Synthesis of Glycopeptides, Oligosaccharides and Neoglycoproteins of Biological Interest

The carbohydrate moieties of glycoproteins play key roles in biological selection processes. For investigations of these biological recognition phenomena, glycopeptides of exactly specified structure are required, e. g. as ligands of cell adhesion components, virus envelope structures or potential tumor-associated antigens. Thus, special emphasis is given to chemical and enzymatic developments in the preparation of these complex molecules in solution and on a solid phase. In addition novel protecting groups that can be selectively removed under mild and neutral conditions are of interest. Employing N-terminal fluorenylmethoxycarbonyl (Fmoc)-, allyloxycarbonyl (Aloc)-, tert-butyloxycarbonyl (Boc)- or trichloroethoxycarbonyl (Tcoc) protective groups in combination with C-terminal benzyl, tert-butyl or allyl esters, syntheses of the Thomson-Friedenreich antigen, TN antigen glycopeptides as well as Lewisx and Lewisa antigen peptide conjugates of exactly specified structure have been carried out. The deprotected conjugates have been coupled to carrier proteins for the evaluation of biological activity. Recently, novel sialyl Lewisx conjugates have been synthesised and evaluated as inhibitors of E- and P-selectin mediated cell adhesion in cell culture assays. Methods for the synthesis of complex glycoconjugates on the solid phase have been presented, too.

Syntheses on Solid Phases

The allylic protecting principle was elaborated to a novel allyl anchoring in the solid phase synthesis of peptides and glycopeptides. The efficiency of the strategy has been demonstrated for instance in the synthesis of glycosylated Peptide T, a partial sequence of gp120 of HIV-1. Recently, in syntheses of partial sequences of the tandem repeat of a tumor- associated polymeric epithelial mucin MUC-1 the advantages of an allylic anchor (HYCRON) which incorporates a polar, flexible oligoethyleneglycol spacer linked to the aminomethyl polystyrene have been demonstrated. Reactions on carbohydrates linked to solid-phase are also of interest.

Stereoselective Syntheses

Carbohydrates are inexpensive natural products in which numerous functional groups and stereogenic centers are combined in one molecule. By directed regio- and stereoselective formation of derivatives they can be converted into efficient chiral auxiliaries for controlling asymmetric syntheses. For example, Lewis acid-catalysed Diels-Alder reactions of carbohydrate- linked dienophiles are furnishing the corresponding cycloadducts in high diastereoselectivity. The formation of a by-product during Diels-Alder reactions catalyzed with diethylaluminum chloride gave rise to the development of a new synthesis of beta-branched carboxylic acids consisting of the 1,4 addition of dialkylaluminum chlorides to a alpha,beta-unsaturated N-acyl urethanes. The process has been combined with subsequent trapping reactions of the intermediates by electrophiles resulting in the stereoselective syntheses of alpha-functionalized beta-branched carboxylic acid derivatives. Glycosylamines offer the possibility of versatile stereoselecitve applications: in the presence of Lewis acids the corresponding aldimines permit high-yielding syntheses of enantiomerically pure alpha-amino acids by Strecker and Ugi reactions, controlled by steric and stereoelectronic effects and by complex formation. They can be used with equal efficiency for asymmetric syntheses of chiral homoallylamines and for asymmetric Mannich syntheses of beta-amino acids and chiral heterocycles, for example alkaloids.