Automated Synthesis of Oligosaccharides

Abstract

Dedicated to Professor Duilio Arigoni on the occasion of his 75th birthdayThe chemical synthesis of oligosaccharides with an automated solid-phase synthesizer is described. An octenediol linker served to attach the growing oligosaccharide chain to the solid support, and the desired structures were cleaved from the support via olefin metathesis to afford a pentenyl glycoside. The automated syntheses of several important carbohydrates, including a pentarhamnoside, a proteoglycan linkage-region tetrasaccharide, a phytoalexin elicitor dodecasaccharide, and a branched Leishmania lipophosphoglycan tetrasaccharide, were accomplished in higher overall yield and ca. 20 times faster than with solution-phase methods.Introduction. ± Nonspecialists can routinely access peptides and oligonucleotides for biochemical studies with commercially available machines, while only highly specialized laboratories can synthesize complex carbohydrates. Our effort towards the automated synthesis of oligosaccharides was inspired by automated methods for peptide and DNA synthesis, and the impact these techniques have had on proteomics and genomics. Here, we describe the development and use of the first automated oligosaccharide synthesizer.The traditional solution-phase chemistry of complex carbohydrates remains a timeconsuming art. Although a plethora of new methods for the construction of oligosaccharides, such as enzymatic [1] and one-pot procedures, [2] [3] have been described, few are generally applicable. The OptiMer One-Pot approach [4] aims to automate synthesis planning by selecting efficient couplings based on a computer program and has been successfully applied to the construction of several complex oligosaccharides [5]. As an alternative to solution-phase assembly, the solid-phase synthesis of oligosaccharides has received increased attention [6]. The elimination of intermediate purification steps has led to the accelerated synthesis of several complex structures. We sought to exploit the benefits of the solid-phase paradigm, without the need for manual manipulations.Influenced by the peptide-synthesizer platform [7] [8], we envisioned a similar machine that could easily accomplish glycosylation and deprotection reactions in an analogous fashion. In this way, the synthesis of complex carbohydrates could be reduced to the acquisition of suitably protected mono-or disaccharide glycosyl donors. The building blocks and reaction cycles required for automated oligosaccharide

Automated Chemical Synthesis of Oligosaccharides and Glycoconjugates

“…For instance, using the automated approach, heptasaccharides (5b) were obtained in 24 hours in 42% overall yield, whereas the manual synthesis was much more laborious (14 days) and less efficient (9% overall yield) [90]. Working on expanding this promising technology, Seeberger and co-workers approached the synthesis of oligosaccharides containing other important residues and linkages, including aminosugars [91][92][93][94], sialic acids [95], furanosides [96], 1,2-cis glycosides [97], glycopeptides [98], and branched oligosaccharide sequences [69]. Codee et al reported the synthesis of β-mannosides [99][100] using essentially the same automation platform.…”

Auf dem Weg zur automatisierten Oligosaccharid‐ Synthese

“…[124] Die allgemeine Anwendbarkeit der automatisierten SPOS wurde an der Synthese eines Nonasaccharids, des Le yLe x (KH-1)-Antigenderivats 124 gezeigt (Schema 24). [125] Die Glycosylphosphate [126] Mit der automatisierten Oligosaccharidsynthese wurden verschiedene wichtige Kohlenhydrate synthetisiert, darunter das Globo-H-Hexasaccharid 133 (Schema 25), [128] das Kernpentasaccharid N-verknüpfter Glycane, [129] b-Mannosid, [130] Oligomannoside, [131] Oligorhamnoside, [132] die PhytoalexinElicitorfamilie aus Glucan [124a] und die parasitischen Impfstoffkandidaten gegen Malaria und Leishmaniose (siehe Abschnitt 7).…”

Metathesis Reactions in Solid‐Phase Organic Synthesis

“…This latter linker is readily prepared from Merrifield resin and 4-octene-1,8-diol in one step, and affords the n-4-pentenyl glycosides which can be engaged in further glycosylations promoted by electrophilic reagents such as NIS. This linker has been applied to the synthesis of different polysaccharides [67][68][69], including the automated synthesis of antigens Gb-3 and Globo-H [70]. This linker has also been used for amino sugars such as the amino glycoside antibiotics and heparin.…”