprotected amino acids or peptides. 7-22. Unusual phenomena relating to couplings of proline 7-23. Enantiomerization of the penultimate residue during coupling of an Na-protected peptide 7-24. Double insertion in reactions of glycine derivatives. Rearrangement of symmetrical anhydrides to peptide-bond substituted dipeptides 7-25. Synthesis of peptides by chemoselective ligation 7-26. Detection and quantitation of activated forms Chapter 8: Miscellaneous 15 Sections 21 Figures 8-01. Enantiomerization of activated N-alkoxycarbonylamino acids and esterified cysteine residues in the presence of base 8-02. Options for preparing N-alkoxycarbonylamino-acid amides and p-nitroanilides 8-03. Options for preparing peptide amides 8-04. Aggregation during peptide-chain elongation and solvents for its minimization 8-05. Alkylation of peptide bonds to decrease aggregation: ortho-hydroxybenzyl-protectors 8-06. Alkylation of peptide bonds to decrease aggregation: oxazolidines and thiazolidines (pseudo-prolines) 8-07. Capping and the purification of peptides 8-08. Synthesis of large peptides in solution 8-09. Synthesis of peptides in kilogram amounts 8-10. Dangers and possible side reactions associated with the use of reagents and solvents 8-11. Organic and other salts in peptide synthesis. 8-12. Reflections on the use of tertiary and other amines 8-13. Monomethylation of amino groups and the synthesis of N-alkoxycarbonyl-N-methylamino acids 8-14. The unusual chiral sensitivity of N-methylamino-acid residues and sensitivity to acid of adjacent peptide bonds 8-15. Reactivity and coupling at N-methylamino-acid residues.
Library of Congress Subject Headings for this publication:
Peptides -- Synthesis.
Peptide Biosynthesis.