Multigram synthesis of an orthogonally-protected pentasaccharide for use as a glycan precursor in a <i>Shigella flexneri</i> 3a conjugate vaccine: application to a ready-for-conjugation decasaccharide - Archive ouverte HAL Access content directly
Journal Articles Organic Chemistry Frontiers Year : 2021

Multigram synthesis of an orthogonally-protected pentasaccharide for use as a glycan precursor in a Shigella flexneri 3a conjugate vaccine: application to a ready-for-conjugation decasaccharide

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Abstract

The rapidly growing interest in carbohydrate-based bioactive molecules calls for strategies enabling the appropriate design and large-scale delivery of the glycan moiety. Herein, we describe the robust and high-yielding chemical synthesis of an orthogonally-protected pentasaccharide intended for use as a central building block in vaccine development against Shigella flexneri 3a. Elaborated from advanced crystalline intermediates and fine-tuned catalytic processes facilitating regio-and stereoselective conversions, a robust [2 + 3] strategy was designed, which avoided several tedious purifications and efficiently delivered multigram amounts of the target pentasaccharide. Conversion of this intermediate into a donor and a linker-equipped acceptor then merging then into the frame of a [5 + 5] glycosylation step furnished a decasaccharide encompassing one trichloroacetamide moiety per repeat. Chemoselective delevulination and subsequent Pd(OH) 2-mediated hydrogenolysis enabling concomitant hydrodechlorination and azide reduction gave the ready-for-conjugation dimer of the repeating unit of the O-antigen from S. flexneri 3a featuring the natural stoichiometric O-acetylation. The proof-of-concept was established, opening the way to larger S. flexneri 3a oligosaccharides and fine-tuned glycoconjugates.
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pasteur-03722329 , version 1 (13-07-2022)

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Attribution - CC BY 4.0

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Johan Cornil, Zhaoyu Hu, Marion Bouchet, Laurence A Mulard. Multigram synthesis of an orthogonally-protected pentasaccharide for use as a glycan precursor in a Shigella flexneri 3a conjugate vaccine: application to a ready-for-conjugation decasaccharide. Organic Chemistry Frontiers, 2021, 8 (22), pp.6279-6299. ⟨10.1039/d1qo00761k⟩. ⟨pasteur-03722329⟩

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