Phenanthroline‐Catalyzed Stereoretentive Glycosylations

Abstract

Carbohydrates are essential moieties of many bioactive molecules in nature. However, efforts to elucidate their modes of action are often impeded by limitations in synthetic access to well‐defined oligosaccharides. Most of the current methods rely on the design of specialized coupling partners to control selectivity during the formation of glycosidic bonds. Reported herein is the use of a commercially available phenanthroline to catalyze stereoretentive glycosylation with glycosyl bromides. The method provides efficient access to α‐1,2‐cis glycosides. This protocol has been performed for the large‐scale synthesis of an octasaccharide adjuvant. Density‐functional theory calculations, together with kinetic studies, suggest that the reaction proceeds by a double SN2 mechanism.

Guidelines for O-Glycoside Formation from First Principles

“… 100 Recent advances with the use of 1,10-phenanthroline derivatives as an additive ( Figure 1 ), however, show promise in terms of excellent axial selectivity for glycosylation in reasonable reactions times. 101 , 102 The use of ethers as a solvent is widely reputed to involve the use of equatorial glycosyl oxonium ion adducts, 83 for which the best evidence is found in the form of equatorial ω-haloalkyl glycosides arising from the nucleophilic opening of the adduct by the halide counterion, 103 − 105 and typically leads to axially selective reactions.…”

Matching Glycosyl Donor Reactivity to Sulfonate Leaving Group Ability Permits SN2 Glycosylations

“… 2 Which mechanism dominates, and, consequently, what product distribution is observed, depends on complex interactions between donor, acceptor, protecting groups, and reagents. 3 While many useful methods successfully leverage these interactions to generate certain glycosidic linkages in a stereoselective manner, 4 − 25 a general solution for the construction of broad classes of linkages has yet to emerge. 26 Here, we show that by matching the electronics of the leaving group to the reactivity of the glycosyl donor, it is possible to obtain S N 2-type glycosylations that afford products with high β-selectivity for a range of acceptors.…”