Dr Beat Ernst CIDA CH-4002 Basel, Switzerland Prof Dr Christian Leumann Institut fur Organische Chemie Universitat Bern Freiestrasse CH-3012 Bern, Switzerland This book was carefuliy produced Nevertheless, editor and publisher not warrant the information contained therein to be free of errors Readers are advised to keep in mind that statements, data, illustrations, procedural details, or other items may inadvertently be inaccurate Published jointly by VHCA,Veriag Helvetica Chimica Acta, Basel (Switzerland) VCH Verlagsgeselischaft mbH, Weinheim (Federal Republic of Germany) VCH Publishers, Inc., New York, NY (USA) Editorial Director: Dr M Volkan Kisakiirek Production Manager: Jakob Schiipfer Cover Design: Bruckmann EtPartner, Basel ~ Library of Congress Card No applied for A CIP catalogue record for this book is available from the British Library Deutsche Bibliothek Cataloguing-in-Publication Data: Modern synthetic methods [Basei]: VHCA.Verlag Helvetica Chimica Acta; Weinheim: VHC Erscheint unregelmassig - Erhielt friiher Einzelbd.-Aufnahmen - Aufnahmen nach Vol (1992) Vol 7, 1995 © Verlag Helvetica Chimica Acta, CH-4010 Basel (Switzerland), 1995 Printed on acid-free paper All rights reserved (including those of translation into other languages) No part of this book may be reproduced in any form _ by photoprinting, micromm, or any other means - nor transmitted or translated into a machine language without written permission from the publishers Registered names, trademarks, etc used in this book, even when not specifically marked as such, are not to be considered unprotected by law Printing: Birkhauser+GBC AG, CH-4153 Reinach BL Printed in Switzerland In memoriam Prof Rolf Scheffold On November 28, 1994, in the middle of the preparations of the present Volume of Modern Synthetic Methods, Rolf SchefJold died from an incurable disease Fascinated by the rapidly expanding world of new synthetic methodologies and the molecules that are accessible through these techniques, he had early recognized that there is need to continuously update important new developments, not only in theory but also especially in practice With this in mind, he had organized in 1976 the first seminar on Modern Synthetic Methods in Interlaken and edited Volume of the present series The echo to this seminar was so overwhelming that a second was held in 1980, and from that time follow-up meetings were held regularly in triennial intervals Rolf Scheffold had organized and chaired the Symposia, and edited the proceedings He initiated with us the preparations of the 1995 meeting with great enthusiasm and energy We have not only lost the founder of an important seminar series but also an impressively experienced and inspiring colleague and a very good friend The Editors PREFACE Some of the most important developments in chemistry within the last years took place at the interface between chemistry and biology or physics As a consequence, the formerly well separated disciplines started a process of fusion towards a more general molecular science Messengers of this process are new periodicals, e.g Chemistry & Biology, which announce this going-together of disciplines explicitly in their titles Within this environment, the molecules of interest become more and more complex, and the methods of their preparation more and more sophisticated It is the aim of the Modern Synthetic Methods seminars to focus on timely, rapidly developing areas of synthetic organic and bioorganic chemistry This year's interest is centered on solvent effects in chemical transformations, reactions at surfaces, the importance of surface proteins in biology, the chemistry of complex carbohydrates and nucleic-acid analogues, and antibody-cataly~d reactions The present volume compiles the contributions of six authors, each leading expert in his field The chapters not only outline the general background, basic principles, and their application on synthesis, but also give, as an integral part, representative experimental procedures and an impressive body of references As in previous years, the publication of this volume coincides with the Modern Synthetic Methods seminar in Interlaken, which is organized by the New Swiss Chemical Society One goal is to assist the participants of the seminar in following the lectures Besides this, it is also intended to be a guide for students and synthetic chemists in both academia and industry The editors are indepted to all contributors for their willingness to prepare the manuscripts Special thanks goes to the Verlag Helvetica Chimica Acta, directed by Dr M V Klsakurek, as well as to the printers staff of Birkhiiuser+GBC AG, who managed the realization of this book superbly and in record time Last but not least, financial support from the Kontaktgruppe fur Forschungsfragen (KG F) and the Schweizerische Akademie der Technischen Wissenschaften (SA TW) is gratefully acknowledged Bern and Basel, February 3, 1995 B Ernst G Leumann CONTENTS Some Effects of Lithium Salts, of Strong Bases, and of the Cosolvent DMPUin Peptide Chemistry, and Elsewhere Dieter Seebach, Albert K Beck, and Armida Studer Reactions at Surfaces: Opportunities and Pitfalls for the Organic Chemist 179 Hans Ulrich Blaser The Biology of the Trypanosome Cell Surface Isabel Roditi 259 ~ Glycosylatlon Methods In Oligosaccharide Synthesis Frank Barresi and Ole Hindsgaul 281 Nucleic Acid Analogues: Synthesis and Properties and Christian Leumann 331 Controlling Chemical Reactivity and Selectivity with Catalytic Antibodies 419 JOrg Hunziker Donald Hilvert Subject Index 447 Some Effects of Lithium Salts, of Strong Bases, and of the Cosolvent DMPU in Peptide Chemistry, and Elsewhere by Dieter Seebach, Albert K Beck, and Armido Studer Some Effects of Lithium Salts, of Strong Bases, and of the Cosolvent DMPU in Peptide Chemistry, and Elsewhere Dieter Seebach*, Albert K Beck, Armido Studer Laboratorium flir Organische Chemie der Eidgenossischen Technischen Hochschule, ETH-Zentrum, Universitiitstrasse 16, CH-8092 Zurich (Switzerland) In memoriam of Rolf Scheffold, the initiator of the Interlaken Symposia and founder of the Series ~ Modern Synthetic Methods CONTENT I LiX, AMINE, AND SOL VENT EFFECTS IN ORGANIC I.1 Introduction 1.2 Lithium Salt Effects 1.2.1 Lithium Salt Effects in Various Types of Reactions 1.2.2 SYNTHESIS LiCI04 in Diethyl Ether (a very special solvent system for Diels-Alder reactions) 1.2.3 Lithium Salt Solutions for Specific Purposes (from spinning fibers to 1.2.4 lithium batteries) LiCI or LiBr and DBN, DBU or tert Amines (strong base chemistry 1.3 Effects of Additives in Lithium Enolate Chemistry 1.4 DMPU (a non-mutagenic aprotic dipolar cosolvent) 1.5 The Phosphazene Super-Bases (extremely strong, uncharged, metal- 1.6 free! ) Electrochemical Oxidative Decarboxylation (a neglected synthetic with weak bases, or, a case of bifunctional catalysis) transformation) II PEPTIDE MODIFICATION II.1 Introduction 11.2 Interaction of Lithium Salts with Peptides in Organic Solvents (or how to force a peptide into an unusual conformation to study folding rates) 11.3 Some Contributions to Peptide Building Block Synthesis 11.3.1 The LiX Effect Exploited in Solid-State Peptide Synthesis 11.3.2 Oligopeptides Built in 11.4 Modification of Peptides by Functional Group Reactions (electrolysis, acetalization, dehydration, and oxidation) 11.4.1 Electrolytic Decarboxylation and Reactions of the Resulting Amido- with 2,3-Diamino-propanoic Acids and 3-Amino Acids acetals (phosphorus- and sulfur-containing peptide isosteres) 11.4.2 Acetalizations, Dehydrations, and Oxidative Degradations Involving the Side-Chain of Serine in Peptides 11.4.3 Selenylation of Cyclosporin A (for nanogram detection in serum) 11.5 Peptide Backbone Modifications - General Remarks 11.5.1 Thionation of Cyclosporin A ( a very simple way of preparing derivatives) 11.5.2 N-Alkylation of Peptides (also possible with alkyl halides and the P4 base) 11.5.3 Lithium Enolates of Peptide Derivatives (a different approach to analogs) 11.5.3.1 Enolates of Open-Chain and Cyclic Dipeptide Derivatives and of Phosphorus Analogs 11.5.3.2 Lithium Enolates of Various Glycine- and Sarcosine-Containing Peptides of up to Six Amino-Acid Residues 11.5.3.3 Generation of Lithium Enolates in Sarcosine Moieties of Cyclic ~ Linear Tetrapeptides, and Reactions with Electrophiles 11.5.3.4 Attachment of Side-Chains on the Sarcosine Residue of Cyclosporins (or how to catch a single hydrogen in C62 HlllNl1012) 11.5.3.5 Aminomalonate-containing down) 11.5.4 III Radical Reactions at Glycine Residues of Peptides (the neutral variant) Conclusions IV Acknowledgments Peptides (or how to turn things upside I LiX, AMINE, AND SOL VENT EFFECTS IN ORGANIC SYNmESIS 1.1 Introducti-oD Originally, the title of my contribution to this year's MSM happening was "Reactions in Solution, Solvation, Complexation" It was loosely agreed upon in a telephone conversation with Rolf Scheffold When we started thinking about which part of our own work could be included it became clear that it had to be the investigations on modifications of peptides which actually evolved from our interest in the structure and reactivity of Li enolates [1,2] A brief outline about how we got into this field has been published [3,4], and will be the basis of the main section, the second part of the present article First we want to prepare the reader by giving several mini-reviews on effects which turned out to be decisive in the peptide work The importance of medium effects in chemistry is paramount There are hardly any reactions in organic chemistry which are carried out in the condensed phase without a solvent [5], and the solvents are modified by the addition of cosolvents or additives such as salts and complexing agents to provide optimum conditions Also in the center of chemistry are acids and bases G de Morveau stated more than 200 years ago "Tenir la definition des acides, c'est tenir la clef de la chimie" (Encyclopedie Methodique I, Paris, 1786) Thus, every chemist is familiar with the general concepts of Bronsted and Lewis acidity/basicity, of hydrogen bonding and solvation, and of salt and solvent effects, all alluded to in the title of this article! There are excellent books covering these areas which I consult regularly Thus, Salt Effects in Organic and Organometallic Chemistry by Loupy and Tchoubar [6] containing complete lists of references up to 1989 is a true orgy of lithium salt effects The 1988 second edition of Christian Reichardt's book Solvents and Solvent Effects in Organic Chemistry [7] has a 55 page list of references in narrow print The two volumes of Szwarc's monography Ions and Ion Pairs in Organic Reactions [8] is a classic Related to these topics is of course Phase Transfer Catalysis [9] which is the title of Eckehard and Sigrid Dehmlow's book and which is the subject of excellent compilations by Keller [10] Other favorites in my bookshelf relevant to the theme are The Lewis Acid-Base Concepts by Jensen [11], The Donor-Acceptor Approach to Molecular Interactions by Victor Guttmann [12], Hard and Soft Acids and Bases Principle in Organic Chemistry by Tse-Iok Ho [13], Macrocyclic Chemistry by Jean-Marie Lehn and his colleagues [14], Hydrogen Bonding by Vinogradov and Linnell [15], and Synthetic Organic Electrochemistry by Fry [16] 1.2 Lithium Salt Effects When browsing through Loupy and Tchoubar's book [6] it becomes clear that the most studied and probably the most important salt effects in organic chemistry are those brought about by Li salts; the "supplement on recent pub- lications" (mainly 1989) in that book contains fifty entries, and with twenty of them LiX is part of the title! Lithium appears in all chapters of this thorough monograph, reactions, dealing with Lewis-acid ionic dissociation equilibria, or -base character, associations ion-pair exchange with protic solvent (the "drying" effect), common-ion mass effect, deaggregation and mixed aggregates, bifunctional catalysis, and the "salting-in" and "salting-out" effects The uniqueness of lithium among the alkali and alkaline earth ions results mainly from the following properties of Li and its derivatives: Li+ has the smallest ion radius, i.e the highest charge density of the alkali ions and thus comes closest to H+; most Li salts and almost all organolithium compounds are soluble in organic solvents; there are commercial Li derivatives which are inexpensive and which are used for metallations or X/Li exchange reactions; lithium is non-toxic, in fact a certain trace amount appears to be necessary for human well-being [17] In the following sections we should like to present some striking Li salt effects, with examples of essentially all types of important synthetic organic reactions Rather than repeating the interpretations of the authors or the critical comments in the "bible" [6], the emphasis will be on synthetic usefulness and on surprize! Also, we have preferred examples in which the outcome of the reaction with and without added Li salt is reported for comparison 1.2.1 Lithium Salt Effects in Various Types of Reactions Most organic reactions involve polar or polarized reactands, transition states and/or intermediates - the reactions of hydrocarbons (with each other) are dull as far as organic synthesis is concerned! This is certainly true of all the classical reactions forming the backbone of organic synthesis: in the Ingold nomenclature [18], these are nucleophilic and e1ectrophilic substitutions (SN, SE) and additions (AN, AE), eliminations (E) and fragmentations, as well as the vinylogous cases (SN', SE') and sequences thereof, such as the conjugate additions to a.,~-unsaturated carbonyl and nitro compounds (ANI AE) or olefinations (ANIE); metallations and Theory suggests that improvements in transition-state analog design should lead to more active catalysts Highly efficient antibody catalysis of benzisoxazole decomposition provides some support for this notion The base promotedbreakdown of benzisoxazoles (67) to give salicylonitriles (68) is a classic E2 elimination that is sensitive to base strength and solvent microenvironment [8688] The cationic benzimidazolium hapten 70 (pKa 7.8), which mimics the transition-state geometry of all reacting bonds (69) and bears little resemblance to the reaction product, elicited carboxylate-containing antibodies that accelerate this reaction with more than 103 turnovers per active site and rate accelerations of greater than 108 [89] Moreover, the effective molarity of the active site carboxylate in the antibody 34E4 was calculated to be 41,000 M By way of contrast, effective molarities rarely exceed 10M for intramolecular general base catalysis in model systems or for general catalysis in other antibodies In addition to optimization of hapten design, extensive screening of the immune response (>1200 candidate clones) was important in the identification of an antibody capable of acting as an effective general base catalyst The extraordinary activity of 34E4 demonstrates that very large effects can be achieved by strategic use of haptenic charge = 440 General acid-base catalysis contributes substantially to the efficiency of many enzymes, enabling an impressive array of eliminations, isomerizations, racemizations, hydrolyses and carbon-carbon bond forming reactions to be carried out with high rates and selectivities The ability to induce catalytic groups in antibody active sites using charge complementarity will be essential for effecting these reactions In addition to the examples presented above, this approach has already been applied to a variety of hydrolytic reactions [43,44,90,91] and for interconverting the geometrical isomers of an a,punsaturated ketone [92] Simultaneous induction of acid-base pairs capable of additive bifunctional catalysis may allow an even wider range of reactions to be catalyzed and provide higher efficiencies than a single acid or base Future Challenges The field of catalytic antibodies has developed rapidly since 1986 Particularly notable is the progression from simple reactions with well studied mechanisms to processes difficult to achieve via existing chemical methods Given the degree to which antibody binding energy can be exploited to control mechanism and stereochemistry, it is reasonable to expect that certain problems in organic synthesis will benefit from the use of antibody catalysts For this technology to realize its practical potential, however, a number of technical and cultural obstacles will have to be overcome First, the repertoire of reactions must be greatly expanded Many important transformations of interest to the synthetic chemist, including aldol condensations, SN2 displacements, and phosphoryl and glycosyl group transfers, have yet to be accelerated by antibodies Moreover, most of the transformations catalyzed to date have involved small substrates of limited structural complexity In addition, strategies employed in the past to generate catalysts for some reactions, like amide hydrolysis, are not easily generalizable Clearly, many new approaches are needed, and much effort is currently directed toward extending the scope and defining the limitations of antibody catalysis Second, catalytic efficiency must be greatly enhanced High rates and turnovers multiple have been achieved with some antibodies, but immunoglobulins generally exhibit low activities compared with natural enzymes This is not surprising given that stable haptens mimic transition-states imperfectly; antibodies raised against such molecules are unlikely to provide optimal stabilization of true transition-states Even when excellent transition-state analogs are available for reactions such as ester hydrolysis, statistically significant correlations between hapten structure and the probability of inducing an active antibody have not been determined Such studies will establish guidelines for designing more effective antigens and thereby increase the probability of inducing highly active catalysts The challenge of effective hapten design is particularly daunting in that many energetically demanding reactions require the induction of multiple catalytic groups Strategies exploiting charge complementarity are clearly useful 441 for eliciting general acids, general bases, and nucleophiles at the antibody combining site Mechanism-based ("suicide") inhibitors may further refine our ability to select for specific catalytic mechanisms [93] However, it could prove difficult for a single hapten to generate arrays of residues as sophisticated as the catalytic triad in serine proteases Heterologous immunization with two different but structurally related haptens, each containing a different functional group, was recently proposed as a means of eliciting more than one essential amino acid residue in an antibody combining site [94] If generally viable, this simple approach could obviate the need for complex hapten synthesis Alternatively, as structural information becomes available, it will be possible to engineer catalytic groups into antibody active sites by site-directed mutagenesis Random mutagenesis coupled with genetic selection may prove to be an even more powerful tool for optimizing the activity of these molecules [76,95] Finally, for catalytic antibody technology to realize its full potential, access to and screening of the immune response to individual haptens must be expanded As the most active catalysts may also be the rarest, chances of identifying the best agents will increase with the number of candidates assayed Standard fusion protocols can yield as many as 103 antibody-secreting hybridoma cell lines, [82,89] and combinatorial libraries of immunoglobulin fragments containing > 106 members can now be readily constructed using the polymerase chain reaction (PCR) [96,97] However, only a fraction of these is assayed for catalytic activity in a typical catalytic antibody experiment In principle, sensitive immunoassays [98,99], tagging protocols [100] and biological selection methods [76,95] will allow large populations of antibodies to be screened directly for function The organic chemist's inexperience with techniques for generating, manipulating and assaying antibodies may be the greatest deterrent to broad application of catalytic antibodies In practice, the experimental protocols are relatively straightforward in practice [101], but in the absence of training - or collaborators - from an immunology lab, they may seem intimidating Even under the best of circumstances, production of monoclonal antibodies is time consuming, labor intensive, and relatively expensive The development of easily manipulated combinatorial libraries of antibody fragments may make catalytic antibodies more user-friendly [96,97,102], but considerable expertise in molecular biology will still be required On the other hand, many catalytic antibodies could be made commercially available were there sufficient demand Antibodies can be produced at very high levels in microorganisms [103], so production costs should not be a limiting factor How the relevant catalysts should be identified and developed remains, however, a question For exploratory work, a central repository, such as the American Type Culture Collection, might be established for catalytic antibodies with novel activity This would allow researchers to explore with comparatively little investment of time and energy the specificity and activity of potentially interesting catalysts reported in the literature It would also lend the field a degree of accountability that is currently lacking 442 Assuming these challenges can be met, catalytic antibodies could greatly expand the role enzymes play in synthesis The range of applications will probably include enantioselective and regioselective manipulations of functional groups and the preparation of high value, structurally complex molecules for which alternative conventional methodologies are inadequate Synthesis and/or modification of large macromolecules, such as carbohydrates, nucleic acids and proteins, provides additional opportunities for antibody catalysis The latter class of targets is particularly attractive because of the specific recognition attainable by the large inducible antibody binding site; comparable selectivity might be difficult to achieve with small synthetic catalysts Lastly, the biocompatibility of antibody molecules may make intracellular catalysis and metabolic engineering viable alternatives to more conventional laboratory syntheses Antibodies combine some of the best features of synthetic and enzymatic catalysts They fuse programmable design with powerful selective forces of biology In addition to providing new insights into fundamental aspects of catalysis, this new technology may provide important sets of tools for organic synthesis the next century Acknowledgment Research in the author's laboratory was supported by grants from the National Institutes of Health, the American Cancer Society, the Army Research Office and the Office of Naval Research 443 References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] C.-H Wong, G.M Whitesides, Enzymes in Synthetic Organic Chemistry; Elsevier Science Inc.: Tarrytown, New York, 1994 R.A Lerner, S.I Benkovic, P.G Schultz, Science 1991,252,659-667 D Hilvert, Ace Chem Res 1993,26, 552-558 A Nisonoff, J Hopper, S Spring, The Antibody Molecule; Academic Press: New York, 1975 D Pressman, A Grossberg, The Structural Basis of Antibody Specificity; New York, 1968 E.A Kabat, Structural Concepts in Immunology and Immunochemistry; Holt, Rinehart, and Winston, Inc.: New York, 1976 F.W Alt, T.K Blackwell, G.D Yancopoulos, Science 1987,238, 1079-1087 K Rajewsky, I Forester, A Cllmang, Science 1987,238,1088-1094 D.R Davies, E.A Padlan, S Sheriff, Ann Rev Biochem 1990, 59, 439-473 LA Wilson, R.L Stanfield, Current Opinion in Struct BioI 1993, 3, 113-116 L Pauling, Am Sci 1948, 36,51-58 W.P Jencks, Catalysis in Chemistry and Enzymology; McGraw Hill: New York, 1969 D Hilvert, Chemistry & Biology 1994, 1,201-203 A.P Kaplan, P.A Bartlett, Biochemistry 1991, 30,8165-8170 PA Bartlett, C.K Marlow, Biochemistry 1983,22,4618-4624 K.D Janda, S.I Benkovic, R.A Lerner, Science 1989,244,437-440 T Kitazume, J.T Lin, M Takeda, T Yamazaki, J Am Chem Soc 1991, 113,21232126 T Kitazume, J.T Lin, T Yamamoto, T Yamazaki, J Am Chem Soc 1991, 113,85738575 S Ikeda, M.I Weinhouse, K.D Janda, R.A Lerner, S.I Danishefsky, J Am Chem Soc 1991, 113, 7763-7764 Y Iwabuchi, H Miyashita, R Tanimura, K Kinoshita, M Kikuchi, L Fujii, J Am Chem Soc 1994,116,771-772 P Wirsching, J.A Ashley, S.I Benkovic, K.D Janda, R.A Lerner, Science 1991,252, 680-685 E Fernholz, D Schloeder, K.K.-C Liu, C.W Bradshaw, H Huang, K.D Janda, R.A Lerner, C.-H Wong, J Org Chem 1991, 57,4756-4761 G.W Zhou, J Guo, W Huang, R.I Fletterick, T.S Scanlan, Science 1994,265,10591064 B Golinelli-Pimpaneau, B Gigant, T Bizebard, J Navaza, P Saludjian, R Zemel, D.S Tawfik, Z Eshhar, B.S Green, M Knossow, Structure 1994,2,175-183 J.R Jacobsen, J.R Prudent, L Kochersperger, S Yonkovich, P.G Schultz, Science 1992, 256,365-367 J.R Jacobsen, P.G Schultz, Proc Natl Acad Sci USA 1994, 91,5888-5892 R Hirschmann, A.B Smith III, C.M Taylor, P.A Benkovic, S.D Taylor, K.M Yager, P.A Sprengeler, S.I Benkovic" Science 1994, 265,234-237 K.D Janda, D Schloeder, S.I Benkovic, R.A Lerner, Science 1988,241,1188-1191 J.D Stewart, J.F Krebs, G Siuzdak, A.I Berdis, D.B Smithrud, S.J Benkovic, Proc Natl Acad Sci USA 1994, 91,7404-7409 444 [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] V.A Roberts, J Stewart, S.J Benkovic, E.D Getzoff, J Mol BioI 1994,235, 10981116 J.D Stewart, V.A Roberts, N.R Thomas, E.D Getzoff, S.J Benkovic, Biochemistry 1994,33,1994-2003 R.A Gibbs, S Taylor, S.J Benkovic, Science 1992,258,803-805 L.J Liotta, P.A Benkovic, G.P Miller, S.J Benkovic, J Am Chem Soc 1993, 115,350351 B.L Iverson, R.A Lerner, Science 1989,243; 1184-1188 G.F Blackburn, D.B Talley, P.M Booth, C.N Durfor, M.T Martin, A.D Napper, A.R Rees, Anal.Chem 1990,62,2211-2216 J.D Stewart, V.A Roberts, M.W Crowder, E.D Getzoff, S.J Benkovic, J Am Chem Soc 1994, 116,415-416 H Miyashita, Y Karaki, M Kikuchi, I Fujii, Proc Natl Acad Sci USA 1993, 90, 53375340 D.A Campbell, B Gong, L.M Kochersperger, S Yonkovich, M.A Gallop, P.G Schultz, J Am Chem Soc 1994,116,2165-2166 D.W Landry, K Zhao, G.X.-Q Yang, M Glickman, T.M Georgiadis, Science 1993, 259,1899-1901 B.L Iverson, K.E Cameron, G.K Jahangiri, D.S Pasternak, J Am Chem Soc 1990, 112, 5320-5323 J.-L Reymond, G.K Jahangiri, C Stoudt, R.A Lerner, J Am Chem Soc 1993, 115, 3909-3917 G.K Jahimgiri, J.-L Reymond, J Am Chem Soc 1994,116,11264-11274 J.-L Reymond, K.D Janda, R.A Lerner, Angew Chem Int Ed Engl 1991,30,17111713 J Yu, L.c Hsieh, L Kochersperger, S Yonkovich, J.C Stephans, M.A Gallop, P.G Schultz, Angew Chem Int Ed Engl 1994,33,339-341 S.c Sinha, E Keinan, J.-L Reymond, J Am Chem Soc 1993, 115,4893-4894 J.-L Reymond, J.-L Reber, R.A Lerner, Angew Chem Int Ed Engl 1994, 33,475477 J.I Kim, T Nagano, T Higuchi, M Hirobe, I.; Shimada, Y Arata, J Am Chem Soc 1991, 113, 9392-9394 G.R Nakayama, P.G Schultz, Am Chem Soc 1992,114,780-781 L.c Hsieh, S Yonkovich, L Kochersperger, P.G Schultz, Science 1993,260,337-339 A Koch, J.-L Reymond, R.A Lerner, J Am Chem Soc 1994, 116,803-804 L.C Hsieh, J.C Stephans, P.G Schultz, J Am Chem Soc 1994, 116,2167-2168 J.-L Reymond, K.D Janda, R.A Lerner, J Am Chem Soc 1992, 114,2257-2258 S.c Sinha, E Keinan, J.-L Reymond, Proc Natl Acad Sci USA 1993,90, 1191011913 E.N Jacobsen, N.S Finney, Chemistry & Biology 1994,1,85-90 T.C Bruice, Ace Chem Res 1991,24,243-249 D Ostovic, T.C Bruice, Ace Chem Res 1992,25,314-320 J.T Groves, T.E Nemo, R.S Myers, J Am Chem Soc 1979, 101,1032-1033 A.W Schwabacher, M.I Weinhouse, M.-T.M Auditor, R.A Lerner, J Am Chem Soc 1989, 111,2344-2346 A.G Cochran, P.G Schultz, Science 1990,249,781-783 445 [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] A.G Cochran, P.G Schultz, J Am Chem Soc 1990,112,9414-9415 K.M Shokat, C.J Leumann, R Sugasawara, P.G Schultz, Angew Chem Int Ed Engl 1988,27,1172-1174 B.L Iverson, S.A Iverson, V.A Roberts, E.D Getzhoff, J.A Tainer, S.J Benkovic, R.A Lerner, Science 1990, 249, 659-662 e.-H Wong, Science 1989, 244,1145-1152 G Desimoni, G Tacconi, A Barco, G.P Pollini, Natural Products Synthesis Through Pericyclic Reactions; American Chemical Society: Washington, D.e., 1983 D Hilvert, K.W Hill, K.D Nared, M.-T.M Auditor, J Am Chem Soc 1989,111,92619262 A.C Braisted, P.G Schultz, J Am Chem Soc 1990,112,7430-7431 V.E Gouverneur, K.N Houk, B Pascual-Teresa, B Beno, K.D Janda, R.A Lerner, Science 1993, 262, 204-208 A.C Braisted, P.G Schultz, J Am Chem Soc 1994,116,2211-2212 D Hilvert, S.H Carpenter, K.D Nared, M.-T.M Auditor, Proc Natl Acad Sci USA 1988, 85,4953-4955 D.Y Jackson, J.W Jacobs, R Sugasawara, S.H Reich, P.A Bartlett, P.G Schultz, J Am Chem Soc 1988,110,4841-4842 D Hilvert, K.D Nared, J Am Chem Soc 1988,110,5593-5594 D.Y Jackson, M.N Liang, P.A Bartlett, P.G Schultz, Angew Chem Int Ed Engl 1992,31,182-183 P.R Andrews, G.D Smith, I.G Young, Biochemistry 1973,12,3492-3498 P.A Campbell, T.M Tarasow, W Massefski, P.E Wright, D Hilvert, Proc Natl Acad Sci USA 1993, 90, 8663-8667 M.R Haynes, E.A Stura, D Hilvert, LA Wilson, Science 1994, 263, 646-652 Y Tang, J.B Hicks, D Hilvert, Proc Natl Acad Sci USA 1991, 88, 8784-8786 T Li, K.D Janda, J.A Ashley, R.A Lerner, Science 1994, 264,1289-1293 K.D Janda, e.G Shevlin, R.A Lerner, Science 1993, 259,490-493 J Na, K.N Houk, e.G Shevlin, K.D Janda, R.A Lerner, J Am Chem Soc 1993,115, 8453 K.M Shokat, C.J Leumann, R Sugasawara, P.G Schultz, Nature 1989, 338, 269-271 K Shokat, T Uno, P.G Schultz, J Am Chem Soc 1994, 116,2261-2270 e Lewis, T Kramer, S Robinson, D Hilvert, Science 1991, 253, 1019-1022 T Uno, P.G Schultz, J Am Chem Soc 1992,114,6573-6574 T Uno, B Gong, P.G Schultz, J Am Chem Soc 1994, 116, 1145-1146 B.F Cravatt, J.A Ashley, K.D Janda, D.L Boger, R.A Lerner, Am Chem Soc 1994, 116,6013-6014 M.L Casey, D.S Kemp, K.G Paul, D.D Cox, J Org Chem 1973,38,2294-2301 D.S Kemp, M.L Casey, Am Chem Soc 1973,95,6670-6680 D.S Kemp, K Paul, J Am Chem Soc 1975, 97,7305-7312 S.N Thorn, R.G Daniels, M.-T.M Auditor, D Hilvert, Nature 1994,373,228-230 K.D Janda, MJ Weinhouse, D.M Schloeder, R.A Lerner, S.J Benkovic, J Am Chem Soc 1990, 112,1274-1275 H Suga, O Ersoy, T Tsumuraya, J Lee, A.J Sinskey, S Masamune, J Am Chem Soc 1994, 116,487-494 D.Y Jackson, P.G Schultz, J Am Chem Soc 1991, 113,2319-2321 446 [93] [94] [95] [96] [97] [98] [99] [100] [WI] [102] [103] K Janda, C.-H Lo, T Li, C.F Barbas, P Wirsching, R.A Lerner, Proc Natl Acad Sci USA 1994,91,2532-2536 H Suga, O Ersoy, S.F Williams, T Tsumuraya, M.N Margolies, A.J Sinskey, S Masamune, J Am Chern Soc 1994,116,6025-6026 S.A Lesley, P.A Patten, P.G Schultz, Proc Natl Acad Sci USA 1993,90, II 60-II 65 W.D Huse, L Sastry, S.A Iverson, A.S Kang, M Alting-Mees, D.R Burton, S.J Benkovic, R.A Lerner, Science 1989,246, 1275-1281 L.J Garrard, E.A Zhukovsky, Current Opinion in Biotechnology 1992,3,474 D.S Tawfik, B.S Green, R Chap, M Sela, Z Eshhar, Proc Natl Acad Sci USA 1993, 90,373-377 G MacBeath, D Hilvert, J Am Chern Soc 1994, 116,6101-6106 J.W Lane, X Hong, A.W Schwabacher, J Am Chern Soc 1993,115,2078-2080 J.W Goding, Monoclonal Antibodies: Principles and Practice; Academic Press, Inc.: New York, 1983 Y.-c.J Chen, T Danon, L Sastry, M Mubaraki, K.D Janda, R.A Lerner, J Am Chern Soc 1993, 115, 357-358 P Carter, R.F Kelley, M.L Rodrigues, B Snedecor, M Covarrubias, M.D Velligan, W.L.T Wong, A.M Rowland, C.E Kotts, M.E Carver, M Yang, J.H Bourell, H.M Shephard, D Henner, Bio/Fechnology 1992,10, 163-167 447 SUBJECT INDEX A Acetylation 93 Addition to C=O and C=N groups 233 Additives, effects of 28 Adenylate cyclase 271,272 Aglycon delivery, intramolecular 285 Aldol additions 34 Alkylation of CH-active groups 224 N-Alkylation of peptides 105-107 Amberlite resin 202 Amberlyst resin 202 Aminomalonate residue 138-142 Anomerization, in situ 308 Antibodies 265,272 a-Arabinofuranosylthymine 345 Arabinooligonucleotides 345 L-Arabinose 351 Arndt-Eistert homologation 83, 84 Atomic structure 187 Aza-diene-enolate 121 B C-Benzylation of tripeptides 119 Bicyclo-DNA a degenerate Watson-Crick paring system 408 analysis of 394 hairpin formation 402, 403 in triple-helix formation 396,397,408 Hoogsteen vs Watson-Click base-pair formation 399,401,402 Molecular-dynamics calculation 406 preferred backbone conformation 405 synthesis of monomeric building blocks 388-392 synthesis of oligonucleotides 393 thermodynamics of duplex and triplex formation 396, 398, 400 X-ray structures of monomers and dimers 404,405 Bifunctional catalysis 20 Biopolymer 19 [3,3- Bis(hydrox ymethy I)cyclobutyl ]nucleo sides 356 Boronhydride on polymer supports 203 C Carbon, active or charcoal 191 as catalyst 214 as support 214 Catalytic antibodies as biosensors 428 by heterologous immunizations 441 by random mutagenesis 441 by screening of combinatorial libraries 441 by site-directed mutagenesis 441 in activation of prodrugs 428 in aldol condensation 440 in amide hydrolysis 427, 428 in asymmetric oxidation of olefins 430, 431 in chorismate-prephenate rearrangement 434,435 in cyclization reactions 435,436 in Diels-Alder reactions 432-434 in j3-elimination reactions 437-439 in enantioselective hydrolysis of mesodiesters 424 in enantioselective protonation 429 in enantioselective transesterifications 425 in glycosyl transfer 440 448 in in in in in in in oxime formation 438 oxygenation of sulfides 430, 431 phosphoryl transfer 440 resolution of chiral alchols 424 selective reduction of ketones 430 SN2-displacement reactions 440 stereoselective hydrolysis of fluorinated esters 424 in treatment of drug addiction 428 incorporating flavin derivatives 432 incorporating metal ions 432 incorporating nicotinamide analogues 432 incorporating porphyrin derivatives 432 Chromium oxides on polymer support 204 Claycop 211 Clayfen 211 preparation 211 Clays 185,189 description 210 for Friedel-Crafts acylation 218 for Friedel-Crafts alkylation 219 for isomerization 233 for nitration 219 impregnated with FeCI} 211 pillared 210 Clayzic 211 Condensation reactions 225 Knoevenagel reaction 225 Cyanohydrine addition Cyclic tetrapeptides 125-127 alkylations 128, 129 Cycloadditions 15,24 Cyclophilin 74 Cyclosporin A 60,74,98,99, 101, 102, 104,106,130-136 Dehydro-amino-acid residues 96 Dehydrogenation reactions 230 2'-Deoxy- 2'-fluoro-arabinooligonucleotides 347 2'-Deox y- 2'-fl uoro-nucleosides 346 2'-Deox y- a- D- ribonuc leotides 350 2'-Deox y-a-L-ribonucleotides 350 2'-Deox y-{3-L-ribonucleotides 351 3'-Deox y-ribooligonucleoti des 349 2'-Deoxy- xyloadenosine 346 2'-Deoxy- xylocytidine 364 2'-Deoxy -xylooligonucleotides 346 Hetero-Diels-Alder additions 17 Diels-Alder reactions 13,15,16,221 2',3' -Dideox y-hexopyranosy I-nucleosides 358 2',4' -Dideoxy-hexopyranosy I-nucleosides 358 3',4' -Dideox y-hexopyranosy 1-nucleosides 358 Diffusion 194 difussion step 195 film diffusion 195 pore diffusion 195 2',2'-Difluoro-2'-deoxycytidine 348 (3,4-Dihydroxybutyl)adenine 356 2'-0-(3,3 Dimethylallyl)-ribonucleotides 344 Dimethylpropy1eneurea (DMPU) 40-47 Dipeptides containing Li+ ions 71 di- and trithio derivatives 113 Dispersion 185 Dithiocyclosporin A 103 Drug research 147 E D Decanoic acid, lO-propoxy- 271 Decarboxylation, electrochemical oxidative 55, 58, 86 Dehydrations 93 EcoR I cleavage 375 EcoR V Cleavage 347 Electrolysis 92 Electron micrographs activated characoals 215 449 5% Pd/C catalysts 235 real-life Pt/A1203 catalyst 191 Electronic properties 293 Electrophilic additions 10 Electrophilic substitutions 10 Elimination reactions 232 Enantioselective reactions 37 Ene reactions 17 Enolate trapping 36 Enthalpies of interaction 67 Epoxidation reactions heterogeneous Sharpless epoxidation 228 poly-L-leucine 207 polymeric peracids 227 polypeptides as enantioselective catalysts 206,228 Sharpless epoxidation 228 Epoxides Ethano-bridged nucleosides 359,361 epoxides 288, 289 glycosides, pentenyl 288, 289 glycosyl bromides 289, 303-308 glycosyl chlorides 289,312,313 glycosyl fluorides 289,309-311 glycosyl halides 288, 324 glycosyl phosphorous 288, 289, 314-317 seleno-glycosides 288,289 sugars, reducing 288, 289 sulfoxides 288, 289, 318 thioglycosides 288,289,297-302,324 xanthates 288,289,323 Glycosylation, miscellaneous 320-323 Glycosylation, sequential 285, 311 GPI Anchor 270, 271 GPI Phospholipase C 271 Graphite 191 Graphite intercalation compounds 213 214 CrOrgraphite Zn-graphite 214,224 Grignard reagents 87 F H Fattyacids 271 Fluorination 232 6'-a-Fluorocarbocyclic nucleotides Friedel-Crafts acylation 217 Friedel-Crafts alkylation 219 353 G Galactose 273 Gel 185,188 Glucosamine, N-acetyl- 273 Glucose transporter 271 Glutamic acid/alanine-rich surface protein (GARP) 274 Glyceroo ligothymidy lates 355 Glycosyl donors 288, 289 acetates, anomeric 288, 289 acetimidates, trichloro- 288-296,324 diazirines 288,289,323 Haptens aminophosphinic acids 431 ammonium ions 430, 439 bicyclo[2.2.2]octene derivatives 433 norbomene derivatives 432 N-oxides 429,436 phosophates 424 phosphonamidates 427 phosphonate diesters 425 Heterogeneous reagents and catalysts advantages 196, 197 availability 200 filtration 196 performance 200 problems 198,199 synthetic applicability 200 Hexamethyl phosphoric acid triamide (HMPA) 40-45 120 Hexapeptides 450 Homo-DNA 386, 387 Horner olefination 23 Hydrogenation, catalytic 231,234 apparatus and procedures 241 catalyst choice 237 catalyst costs 238 catalyst performance 238 catalysts 235,236 catalytic activity 237 enantioselective hydrogenation 246,247,250 process modifiers 239 reaction conditions 241 reaction medium 239 selective debenzylation 242, 243 selective debenzylation of N-benzyl groups 245 selective debenzy1ation of O-benzyl groups 244, 245 selectivity 238 glycine-linked nucleosides 363, 364 methylhydroxylamine-linked nucleosides 371 morpholino nuclosides 365 oxo-linked nucleosides 370 oxyamide-linked nucleosides 364,365 riboacetal-linked nucleosides 368 2'-thioformacetal-linked nucleosides 367 3'-thioformacetal-linked nucleosides 367 5'-thioformaceta1-linked nucleosides 367 Invariant surface glycoproteins (ISG) 271 Isocyclosporin A 101 Isomerization reactions 233 K Koenigs-Knorr donors 308 L I Influenza virus 267 Ingold nomenclature of reactions Intemucleoside linkage modifications acetamide-bridged 362 alkyl-linked nucleosides 368 amide-linked nucleosides 362,363 amino-linked nucleosides 369 ary1carboxylguanidine-linked nucleosides 366 arylsulfony1guanidine-linked nucleosides 366 carbamate-linked nucleosides 365 3'-carboxymethyl-ester bridged 362 cyanoguanidine-linked nucleosides 366 deoxy -3'-C -formylthymidine 371 diisopropylsilyl-linked nucleosides 372 di(tert-butyl)silyl-linked nucleosides 372 formacetal-linked nucleosides 367 2',5'-formacetal-linked nucleosides 367 Lawesson reagent 102, 103 Lectin 275 Lipoprotein receptor 271, 272 Lithium amides 29,31 Lithium enolates 28-35, 37 of peptides 1l0, 117, 118 M Macrophages 273 Metal-complex catalysts, immobilized 215 via a covalent bond 216 via adsorption and ion-pair formation 216 via entrapment 217 Metalations 11 Methano-bridged nucleosides 359 1',6'-Methano carbocyclic thymidine 359 4',6'-Methano carbocyclic thymidine 359 1'-Methyl carbocyclic thymidine 353 2' -0- Methyl-ribonucleotides 342,343 451 C-Methylation of tripeptides 119 Michael additions 9,23,96, 139, 140 Michaelis-Arbuzov reaction 87,88,92 Montmorillonite 185,211,218,228 Multifunctional catalyst 194 Myristic acid 271 N Nafion 202 for Friedel-Crafts acylation 217 for Friedel-Crafts alkylation 219 Nagana 262 Naphthy1selenylation 99 Nitration 219 Nucleophiles on oxides 210 aliphatic substrates 220 Nucleophiles on polymers 205 aliphatic substrates 220 Nucleophilic additions Nucleophilic substitutions 7, 86, 220 aliphatic substrates 220 aromatic substrates 221 Oxides, acidic 208 for addition to C=O and C=N groups 223 for Diels-Alder reactions 221 solid superacid 208 Oxides, amorphous 189 aluminas 189,207 silicas 189,207 Oxides, basic 208 basic alumina 208 for addition to C=O and C=N groups 223 for condensation reactions 225 for Knoevenagel reaction 225 KF on alumina 208, 221 NaOEt on alumina 224 super base 208, 234 Oxides, inorganic for Friedel-Crafts alkylation 219 Oxidizing agents on oxides 209 Zn(Mn04h on silica 209, 229 Oxocarbonium ion 324 Ozonolysis 96 p oligo-4' -thiouridy lates 358 Oligosaccharide libraries 323 Oligosaccharide synthesis, solid-phase 285,319 Oxetanosine 356, 357 Oxetanosy 1-nucleosides 356 Oxidants on oxides applications 227 Oxidants on polymers 204 applications 227 Oxidation reactions alcohols 227-229 carboxylic acids 57 oxidative aryl coupling 229 various substrates 229 Oxidative degradations 93 Parasitaemia 264, 266 122-124 Pentapeptides Peptide backbone modifications 100 Peptide conformations 75 Peptide coupling 84 Peptide isosteres 88-91 Peptide synthesis, solid-phase 76 Peptide modification 60, 62 Peptide nucleic acid (PNA) as artificial transcription factor 386 as blocker of the polymerase chain reaction 386 with chiral backbone 384, 385 with extended backbone structure 384,385 with extended linker to the base: 'peptoid'-PNA 386 452 in D-loop formation 379, 380 with inverted backbone-amide function 384,385 kinetics of complex formation 380 parallel vs antiparallel complex formation 380,381 PNA-DNA duplex structure 383 PNA-RNA duplex structure 382, 383 polymerase chain reaction (PCR) 386 in sequence-specific DNA cleavage 386 solid-phase synthesis 378 synthesis of monomeric units 377 thermodynamic stability of complexes 380,381 Peracids, polymeric application 227 preparation 205 Perallylation of peptides 108 Perbenzylation of peptides 108 Phosphazene bases 48, 50 Phosphono-dipeptide diesters 92 Phosphoramidites, recycling of 394 Polvinylpyridinium chlorochromate recycling 204 19 Polyamides Poly1ithiation 60 Polymers, acidic 202 polyvinylpyridine· HF 202, 232, 233 Polymers, basic 203 for condensation reactions 225 N-arylmethylchitosan 203 Polymers, linear 188 Polymers, organic 19,187,201 Polymers, swellable 186,187 Polyvinylpyridinium chlorochromate preparation 204 Pore diameter 185 Pore size 185 Potassium fluoride on alumina for condensation reactions 225 Procyclin coat 273,274 R Radical reactions 12 of glycine 143-145 Reducing agents on oxides 209 application 230 LiAlH4 on silica 209 reduction of benzaldehyde 230 Reducing agents on polymers 203 application 230 Reductions 230 Reformatzky reaction 224 Resins 185, 188 Resitol, 1,2-dimyristoyl-sn-phosphatidyl271 S Sakurai reaction 87 Salmo fario 262 Sarcosine-enolate formation 120 l' ,2'-Seco-2'-nomucleosides 355 l' ,4'-Seco-2'-nucleosides 355 3',4'-Secothymidine 356 Selenylation 98 Sialic acid 273 Sleeping sickness 262,276 Solubilization of peptide derivatives 64-66 Solvent systems for polymers 19 Sulfide contraction 23 Surface area 185 specific 186 Surface coat 265 Surface hydroxy group 190 Surface site accessibility 199 active center 185 active site 185,193,195 Surfaces 183 chemical and physical properties 186 453 T V T Helper cells 272, 273 T-Lymphocytes 272 Telomere 267 Terminology of heterogeneous catalysis and surface science 185 IH-Tetrazole,5-(4-nitrophenyl)343 Thiocyclosporin A 103 Thionation 102-104 353 4' -Thioribothymidine 4'- Thiothymidine 353 111 Transaggregation Transesterification 79 Transfer hydrogenation 231 procedure 232 Transferrin-binding-protein complex 271,272 Transition-metal reactions 12 11 Transmetalations Transport rates 69 Tsetse fly 262 Variant surface glycoprotein (YSG) 268-270 W Wittig reaction polymeric reagents 205,206,226,227 Z Zeolites 186,187,189,194,212 application 213 for Diels-Alder reaction 222 for Friedel-Crafts acylation 219 for Friedel-Crafts alkylation 219 for isomerization 233 properties 212 shape selectivity 213 suppliers 213 ... Data: Modern synthetic methods [Basei]: VHCA.Verlag Helvetica Chimica Acta; Weinheim: VHC Erscheint unregelmassig - Erhielt friiher Einzelbd.-Aufnahmen - Aufnahmen nach Vol (1992) Vol 7, 1995. .. preparations of the present Volume of Modern Synthetic Methods, Rolf SchefJold died from an incurable disease Fascinated by the rapidly expanding world of new synthetic methodologies and the molecules... preparation more and more sophisticated It is the aim of the Modern Synthetic Methods seminars to focus on timely, rapidly developing areas of synthetic organic and bioorganic chemistry This year's