Synthesis of glycopeptides

In 1998, Morten Meldal and coworkers demonstrated the semisynthesis of Asn derivatives of complex-type bi- and triantennary asialo N-glycans [58], After isolation of these oligosaccharides from the glycoproteins fetuin and ribonuclease (RNase) B by hydrazinolysis, the glycans were converted to Fmoc-Asn(oligosaccharide)-OH derivatives with an acetylated sugar part. In 2003, the Yasuhiro Kajihara group 

SCHEME 11.2 Synthetic strategies of glycopeptides. (a) Convergent coupling, (b) solid-phase glycopeptide synthesis, and (c) enzymatic coupling. Asp, aspartic acid. 

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During the synthesis of glycopeptides, Pavia and coworkers had to confront the proposition that racemization of the amino acids may occur during either the peptide-coupling stage, or the glycosylation stage, or both. This presented a potential problem that had to be resolved. 

Haase C, Seitz O (2007) Chemical Synthesis of Glycopeptides. 267 1-36 Hahn F, Schepers U (2007) Solid Phase Chemistry for the Directed Synthesis of Biologically Active Polyamine Analogs, Derivatives, and Conjugates. 278 135-208 Hansen SG, Skrydstrup T (2006) Modification of Amino Acids, Peptides, and Carbohydrates through Radical Chemistry. 264 135-162... 

Thayer DA, Wong C-H (2007) Enzymatic Synthesis of Glycopeptides and Glycoproteins. 267 37-63... 

Nakamura K, Hanai N, Kanno M, Kobayashi A, Ohnishi Y, Ito Y, Nakahara Y. Design and synthesis of silyl ether-based linker for solid-phase synthesis of glycopeptides. Tetrahedron Lett 1999 40 515-518. 

Brik, A. and Wong, C.-H. (2007) Sugar-assisted ligation for the synthesis of glycopeptides. Chemistry - A European Journal, 13, 5670-5675. 

H. Herzner, T. Reipen, M. Schultz, and H. Kunz, Synthesis of glycopeptides containing carbohydrate and peptide recognition motifs, Chem. Rev., 100 (2000) 4495 537. 

J. Vondrasek, and M. Pisacka, Solid phase synthesis of glycopeptide dendrimers with Tn antigenic structure and their biological activities. Part I, J. Pept. Sci., 5 (1999) 46-55. 

C. Ozawa, H. Hojo, Y. Nakahara, H. Katayama, K. Nabeshima, T. Akahane, and Y. Nakahara, Synthesis of glycopeptide dendrimer by a convergent method, Tetrahedron, 63 (2007) 9685-9690. 

Urge, L., Kollat, E., Hollosi, M., Laczko, I., Wroblewski, K., Thurin, J., and Otvos Jr., L. (1991) Solid-phase synthesis of glycopeptides synthesis of Na-fluorenylmethoxycarbonyl L-asparagine Nb-glyco-sides. Tetrahedron Lett. 32, 3445-3448. 

DEVELOPMENTS IN THE SYNTHESIS OF GLYCOPEPTIDES CONTAINING GLYCOSYL l-ASPARAGINE, l-SERINE, AND... 

The afore-mentioned results have stimulated an interest in the synthesis of glycopeptides for the purpose of supplying structurally well-defined derivatives as models for biochemical and immunochemical studies. Synthetic... 

To overcome these difficulties in the selective deprotection and chain extension, several carboxyl-protecting groups, namely, allyl (16,32), benzyl (43,44), tert-butyl (42), 2-bromoethyl (45), 2-chloroethyl (45), heptyl (46), 4-nitrophenyl (47,48), and pentafluorophenyl (49) for L-serine/L-threonine have been introduced or applied. Similarly, amino-protecting groups for L-serine/L-threonine that have proved useful for the synthesis of glycopeptides are tm-butyloxycarbonyl (50), 9-fluorenylmethoxycarbonyl (43,44,48), 2-(2-pyridyl)ethoxycarbonyl (51), 2-(4-pyridyl)ethoxycarbonyl (44,52), and 2-triphenylphosphonioethoxycarbonyl (53). Some applications of these groups have been discussed in earlier reviews (7-11). 

The solid-phase synthesis of glycopeptides was first realized by applying the polymeric benzyl ester principle of Merrifield. According to this methodology, Lavielle and associates (50) used 7V-(tm-butyloxycarbonyl)-<9-glycosyl serine derivative 153 for condensation with resin-linked alanine 154. 

Otvos et al. (27) adopted the Fmoc-pentafluorophenyl ester methodology and have applied O-deacetylated glycopeptide intermediates (170 and 171) for solid-phase synthesis of glycopeptides. In this way, the A-glycopep-tide (26) H-Gly-L-Lys-L-Ala-L-Tyr-L-Thr-L-Ile-L-Phe-L-... 

A number of publications on glycopeptide chemistry have appeared since this manuscript was submitted. Cohen-Anisfeld and Lansbury (94) reported on a convergent synthesis of glycopeptides. Peptides containing aspartic acid unblocked at the / -carboxy group were synthesized and, subsequently, condensed with glycosylamines. 

The convergent synthesis of glycopeptides in which the carbohydrate moiety is attached to the solid support proved an efficient alternative methodology.64 The carbohydrate structure itself was synthesized on solid support via glycal assembly and anomeric amine synthesis (Scheme 13.20). 

Parallel synthesis of glycopeptides is not described in great detail since such synthesis was reviewed previously and may be regarded as an extension of conventional glycopeptide synthesis. 

For the solid-phase synthesis of glycopeptides, both polystyrene and PEG-based resins have been successfully used. Experiments that compare the rates of reactions on various resins have revealed that the rate of reaction completely depends on the nature of the reaction itself 45 Some reactions perform better on hydrophobic resins, while others are better on hydrophilic resins. 

As of this writing, there are presently only two examples of successful synthesis of glycopeptide libraries in the literature, and these have been generated using PEG-based resins (PEGA and POEPOP), thus enabling rapid solid phase screening of the library (see Sections 14.8 and 14.7.2). 

PARALLEL AND LIBRARY SYNTHESIS OF GLYCOPEPTIDES 14.7.1 Parallel Synthesis of Glycopeptide Arrays... 

Scheme 14.1 Strategies for glycopeptide library synthesis Strategy 1 chemical or enzymatic glycosylation of peptide or glycopeptide Strategy 2 the building-block approach. While enzymes have not yet been used in the solid-phase synthesis of glycopeptide libraries, several resin-bound glycopeptides have been glycosylated enzymatically.36,114...

FIGURE 7.14 Activated esters for temporary protection and activation of Fmoc-amino acids for the synthesis of glycopeptides. (A) Reaction of a-D-glucopyranosyl bromide with esterified Fmoc-serine. (B) Reaction of 2-acetamido-2-deoxy-3,4,6-triacetyl- 3-D-glucopyranosyl amine with esterified Fmoc-aspartyl chloride.37-38 Pfp = pentafluorophenyl. 

However, better results have been reported when the polarity of the reaction is reversed. In this indirect path, an initial radical addition of a thio- or selenophenyl group affords a compound that can be the precursor of a difluoromethyl radical. This latter species can further add onto an activated double bond. These radical approaches have also allowed the synthesis of glycopeptides and difluorophosphonates (Figure... 

Synthesis of glycopeptides in solution has been successfully applied in the preparation of glycopeptides of moderate lengths (see Sections 6.3.2 and 6.3.3). However, yields in solution synthesis are often only modest and isolation of intermediates makes the approach inconvenient. 

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