Synthesis of Glyphaeaside C and Structural Revisions of the Glyphaeaside Alkaloids

In 2015, ten C-alkylated iminosugars were isolated from the roots of Glyphaea brevis (Malvaceae). The alkaloids were purported to possess 1,5-dideoxy-1,5-iminohexitol cores, with the A-, B-, and C-type glyphaeasides bearing L-fuco, D-galacto, and D-gluco configurations, respectively; as well as unprecedented di-, tri-, and tetra-hydroxylated nine-carbon side chains with terminal aryl substituents. Glyphaeaside C—the only member of its type—was found to be a potent and competitive inhibitor of almond β- glucosidase (IC50 = 0.15 μM, Ki = 0.031 μM), which was especially remarkable considering the absence of any significant α-glucosidase inhibition, for which other related iminosugars with the same configuration—including α-homonojirimycin, α-1-C-(n-octyl)- 1-deoxynojirimycin, and α-1-C-(8-hydroxyoct-1-yl)-1-deoxynojirimycin—are known to possess. The structural uniqueness and peculiar glycosidase inhibitory activity of glyphaeaside C thus prompted a total synthesis investigation of its purported structure. The α-aza- C-glycoside unit was accessed via a stereoselective Grignard addition to a protected Dglucosylamine, eventually followed by a reductive amination–cyclisation to afford the D-gluco piperidine ring analogous to reported methods. After a cross-metathesis reaction to install the terminal phenol substituent, the side chain alkene moiety was subjected to complementary Sharpless asymmetric dihydroxylation reactions, followed by global deprotection to afford the two 7′,8′-threo-diols as the major products. While the NMR spectroscopic data of the afforded C-alkylated piperidine iminosugars were in agreement with similar compounds reported in the literature, they were notably dissimilar to that of natural glyphaeaside C. The iminosugars prepared from this pathway were found to be good inhibitors of human lysosomal α-glucosidase and α-galactosidase, as well as of related glycosidases from other sources.