Synthesis of heteroglycoclusters by using orthogonal chemoselective ligations

Abstract

Synthetic heteroglycoclusters are being subjected to increasing interest due to their potential to serve as selective ligands for carbohydrate-binding proteins. In this paper, we describe an expedient strategy to prepare cyclopeptides displaying well-defined distributions and combinations of carbohydrates. By using both oxime ligation and copper(I)-catalyzed alkyne-azide cycloaddition, two series of compounds bearing binary combinations of αMan, αFuc or βLac in an overall tetravalent presentation, and either 2:2 or 3:1 relative proportions, have been prepared.

Keywords: chemoselective ligation; click chemistry; cyclopeptide; heteroglycocluster; oxime.

Figure 1

(a) Schematic representation of a heteroglycocluster of the 2:2 series containing Man and Fuc. (b) Schematic representation of a heteroglycocluster of the 3:1 series containing Lac and Man. (c) Structure of carbohydrates used for the construction of heteroglycoclusters.

Scheme 1

Synthesis of heteroglycoclusters of the 2:2 series. Reagents and conditions: (i) 0.1% TFA in H₂O; (ii) Cu micropowder, t-BuOH, AcONH₄ 100 mM pH 7.4 (1:1, v/v). The wavy bond represents the aliphatic part (i.e., (CH₂)₄) of the lysine (Lys) and the norleucine (Nle) side chain.

Scheme 2

Synthesis of heteroglycoclusters of the 3:1 series. Reagents and conditions: (i) 1a, 2a or 3a, 0.1% TFA in H₂O; (ii) 1b, 2b or 3b, Cu micropowder, t-BuOH, AcONH₄ 100 mM pH 7.4 (1:1, v/v).