Total Synthesis of a Pentasaccharide O-Glycan from Acinetobacter baumannii

Abstract

Acinetobacter baumannii is a Gram-negative bacteria associated with drug resistance and infection in healthcare settings. An understanding of both the biological roles and antigenicity of surface molecules of this organism may provide an important step in the prevention and treatment of infection through vaccination or the development of monoclonal antibodies. With this in mind, we have performed the multistep synthesis of a conjugation-ready pentasaccharide O-glycan from A. baumannii with a longest linear synthetic sequence of 19 steps. This target is particularly relevant due to its role in both fitness and virulence across an apparently broad range of clinically relevant strains. Synthetic challenges include formulating an effective protecting group scheme as well as the installation of a particularly difficult glycosidic linkage between the anomeric position of a 2,3-diacetamido-2,3-dideoxy-D-glucuronic acid and the 4-position of D-galactose.

Keywords: Carbohydrates; Drug-resistant bacteria; Multistep synthesis; O-Glycans.

Scheme 1.

A. baumannii Pentasaccharide O-Glycan

Scheme 2.

Targeted Product and Retrosynthesis

Scheme 3.

“DADA” Donor 4 Synthesis

Scheme 4.

Synthesis of GalNAc Donor

Scheme 5.

Synthesis of Glc, Gal, and GlcNAc Donors

Scheme 6.

Synthesis of Disaccharide Acceptor 26

Scheme 7.

Asssembly of Fully Protected Pentasaccharide

Scheme 8.

Global Deprotection