Glycosylations of Tertiary Alcohols: Synthesis of Fully Protected Disaccharides with Sterically Demanding Groups Attached to the Sugar Core

Abstract

Modified gluco-and galactopyranosides with sterically demanding groups in the 4-position were synthesized. Glycosylation studies of these tertiary alcohols with glycosyl trichloroacetimidates and glycosyl phosphates were performed. Despite steric hindrance the modified disaccharide moieties could be assembled in moderate yields.Carbohydrates play an important role in a large number of biological processes such as cell-cell recognition, immunological response, metastasis, information transfer, and viral infection. 1 In bacteria carbohydrate oligomers or polymers constitute often a major part of the bacterial cell wall 2 or are used as important points of attachment when interacting with other cells. 3 In contrast to mammalian carbohydrates the variety of different monosaccharide units found in plants, fungi, and microorganisms is enormous. 4 Besides the so-called ten mammalian monosaccharide units even highly deoxygenated units or examples with quaternary stereocenters (e.g., 1-3) are found in these species (Figure 1). 5 Figure 1 Examples 1-3 of microbial monosaccharide units with quaternary stereocentersHowever, nature uses only very rarely tertiary hydroxy groups to form glycosidic bonds. 5b In such cases commonly C-methyl derivatives are utilized. Such methylsubstituted species have also been used in biochemical studies elucidating the substrate scope of glycosyltransferases. 6 From a synthetic chemical point of view we were interested in the question whether glycosylations of tertiary alcohols with geminal sterically demanding groups are still possible. 7 Therefore, we envisioned a manipulation of the core structure of glycosyl acceptors by attaching further sterically demanding alkyl or alkynyl moieties directly to the carbon atoms of the six-membered ring. In contrast to C-branched monosaccharide units which have recently attracted some interest, 8 the glycoside formation with tertiary hydroxy acceptors by chemical means has not been investigated except for the less sterically encumbered tert-butyl alcohol, 1-adamantanol, and cholesterol derivatives as substrates. 7 For the glycosylation of hindered and deactivated phenols the Kahne protocol using sulfoxides as glycosyl donors proved to be the best choice. 9 Disaccharides with sterically demanding groups attached to the sugar core have not been prepared so far.In order to achieve this goal, we prepared several pyranoside building blocks with an alkyl or an alkynyl moiety directly attached to the carbon with the free hydroxy group. These monosaccharide units with tertiary hydroxy groups were obtained by reaction of the corresponding ketone with organolithium species such as MeLi, BuLi, and lithiated alkynes, respectively. Alkynes were chosen for several reasons. On the one hand they would allow a further functionalization by Huisgen 1,3-dipolar cycloaddition 10 or in the case of terminal alkynes by Sonogashira coupling. 11 On the other hand, the stiff alkyne unit presents a moiety with limited steric bulk that could be of advantage during the glycosylation re...