Abstract
Ethynylation and propargylation of chiral nonracemic polyhydroxylated cyclic nitrones with Grignard reagents are efficient methods for preparing building blocks containing an alkyne moiety to be used in copper-catalyzed azide alkyne cycloaddition click chemistry. Whereas ethynylation takes place with excellent diastereoselectivity, propargylation afforded mixtures of diastereomers in some cases. The use of (trimethylsilyl)propargyl bromide as precursor of the Grignard reagent is necessary to avoid the formation of undesired allene derivatives. DFT calculations explain, within the experimental error, the observed behavior. Cycloaddition of the obtained pyrrolidinyl alkynes with sugar azides derived from β-(1,3)-glucans provides glycomimetics suitable to be used against fungal transglycosylases.
Highlights
Scleroglucan is a polymer that forms the fungal cell wall which consists of a linear β-(1,3)-D-glucose backbone with one β-(1,6)-D-glucose side chain every three main residue cross-linked with quitin through a unit of N-Ac glucosamine.[1]
Propargylation of nitrones 5-7 was trickier than ethynylation
Installation of a triple bond in a pyrrolidine ring can be done by means of ethynylation and propargylation reactions
Summary
Scleroglucan is a polymer that forms the fungal cell wall which consists of a linear β-(1,3)-D-glucose backbone with one β-(1,6)-D-glucose side chain every three main residue cross-linked with quitin through a unit of N-Ac glucosamine.[1]. 4 it is well-know that polyhydroxylated pyrrolidines (iminosugars) are excellent surrogates of carbohydrates mimicking the transition state of several enzymes, mainly glycosyl hydrolases.[5]. In a research project focused on the design of polyhydroxylated pyrrolidinylderived glycomimetics 1 incorporating β-(1,3)-D-glucose units targeting fungal transglycosylases,[6] we envisaged that the triazole ring, accessible through wellknown click-chemistry[7] and extensively used in glycobiology,[8] would be a suitable linker between the nitrogenated heterocycle and the carbohydrate unit. According to the retrosynthetic approach shown in Scheme 1 where the corresponding carbohydrate azide 2 is accessible, it is necessary to develop an efficient methodology for introducing the required triple bond into the pyrrolidine ring providing key intermediates 3. A well-established synthetic route to 2-substituted polyhydroxylated pyrrolidines consists of a nucleophilic addition to the corresponding cyclic nitrone 4
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