Peptidomimetics 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 and .P Frederick Sparling, 1999 .91 Hepatitis C Protocols, edited by Johnson .Y .N Lau, 1998 .81 Tissue Engineering Methods and Protocols, edited by Jeffrey .R Morgan and Martin Yarmush, 1999 .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 and Alan .P Johnson, 1998 .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 II. Therapeutic Applications of Ribozymes, edited by Kevin J. Scanlon, 1998 .01 Herpes Simplex Virus Protocols, edited by .S Moira Brown and Alasdair .R MaeLean. 1998 9. Lectin Methods and Protocols, edited by Jonathan .M Rhodes and Jeremy .D Milton, 1998 8. Helicobacter priori Protocols, edited by Christopher .L Clayton and Harry .L ."7 Mobley, 1997 7. Gene Therapy Protocols, edited by Paul D. Robbins, 1997 6. Molecular Diagnosis of Cancer, edited by Finbarr .E Cotter, 1996 5. Molecular Diagnosis of Genetic Diseases, edited by Rob Elles, 1996 4. Vaccine Protocols, edited yb Andrew Robinson, Graham .H Farrar, and Christopher .N Wiblin, 6991 3. Prion Diseases, edited by Harry .F Baker and Rosalind .M Ridley, 1996 2. Human Cell Culture Protocols, edited by Gareth .E Jones, 1996 .1 Antisense Therapeutics, edited by Sudhir Agrawal, 1996 scitemimoditpeP slocotorP Edited yb Wieslaw M. Kazmierski Glaxo Wellcome, Inc., Research Triangle Park, NC Humana Press ,awotoT weN yesreJ © I999 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permis- sion from the Publisher. Methods in Molecular Medicine MT is a trademark of The Humana Press Inc. All authored papers, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher. This publication is printed on acid-free paper. ANSI Z39.48-1984 (American Standards Institute) Permanence of Paper for Printed Library Materials. Cover illustration: Fig. I from Chapter 22, "A Conformationally Restricted 13-Strand HIV Protease Inhibitor," by Michael C. Hillier and Stephen F. Martin. Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press Inc., provided that the base fee of US $5.00 per copy, plus US $00.25 per page, is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service is: [0-89603-517-4/99 $5.00 + $00.25]. Printed in the United States of America. 01 9 8 7 6 5 4 3 2 1 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