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Chemoenzymatic Synthesis of O-Mannosylpeptides in Solution and on Solid Phase

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Robert Šardzík, Anthony P. Green, Nicolas Laurent, Peter Both, Carolina Fontana, Josef Voglmeir, Martin J. Weissenborn, Rose Haddoub, Paola Grassi, Stuart M. Haslam, Göran Widmalm, and Sabine L. Flitsch

J. Am. Chem. Soc., 2012, 134 (10), pp 4521–4524 DOI: 10.1021/ja211861m

Abstract
O-Mannosyl glycans are known to play an important role in regulating the function of α-dystroglycan (α-DG), as defective glycosylation is associated with various phenotypes of congenital muscular dystrophy. Despite the well-established biological significance of these glycans, questions regarding their precise molecular function remain unanswered. Further biological investigation will require synthetic methods for the generation of pure samples of homogeneous glycopeptides with diverse sequences. Here we describe the first total syntheses of glycopeptides containing the tetrasaccharide NeuNAcα2-3Galβ1-4GlcNAcβ1-2Manα, which is reported to be the most abundant O-mannosyl glycan on α-DG. Our approach is based on biomimetic stepwise assembly from the reducing end and also gives access to the naturally occurring mono-, di-, and trisaccharide substructures. In addition to the total synthesis, we have developed a “one-pot” enzymatic cascade leading to the rapid synthesis of the target tetrasaccharide. Finally, solid-phase synthesis of the desired glycopeptides directly on a gold microarray platform is described.