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Amino Acids, Peptides and Proteins in Organic Chemistry, Volume 4, Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis

Amino Acids, Peptides and Proteins in Organic Chemistry, Volume 4, Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis

Andrew B. Hughes (Series Editor)

ISBN: 978-3-527-64157-4

Jun 2011

552 pages



This is the fourth of five books in the Amino Acids, Peptides and Proteins in Organic Synthesis series. 

Closing a gap in the literature, this is the only series to cover this important topic in organic and biochemistry. Drawing upon the combined expertise of the international "who's who" in amino acid research, these volumes represent a real benchmark for amino acid chemistry, providing a comprehensive discussion of the occurrence, uses and applications of amino acids and, by extension, their polymeric forms, peptides and proteins.

The practical value of each volume is heightened by the inclusion of experimental procedures.


The 5 volumes cover the following topics:

Volume 1: Origins and Synthesis of Amino Acids

Volume 2: Modified Amino Acids, Organocatalysis and Enzymes

Volume 3: Building Blocks, Catalysis and Coupling Chemistry

Volume 4: Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis

Volume 5: Analysis and Function of Amino Acids and Peptides


The fourth volume in this series is structured in three main sections. The first section is about protection reactions and amino acid based peptidomimetics. The second, and most extensive, part is devoted to the medicinal chemistry of amino acids. It includes, among others, the chemistry of alpha- and beta amino acids, peptide drugs, and advances in N- and O-glycopeptide synthesis. The final part deals with amino acids in combinatorial synthesis. Methods, such as phage display, library peptide synthesis, and computational design are described.


Originally planned as a six volume series, Amino Acids, Peptides and Proteins in Organic Chemistry now completes with five volumes but remains comprehensive in both scope and coverage.

Further information about the 5 Volume Set and purchasing details can be viewed here.

List of Contributors.

1 Protection Reactions (Vommina V. Sureshbabu and Narasimhamurthy Narendra ).

1.1 General Considerations.

1.2 α-Amino Protection (Nα Protection).

1.3 Carboxy Protection.

1.4 Side-Chain Protection.

1.5 Photocleavable Protections.

1.6 Conclusions.

1.7 Experimental Procedures.


Part One Amino Acid-Based Peptidomimetics.

2 Huisgen Cycloaddition in Peptidomimetic Chemistry (Daniel Sejer Pedersen and Andrew David Abell ).

2.1 Introduction.

2.2 Huisgen [2 + 3] Cycloaddition Between Azides and Acetylenes.

2.3 Mechanistic Consideration for the Cu-Huisgen and Ru-Huisgen Cycloadditions.

2.4 Building Blocks for the Synthesis of Triazole-Modified Peptidomimetics.

2.5 Cyclic Triazole Peptidomimetics.

2.6 Acyclic Triazole Peptidomimetics.

2.7 Useful Experimental Procedures.


3 Recent Advances in ß-Strand Mimetics (Wendy A. Loughlin and David P. Fairlie ).

3.1 Introduction.

3.2 Macrocyclic Peptidomimetics.

3.3 Acyclic Compounds.

3.4 Aliphatic and Aromatic Carbocycles.

3.5 Ligands Containing One Ring with One Heteroatom (N).

3.6 Ligands Containing One or Multiple Rings with One Heteroatom (O, S).

3.7 Ligands Containing One Ring with Two Heteroatoms (N,N).

3.8 Ligands Containing One Ring with Two Heteroatoms (N,S) or Three Heteroatoms (N,N,S or N,N,N).

3.9 Ligands Containing Two Rings with One Heteroatom (N or O).

3.10 Ligands Containing Two Rings with Two or Three Heteroatoms (N,N or N,S or N,N,N).

3.11 Conclusions.


Part Two Medicinal Chemistry of Amino Acids.

4 Medicinal Chemistry of α-Amino Acids (Lennart Bunch and Povl Krogsgaard-Larsen ).

4.1 Introduction.

4.2 Glutamic Acid.

4.3 Conformational Restriction.

4.4 Bioisosterism,

4.5 Structure–Activity Studies.

4.6 Conclusions.


5 Medicinal Chemistry of Alicyclic ß-Amino Acids (Nils Griebenow ).

5.1 Introduction.

5.2 Five-Membered Alicyclic ß-Amino Acids.

5.3 Six-Membered Alicyclic ß-Amino Acids.


6 Medicinal Chemistry of a-Hydroxy-ß-Amino Acids (Zyta Ziora, Mariusz Skwarczynski, and Yoshiaki Kiso ).

6.1 Introduction.

6.2 α-Hydroxy-ß-Amino Acids.

6.3 Antibacterial Agents.

6.4 Inhibitors of Aminopeptidases.

6.5 Aspartyl Proteases Inhibitors.

6.6 Paclitaxel and its Derivatives.


7 Peptide Drugs (Chiara Falciani, Alessandro Pini, and Luisa Bracci ).

7.1 Lights and Shades of Peptide and Protein Drugs.

7.2 Peptide Drugs Available on the Market.

7.3 Approved Peptides in Oncology.

7.4 Antimicrobial peptides.

7.5 Perspectives.


8 Oral Bioavailability of Peptide and Peptidomimetic Drugs (Arik Dahan, Yasuhiro Tsume, Jing Sun, Jonathan M. Miller, and Gordon L. Amidon ).

8.1 Introduction.

8.2 Fundamental Considerations of Intestinal Absorption.

8.3 Barriers Limiting Oral Peptide/Peptidomimetic Drug Bioavailability.

8.4 Strategies to Improve Oral Bioavailability of Peptide-Based Drugs.

8.5 Conclusions.


9 Asymmetric Synthesis of ß-Lactams via the Staudinger Reaction (Monika I. Konaklieva and Balbina J. Plotkin ).

9.1 Introduction.

9.2 Staudinger Reaction.

9.3 Influence of the Geometry of the Imine on Stereoselectivity in the Reaction.

9.4 Influence of the Polarity of the Solvent on Stereoselectivity of the Reaction.

9.5 Influence of the Isomerization of the Imine Prior to its Nucleophilic Attack onto the Ketene Stereoselectivity in the Reaction.

9.6 Influence of the Order of Addition of the Reactants to the Reaction.

9.7 Influence of Chiral Substituents on the Stereoselectivity of the Reaction.

9.8 Asymmetric Induction from the Imine Component.

9.9 Asymmetric Induction from the Ketene Component.

9.10 Double Asymmetric Cycloinduction.

9.11 Influence of Catalysts on the Stereoselectivity of the Reaction.

9.12 Conclusions.


10 Advances in N- and O-Glycopeptide Synthesis – A Tool to Study Glycosylation and Develop New Therapeutics (Ulrika Westerlind and Horst Kunz ).

10.1 Introduction.

10.2 Synthesis of O-Glycopeptides.

10.3 Synthesis of N-Glycopeptides.


11 Recent Developments in Neoglycopeptide Synthesis (Margaret A. Brimble, Nicole Miller, and Geoffrey M. Williams ).

11.1 Introduction.

11.2 Neoglycoside and Neoglycopeptide Synthesis.

11.3 Protein Side-Chain Modifications.

11.4 Cu(I)-Catalyzed Azide–Alkyne ‘‘Click’’ Cycloaddition.

11.5 Cross-Metathesis.

11.6 Application of Neoglycopeptides as Synthetic Vaccines.

11.7 Enzymatic, Molecular, and Cell Biological Techniques.


Part Three Amino Acids in Combinatorial Synthesis.

12 Combinatorial/Library Peptide Synthesis (Michal Lebl ).

12.1 Introduction.

12.2 High-Throughput Synthesis of Peptides.

12.3 Synthesis of Peptide Arrays.

12.4 Peptide Libraries.

12.5 Future of Peptide Libraries.

12.6 Synthetic Protocols.


13 Phage-Displayed Combinatorial Peptides (Renhua Huang, Kritika Pershad, Malgorzata Kokoszka, and Brian K. Kay ).

13.1 Introduction.

13.2 Conclusions.


14 Designing New Proteins (Michael I. Sadowski and James T. MacDonald ).

14.1 Introduction.

14.2 Protein Design Methods.

14.3 Protocol for Protein Design.

14.4 Conclusions.


15 Amino Acid-Based Dendrimers (Zhengshuang Shi, Chunhui Zhou, Zhigang Liu, Filbert Totsingan, and Neville R. Kallenbach ).

15.1 Introduction.

15.2 Peptide Dendrimer Synthesis: Divergent and Convergent Approaches.

15.3 Applications of Peptide Dendrimers.

15.4 Conclusions.