Multifunctional Hydrogen-Bond-Donor Catalysts for Selective Furanosylation

Abstract

Hydrogen-bond-donor catalysts are applied to the construction of challenging 1,2-cis glycosidic linkages of arabinose and other furanose sugars. Identification of an unusual dialkylphosphate leaving group enables preparation of anomerically-pure furanoside substrates suitable for use in a stereospecific glycosylation method. Based on previous glycosylation studies performed in the Jacobsen lab, we propose that hydrogen-bond-donor catalysts promote stereospecificity through concomitant nucleophile- and electrophile-activation. This stereospecific glycosylation method enables synthetic access to diverse furanose linkages in high anomeric ratios. Catalyst-promoted anomerization of the substrate is identified as a major factor leading to the formation of the undesired minor glycoside product. Multifunctional activation in hydrogen-bond-donor catalysis is further examined from a fundamental perspective in transesterification reactions promoted by trifunctional ureas designed to mimic mechanistic features of serine proteases. The importance of the hydrogen-bond donor to catalytic activity in these reactions is quantified, and the mechanistic role of the hydrogen-bond-donor is evaluated.