Abstract
Differentially protected galactosamine building blocks are key components for the synthesis of human and bacterial oligosaccharides. The azidophenylselenylation of 3,4,6-tri-O-acetyl-d-galactal provides straightforward access to the corresponding 2-nitrogenated glycoside. Poor reproducibility and the use of azides that lead to the formation of potentially explosive and toxic species limit the scalability of this reaction and render it a bottleneck for carbohydrate synthesis. Here, we present a method for the safe, efficient, and reliable azidophenylselenylation of 3,4,6-tri-O-acetyl-d-galactal at room temperature, using continuous flow chemistry. Careful analysis of the transformation resulted in reaction conditions that produce minimal side products while the reaction time was reduced drastically when compared to batch reactions. The flow setup is readily scalable to process 5 mmol of galactal in 3 h, producing 1.2 mmol/h of product.
Highlights
Galactosamine (GalN) is ubiquitous in living organisms, and the N-acetyl galactosamine (GalNAc) is one of the nine monosaccharide building blocks that give rise to all mammalian glycans.[1]
Initial experiments showed that mixing 3,4,6-tri-O-acetyl-Dgalactal (1), Ph2Se2, and TMSN3 did not result in any reaction over a 2 h period, and the reaction only started after bisacetoxy iodobenzene (BAIB) addition
A flow setup consisting of two reagent feeds (Feed A: 3,4,6-tri-Oacetyl-D-galactal (1), Ph2Se2 and TMSN3 in anhydrous DCM; Feed B: BAIB in anhydrous DCM) was assembled (Figure 1)
Summary
Galactosamine (GalN) is ubiquitous in living organisms, and the N-acetyl galactosamine (GalNAc) is one of the nine monosaccharide building blocks that give rise to all mammalian glycans.[1]. Several strategies to prepare 2-nitrogenated glycoside analogues from inexpensive starting materials have been developed.[7−13] Azidophenylselenylation (APS) is a commonly used nitrogen transfer reaction to prepare galactosamine building blocks from the corresponding galactals.[14−16] APS introduces two functional groups in a single step, the resulting selenoglycosides are compatible with a wide range of protecting group manipulations and can be activated to prepare 1,2-cis and 1,2-trans glycosides (Scheme 1)
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