Synthesis of 2‐C‐Branched Oligo(glyco–amino acid)s (OGAAs) by Ring Opening of 1,2‐Cyclopropanecarboxylated Sugar Donors

Abstract

Carbohydrates decorated with amino acids are becoming an important area of glyco-chemistry research. Possessing the architecture of a sugar and an amino acid in a single molecule, these glyco–amino acids (GAAs) are expected to exhibit the characteristics of both carbohydrates and amino acids, which are both biological polymer precursors. C-branched glyco–a-amino acid moieties are found in a ACHTUNGTRENNUNGvariety of nucleoside antibiotics, such as polyoxins, miharamycins, nikkomycin and amipuramycin. Very few methods are available in the literature for the synthesis of monosaccharide-derived C-branched GAA derivatives. Linking an a-amino acid at C-2 or C-4 through a C C bond has been found to be very difficult. For this reason, the biological importance of these GAAs is not yet fully understood. It has been shown that unnatural 2-C-acetonylsugars serve as metabolic substrates for cell surface engineering by mimicking 2-N-acetylsugars. Similarly, a 2-C-N-hydroxy ACHTUNGTRENNUNGacetamide mimic of GlcNAc was synthesised and shown to be an inhibitor of the biosynthesis of lipid A. Herein, we report the first stereoselective synthesis of 2-C-branched oligo(glyco– amino acid)s (OGAAs) by ring opening of 1,2-cyclopropanecarboxylated sugar donors. The high reactivity and regioselectivity of donor–acceptor cyclopropanes has been well documented in the literature. 1,2-cyclopropanecarboxylated sugars have been used as donor–acceptor cyclopropanes in the synthesis of 2-Cbranched monosaccharides through electrophilic C1–C7 ACHTUNGTRENNUNGcyclopropane ring opening or by transition-metal-catalysed glycosylation. Recently, a four-component Pavarov reaction and a transition-metal-mediated radical reaction were developed for the direct synthesis of 2-C-branched carbohydrate derivatives from glucals. These branched glycosides were further derivatised to bicyclic carbohydrate 1,2lactones. Glucal-derived donor–acceptor cyclopropanes have also been used as 1,3-dipoles under acidic conditions, which result in (3+2) cycloaddition reactions in presence of dipolarophiles. By using the ability of 1,2-cyclopropanecarboxylated sugars to undergo electrophilic ring opening assisted by the adjacent oxygen in presence of an electrophile, we herein present the N-iodosuccinimide (NIS)mediated ring opening of 1,2-cyclopropanecarboxylated glycosyl donors with carbohydrate O-nucleophilic glycosyl bond acceptors. To achieve this novel glycosylation reaction, we began by using 1,5-anhydro-2,6-dideoxy-1,2-C-(exo-carbomethoxymethylene)-3,4-di-O-benzyl-a-l-rhamnal 1 as the donor and 1,2-3,4-diisopropylidine-a-d-galactose 2 as the acceptor with NIS as the electrophile at 0 8C in acetonitrile. However, no expected disaccharide was observed under these reaction conditions, even with an excess of acceptor 2 (>3 equiv). Similar reaction conditions with dichloromethane as the