Insights Derived from the Synthesis of a Complex Core 2 Glycan

Abstract

We describe the synthesis of a benzoyl-based C2-O-sLe X -Thr-COOH building block devoid of any aglycone transfer or orthoester-formed byproducts. The absence of byproducts was achieved in the course of both [1 + 1] glycosylation reactions with thiophenol aglycone containing galactose acceptors, as well as a [2 + 2] glycosylation in the presence of a p-methoxy benzyl containing glucosamine-fucose disaccharide. We also report an efficient [2 + 1 + 1] synthesis of a peracetylated sLe X en route to a peracetylated C2-O-sLe X -Thr-COOH. While the total synthesis of the latter compound was recently reported by a related route, the divergent [2 + 1 + 1] synthesis provided good reaction yields for each step of the sequence, establishing this scheme as an alternate approach to the peracetylated C2-O-sLe X -Thr-COOH. Importantly, the current report details the role of a variety of hydroxy-protecting groups, including acetyl, benzoyl, p-methoxy benzyl, and naphthylmethyl that may be considered in designing a route to this complex Core 2 glycan. While we have previously described the use of more glycosylation-friendly naphthylmethyl protecting groups, the current synthesis used p-methoxy benzyl protecting groups with excellent reaction yields, demonstrating the feasibility of applying this side reaction-prone protecting group for this challenging synthesis.