Microwave-Assisted One-Pot Synthesis of 1,6-Anhydrosugars and Orthogonally Protected Thioglycosides

Abstract

Living organisms employ glycans as recognition elements because of their large structural information density. Well-defined sugar structures are needed to fully understand and take advantage of glycan functions, but sufficient quantities of these compounds cannot be readily obtained from natural sources and have to be synthesized. Among the bottlenecks in the chemical synthesis of complex glycans is the preparation of suitably protected monosaccharide building blocks. Thus, easy, rapid, and efficient methods for building-block acquisition are desirable. Herein, we describe routes directly starting from the free sugars toward notable monosaccharide derivatives through microwave-assisted one-pot synthesis. The procedure followed the in situ generation of per-O-trimethylsilylated monosaccharide intermediates, which provided 1,6-anhydrosugars or thioglycosides upon treatment with either trimethylsilyl trifluoromethanesulfonate or trimethyl(4-methylphenylthio)silane and ZnI2, respectively, under microwave irradiation. We successfully extended the methodology to regioselective protecting group installation and manipulation toward a number of thioglucosides and the glycosylation of persilylated derivatives, all of which were conducted in a single vessel. These developed approaches open the possibility for generating arrays of suitably protected building blocks for oligosaccharide assembly in a short period with minimal number of purification stages.

SnCl4-catalyzed solvent-free acetolysis of 2,7-anhydrosialic acid derivatives

“…It is known that Sc(OTf) 3 [29,32] and trimethylsilyl trifluoromethanesulfonate [33] in the presence of acetic anhydride act as acetolysis agents to cleave the 1,6-anhydro ring. In these reactions, Ac 2 O is used as both reactant and solvent, which can be easily removed in vacuo.…”

“…Differently, ring-opening reactions of 6 with BF 3 ⋅OEt 2 , TMSOTf, and Sc(OTf) 3 in Ac 2 O afforded glycal 13 (Table 1, entries 1-4). None of these conditions were successful for the acetolysis of these 2,7-anhydro derivatives, although they worked for the 1,6-anhydro sugars [29,32,33]. Adding 10 equiv of acetic acid to suppress the 2,3elimination reaction failed to give the desired compound 12.…”

“…Moreover, it is the main precursor in the synthesis of inhibitors for N-acetylneuraminidases from different sources [42]. The ring opening of 5 was not trivial since the substrate had a sterically hindered quaternary anomeric center, unlike the tertiary anomeric center C-1 of 1,6-anhydro sugars [29][30][31][32][33]43]. Furthermore, SnCl 4 and Sn(OTf) 2 might have formed a coordination bond with the carbonyl oxygen atom of the C-5 NHAc group and the O-6 position of the glucose glucopyranosyl ring.…”

“…Our group has developed one-pot syntheses of several anhydro sugars via microwave (MW)-assisted intramolecular anomeric protection (iMAP) of silylated sugars as well as ring-opening protocols for their 1,6-anhydro bridges [29][30][31]. Accordingly, ᴅ-galactosamine and ᴅ-allosamine derivatives were synthesized Scheme 1: Concise synthesis of 2,7-anhydrosialic acid derivatives 2-6.…”

“…Conditions for the preparation of 2 and 3, respectively, from 1 have been reported previously [6]. via scandium(III) triflate-catalyzed ring opening of 1,6-anhydroglucosamine derivatives [29,32]. However, there is a paucity of reports on the Lewis acid-catalyzed acetolysis of the 2,7anhydro backbone of Neu5Ac.…”