Table Of ContentPeptidomimetics Protocols
METHODS IN MOLECULAR MEDICINE ~T
II I I IIIIIIII I IIIIII III I IIII II IIII I
John .M ,reklaW SEIRES ROTIDE
29. AND Vaccines: Methods and Protocols, edited by Douglas .B Lowrie and Robert Whalen. 1999
28. Cytotoxic Drug Resistance Mechanisms, edited by Robert Brown and Uta B6ger-Brown, 1999
27. Clinical Applications of Capillary Electrophoresis, edited by Stephen .M Palfrey, 1999
26. Quantitative PCR Protocols, edited by Bernd Kochanowski and Udo Reischl, 1999
25. Drug Targeting, edited by .G .E Francis and Cristina Delgado, 1999
.42 Antiviral Chemotherapy Protocols, edited yb Derek Kinchington and Raymond .F Schinazi, 9991
23. Peptidomimetics Protocols, edited by Wieslaw .M Kazmierski, 1999
22. Neurodegeneration Methods and Protocols, edited by Jean Harry and Hugh A. Tilson, 1999
21. Adenovirus Methods and Protocols, edited by William .S M. Wold, 1999
20. Sexually Transmitted Diseases: Methods and Protocols, edited by Rosanna .W Peeling
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.91 Hepatitis C Protocols, edited by Johnson .Y .N Lau, 1998
.81 Tissue Engineering Methods and Protocols, edited by Jeffrey .R Morgan and
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.71 HIV Protocols, edited by Nelson Michael and Jerome .H Kim. I999
.61 Clinical Applications of PCR, edited by .Y .M Dennis Lo, 1998
.51 Molecular Bacteriology: Protocols and Clinical Applications, edited by Neil Woodford
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.41 Tumor Marker Protocols, edited yb Margaret Hanausek and Zbigniew Walaszek, 8991
.31 Molecular Diagnosis of Infectious Diseases, edited yb odU Reischl, 8991
.21 Diagnostic Virology Protocols, edited by John .R Stephenson and Alan Warnes, 8991
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Edited yb
Wieslaw M. Kazmierski
Glaxo Wellcome, Inc., Research Triangle Park, NC
Humana Press ,awotoT weN yesreJ
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Library of Congress Cataloging in Publication Data
Main entry under title:
Methods in molecular medicine .MT
Peptidomimetics protocols / edited by Wieslaw M. Kazmierski
p. cm. -- (Methods in molecular medicine MT ; v. 23)
Includes index.
ISBN 0-89603-517-4 (alk. paper)
I. Peptides. 2. Amino acids--Synthesis. 3. Heterocyclic chemmmistry. 4. Prodrugs. I.
Kazmierski, Wieslaw M. II. Series.
[DNLM: QU 68P4256 1998]
QD431.P38 1998
615'.19---dc21
DNLM/DLC
for Library of Congress 98-26947
CIP
Preface
Many physiologically important receptors and enzymes are regulated by
their endogenous ligands and inhibitors. Nature chose to utilize these pep-
tides as chemical switches since they can be efficiently synthesized and de-
graded in cells, thus providing an immediate response to a fast changing
environment. Such properties, so critical in cell survival, make peptides less
than ideal drug candidates. Other frequently desired properties in drug mol-
ecules include oral bioavailability, the ability to cross membranes, including the
blood-brain barrier, and sufficient stability for administration 1-2 times a day.
In spite of these obstacles, some natural peptides and proteins are indis-
putably successful medicines and have become drugs of choice. Further ad-
vances in peptide-based pharmaceuticals are critically dependent on both new
delivery methods and new chemical approaches to the conversion of these
molecules to druglike entities. In addition, peptides are also the natural start-
ing points for optimization of their pharamacological and chemical proper-
ties, which may lead to superior drugs. Peptidomimetics Protocols deals with
both aspects of peptide pharmaceuticals, through the tools of modern syn-
thetic and medicinal chemistry. The last decade has witnessed a steady stream
of new synthetic approaches to peptide mimetics, compounds that replace physi-
ologically vulnerable peptide functionalities with chemical modules of in-
creased stability and cellular penetration. The chapters have been written by
both academic and industrial chemists, and focus on the practical synthetic
preparation of peptide mimetics.
The first set of chapters focuses on selected (asymmetric) syntheses of
amino acids. Proline derivatives (Chapter l), cyclopropy! (Chapters 2 and 3),
topographically constrained ~-alkyl derivatives, and cyclic amino acids with
constrained rotation around the Z l and 2Z bonds (Chapters 4 and 5) are supple-
mented by methods leading to allyl (Chapters 1 and 3) and vinyl (Chapter 6)
amino acids amenable for further derivatization.
The next 01 chapters describe the use of a variety of linear and heterocy-
clic scaffolds in place of the peptide backbone, which is often associated with
poor peptide pharmacokinetics. Cyclic scaffold-based turn structures are cov-
vi Preface
ered by Chapters ,7 ,8 and 12-16, whereas linear scaffolds (potentially uti-
lized by protease inhibitors) are described in Chapters 9-11. Chapter 21 pro-
vides chemistry leading to functionalized benzodiazepines, a scaffold found
in many successful drugs, and Chapter 31 focuses on carbohydrate scaffolds
as peptide mimetics. The chemistry of aromatic ethers as conformational con-
straints is explored in Chapter .41
The chemistry in Chapters 17-21 replaces peptides' "Achilles heel"
peptide bonds~with pentacyclic rings (Chapters 71 and 19), olefins and
fluoroolefins (Chapters 12 and ,81 respectively), ~[CH O]ether isoteres (Chap-
ter 20), and ketomethylenes (Chapter 22).
Novel chemistry (Chapters 23-25) allows the transient protection of
charged peptides as neutral prodrugs. Following their uptake by the brain,
peptides are liberated by esterases owing to the chemical instability of the
resulting intermediates.
The final chapters cover those transition-state mimics and reactive "war-
heads" applicable in enzyme inhibitors. Chapters 26, 28, and 29 deliver syn-
thetic methodologies to a variety of potential aspartyl protease amino acid-
and dipeptide-based precursors, whereas Chapter 27 focuses on oxiranes as
cysteine- and serine-protease inhibitors.
It is my hope that Peptidomimetics Protocols will provide both synthetic
procedures for key peptide mimetics and stimulate new ideas. Many of the
chemistries described are amenable to combinatorial techniques.
The work on this volume took place in Research Triangle Park, NC and
Verona, Italy, during my stay there in 1997-1998. I am truly grateful to Gor-
don Hodgson and Tino Rossi, respectively, for their encouragement.
Professor John Walker is to be acknowledged for his bright selection of
Peptidomimetics Protocols as a volume in the Methods ni Molecular Medicine
series, as well as his valuable comments and advice. This book would not be-
come a reality without the hardworking and talented staff of Humana Press"
Thomas L. Lanigan, Fran Lipton, James Geronimo, and many others.
Investigators at more than 27 different laboratories from six countries
contributed chapters to this book. I am truly indebted to all of them for their
professionalism, their adherence to schedules, their enthusiasm, and, most of
all, their high-quality contributions.
Finally, this editor would like to dedicate his work to Maria, Konstantin,
and Christian. Their support and understanding during countless lonely week-
ends and evenings contributed enormously to this volume.
Wieslaw M. Kazmierski
Contents
Preface ............................................................................................................. v
Abstracts .......................................................................................................... xi
Contributors ................................................................................................ xxvii
1 Synthesis and Use of Pseudopeptides Derived from
1,2,4-Oxadiazole-, 1,3,4-Oxadiazole-, and
1,2,4-Triazole-based Dipeptidomimetics
Kristina Luthman, Susanna Borg, and Uli Hacksell .......................... 1
2 Syntheses of FMOC-2,3-Methanoleucine Stereoisomers and
Their Incorporation into Peptidomimetics
Kevin Burgess and Wen Li ................................................................. 25
3 Synthesis of an Esterase-Sensitive Cyclic Prodrug of a Model
Hexapeptide Having Enhanced Membrane Permeability and
Enzymatic Stability Using na Acyloxyalkoxy Promoiety
Sanjeev Gangwar, Giovanni M. Pauletti, Teruna J. Siahaan,
Valentino J. Stella, and Ronald .T Borchardt .............................. 37
4 Synthesis of an Esterase-Sensitive Cyclic Prodrug of a Model
Hexapeptide Having Enhanced Membrane Permeability and
Enzymatic Stability Using a 3-(2'-Hydroxy-4',6'-Dimethylphenyl)-
3,3-Dimethyl Propionic Acid Promoiety
Binghe Wang, Sanjeev Gangwar, Giovanni Pauletti,
Teruna Siahaan, and Ronald .T Borchardt ................................... 53
5 Synthesis of Coumarin-Based, Esterase-Sensitive Cyclic Prodrugs
of Opioid Peptides with Enhanced Membrane Permeability
and Enzymatic Stability
Binghe Wang, Oaxian Shan, Wei Wang, Huijuan Zhang,
Olafur Gudmundsson, and Ronald .T Borchardt ........................ 71
6 Azatides as Peptidomimetics: Solution and Liquid Phase Syntheses
Hyunsoo Han, Juyoung Yoon, and Kim D. Janda ........................... 87
7 Synthesis of Cbz-Protected Ketomethylene Dipeptide isosteres
Robert .V Hoffman and Junhua Tao ................................................ 103
viii Contents
8 (E)-Alkene Peptide Bond Isosteres by Cuprate Opening of
Vinyl Aziridines
Todd .C Henninger and Peter Wipf .................................................. 125
9 Syntheses of Norstatine, stI Analogs, and Dipeptide Isosteres
by Means of matcaL-31 Synthon Method
Iwao Ojima and Francette Delaloge ................................................ 137
01 Synthesis of a Versatile Peptidomimetic Scaffold
Stephen Hanessian and Grant McNaughton-Smith ...................... 161
11 An Asymmetric Synthesis Protocol to Prepare Topographically
Constrained detutitsbuS-31 Aromatic Amino Acids
Subo Liao and Victor J. Hruby ......................................................... 175
21 Synthesis of Oligopeptides Containing an Oxirane Ring ni the
Place of a Peptidic Bond
Maurizio Taddei .................................................................................. 189
31 Synthesis of Protected Lactam-Bridged Dipeptides
Debra .S Perlow and Roger M. Freidinger ...................................... 209
14 Synthesis of Peptidomimics Through Sugar-Based Scaffolds
Yves Le Merrer, L ydie Poitout, and Jean-Claude Depezay .......... 227
15 The Synthesis of Bicyclic Piperazinone and Related
Derivatives
Yvette M. Fobian and Kevin .D Moeller ........................................... 259
61 Synthesis of Dipeptides with ~[CH20 ] Amide Bond Mimetics
Wieslaw M. Kazmierski and Paul .C Fritch ..................................... 281
17 SNAr-Based Cycloetherification Methodology: Application in the
Synthesis of Heterodectic Macrocyclic Peptides with Endo
Aryi-Aryl and Aryt-Alkyi Ether Bonds
Jieping Zhu ......................................................................................... 293
18 Cyclic Aromatic Amino Acids with Constrained ~.7 and 2,X
Dihedral Angles
Oirk Tourwe, Koen Iterbeke, Wieslaw M. Kazmierski,
and Geza Toth ................................................................................ 321
91 Asymmetric Syntheses of Unnatural Amino Acids and
Hydroxyethylene Peptide Isosteres
Robert M. Williams ............................................................................. 339
20 Fluoroolefin Isosteres
J. .T Welch and .T AIImendinger ...................................................... 357
Contents ix
12 Synthesis of 3-Amino-l-CarboxymethyI-Benzodiazepine
(BZA) Peptidomimetics
James C. Marsters, Jr. and Thomas E. Rawson ............................ 385
22 A Conformationally Restricted t3-Strand HIV Protease Inhibitor
Michael C. Hillier and Stephen F. Martin ........................................ 397
23 Synthesis of Cyclopropane-Containing Leu-Enkephalin
Analogs
Michael .P Owyer and Stephen .F Martin ........................................ 407
24 The 1,5-Disubstituted Tetrazole Ring as a cis-Amide
Bond Surrogate
Janusz Zabrocki and Garland R. Marshall ..................................... 417
25 Synthesis of (2R, 3R, 4R, 5S)-5-tert-Butyloxycarbonylamino-
3,4-Dihydroxy-2-1sopropyl-3,4-O,O-Isopropylidene-6-
CyctohexyI-Hexanoic Acid
Allen Scott, Brian G. Conway, and Mark A. Krook ........................ 437
26 Synthesis of (2S, ,S4 5S)-5-(t-Butoxycarbonylamino)-4-
(t-Butyldimethylsilyloxy)-2-1sopropyl-7-Methyl Octanoic Acid
Mark A. L yster and Brian .G Cenway .............................................. 453
27 Synthesis of lyniV-~c Amino Acids
David B. Berkowitz, Jill M. McFadden, Marianne K. Smith,
and Michelle L. Pedersen ............................................................. 467
28 A Novel Synthetic Protocol for the Preparation of Enantiopure
3-, 4-, and 5-Substituted Prolines
.VI Andre Sasaki ................................................................................. 489
29 Synthesis of Aminobenzoic Acid-Based Nonpeptide Templates:
Applications in Peptidomimetic Drug Discovery
Kimberly .S Para and Tomi K. Sawyer ............................................ 513
30 Aminimides as Peptidomimetics
Brian S. Fulton, Alan P. Kaplan, Joseph C. Hogan, Jr.,
and Steven L. Gallion .................................................................... 527
Index ........................................................................................................ 539
