Synthesis of 2-Propynyl 2-Acetamido-3,4,6-tri-O-Acetyl-2-Deoxy-1-Thio-β-D-Glucopyranoside, 2-Propynyl 3,4,6-tri-O-Acetyl-2-Deoxy-2-Phthalimido-1-Thio-β-D-Glucopyranoside and their 2-(2-Propynyloxyethoxy)ethyl Analogs

CRISTOFALO, ALEJANDRO E.; MONTENEGRO, HUGO O.; CANO, MARIA EMILIA; COLOMER, JUAN P.; UHRIG, MARÍA LAURA

Carbohydrate Chemistry Proven Synthetic Methods, Volume 5

CRC Press

Año: 2021; p. 215 - 225

The popular CuAAC (Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition), alsoreferred to as the click reaction, has been adopted by carbohydrate chemists for construction of neoglycoconjugates. Thus, the synthesis of alkynyl- and azide-sugar precursors through readily available and high-yielding methods has become an important topic. One option for the synthesis of neoglycoconjugates is to employ thiosugars as recognition elements, which are more flexible isosteric structures than the naturally occurring O-glycosides. Still, they are recognized by carbohydrate-binding proteins without loss of affinity, with the advantage of their increased resistance to hydrolysis. Among the most abundant monosaccharides, N-acetyl glucosamine is found as component of N- and O- linked glycans in glycoproteins, and also as fundamental component of glycosaminoglycans. It is well known that the presence of the 2-N-acetamido group diminishes the reactivity of the anomeric position towards glycosylation. The phthalimido group is a useful alternative for the preparation of hexosamine building blocks, as it prevents the participation of the NH group in many side reactions.Here, we describe the synthesis of precursors of alkynyl-functionalized β-N-protected thioglucosamine by a one-pot procedure starting from either N-acetyl or N-phthaloyl glucosamine peracetates. Our methodology involves the isothiouronium salt intermediate which decomposes to the thioaldose. The latter reacts by the highly electrophilic propargylbromide to give the desired products. Alternative alkynyl functionalized electrophiles derived from diethylene glycol can be used to obtain the corresponding thioglycosides which are suitable for conjugation with biologically-active compounds. This one-pot method employing employing N-acetyl or N-phthaloyl glucosamine peracetates as starting materials, is a convenient alternative to obtain alkynyl-functionalized β-thioglucosamine analogs.