G qjj

Scheme 23.28. Synthesis of dihydrocinnolines via three-component condensation.

The four-component reaction of arylglyoxals, primary amines, carboxylic acids, and isocyanides was reported by Zhang et al. in 1996 [58]. First carried out in solution, the reaction of phenylglyoxal, isobutylamine, benzoic acid, and n-butyliso-cyanide gave amide 50 and was cyclized to the imidazole 51 (16 h at 100 °C) with an overall yield of 43% (Scheme 23.29).

The solid-phase synthesis began with the formulation of aliphatic amino acids attached to Wang resin with HCOOEt or HCOOH/Ac2O followed by the dehydration with PPh3/NEt3/CCl4 to provide the resin-bound isocyanides. The reaction with phenylglyoxal, isobutylamine, and benzoic acid in CHCl3/CH3OH/pyridine (1:1:1) at 65 °C for 3 days led to the tetrasubstituted imidazole. The construction of a'

R1NH2 R2COOH condensation

NH4OAc, AcOH TFA-DCM

100 "C cyclisation cleavage

NyN~Rl O

Scheme 23.29. Synthesis of the imidazole 51 on solid phase via four-component condensation.

the imidazole nucleus using the above-described methodology increases the overall diversity and size of an imidazole library.

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Strategies for Creating the Diversity of Oligosaccharides

Pamela Sears and Chi-Huey Wong 24.1

Introduction

Carbohydrates are essential for many important biological functions [1-4]. When conjugated to protein to form glycoproteins, they can alter protein structure and function. As components of glycolipids, they can play pivotal roles in intercellular recognition and signaling. The extracellular matrix contains proteoglycans that not only modify the physicochemical properties of the matrix, but also are involved in a variety of recognition processes such as cell adhesion in response to inflammatory factors and cancer metastasis. Although numerous carbohydrate structures occur in nature, in general the role of saccharide structure in function at the molecular level has been minimally studied. This longstanding problem can be attributed mainly to the difficulty of synthesizing saccharides, especially when compared to proteins and nucleic. Nucleic acids can now be easily made via chemical and biological synthetic techniques, and proteins, which are encoded by DNA, can therefore be easily produced and manipulated through recombinant DNA technology. In addition, automatic synthesizers are available for the synthesis of polypeptides and oligonucleotides. Saccharides, however, are made in nature with a diverse set of enzymes competing to produce very diverse products [1]. There is no information carrier that ''encodes'' a particular saccharide structure, and so creating libraries of saccharides with methods analogous to protein mutagenesis is not possible. Furthermore, unlike proteins and nucleic acids, saccharides are more difficult to synthesize chemically because (1) oligosaccharides are typically branched rather than linear; (2) the monosaccharide units can be connected by a- or b-linkages; and (3) oligosaccharide synthesis requires multiple selective protection and deprotection steps, a process called protecting group manipulation.

This last requirement is quite formidable, and currently there is no general route for combinatorial saccharide synthesis. In a glycosidation reaction, both donors (monosaccharides activated for reaction) and acceptors (which receive the activated monosaccharide) contain many hydroxyl and other functional groups that must be differentially and selectively protected. The product must then be selectively deprotected for the next round of reactions. The complexity of protecting

Handbook of Combinatorial Chemistry. Drugs, Catalysts, Materials. Vol. 2. Edited by K. C. Nicolaou, R. Hanko, and W. Hartwig Copyright © 2002 WILEY-VCH Verlag GmbH, Weinheim ISBN: 3-527-30509-2

group manipulation increases with each additional glycosidic linkage. Development of stepwise solid-phase synthesis can simplify the intermediate work-up and purification steps, but the complexity of protecting group manipulation remains the same. Because of this problem, there is currently no single stepwise method that is applicable to the synthesis of all oligosaccharides or even just the >15 million possible tetrasaccharides that can be assembled from the nine common mon-osaccharides found in humans. In contrast, solid-phase synthesis of peptides and oligonucleotides involves only one protecting group manipulation in the iterative process.

In the last few decades, however, the work of many research groups has started to open up new paths to saccharide and glycoconjugate synthesis. Coupling techniques with better yields and stereoselectivity have been worked out, and new protecting group chemistries have also become available. The possibility of constructing libraries of saccharides, which was considered at one time to be a hopeless prospect, is now starting to appear feasible. The next step in making oligosac-charides widely accessible will be the automation of saccharide synthesis. This chapter will focus on the current state of the subject and emphasize the developments with potential application to automated combinatorial synthesis of saccha-rides, glycopeptides, and glycoproteins.

24.2

Chemical Synthesis of Oligosaccharides

Several practical approaches have been taken with success for the chemical synthesis of oligosaccharides (Fig. 24.1) [5-24]. Most involve the activation of the anomeric leaving group with a Lewis acid and then displacement of that leaving group by the free hydroxyl of the acceptor sugar. The Koenigs-Knorr method of coupling glycosyl halides, one of the first techniques to gain widespread use, is still employed [5] and most other glycosidation reagents used to date proceed by the same basic mechanism. The relative instability of the sugar halide necessitates the construction of the saccharide from the reducing end, and in fact, many of the most successful approaches are those that minimize side-reactions of the activated sugar. New leaving groups have been further developed to improve the stability of the glycosyl donors and their reactivity. Trichloroacetimidates [6], prepared by the reaction of free sugars with trichloroacetonitrile and base, are used most frequently for coupling, as are glycosyl sulfoxides [7], phosphites [8, 9], phosphates [10], thio-glycosides [11], and pentenyl-glycosides [12]. Another scheme for glyco-side synthesis is to build the saccharide from the nonreducing to the reducing end using glycals [13], which can be activated through epoxidation for either direct attack of the epoxide with the aglycon or intermediate formation of, for example, the thioacetal or phosphate (Fig. 24.2).

The control of anomeric configuration of the product can be complicated, especially because the reaction can occur readily via either an SN1- or an SN2-type process. The anomeric configuration of the activated sugar, therefore, does not ensure

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