Research Projects

C-hydroxymethyne glycosides, a type of C-glycosides, have attracted the glyco-chemists and biologists due to their occurrence in various bioactive natural products 1-4 (Figure 1). It was assumed that the hydroxymethyne functionality at the anomeric position would mimic the function of the endocyclic oxygen of the pyranose ring in carbohydrates. As a result, carbohydrate derivatives with a hydroxymethyl group at the anomeric position not only provide stability, being a C-glcoside, but also enhance the biological interaction. The hydroxymethyne group at the anomeric position would act as a biosimilar to a sugar unit. For example, some of the C-mannosides studied for the treatment of urinary tract infection, the hydroxymethylene C-glycoside 5 (HAI 31 nM) showed a 60-fold higher activity when compared with methylene C-glycoside 6 (HAI 6000 nM). Interestingly, the O-glycoside 7 has shown HAI 61 nM, though its stability is low when compared to 2 or 3 (Figure 2). Compound 5 (GSK3882347) is a drug developed by GlaxoSmithKline (GSK) for treating Urinary Tract Infections (UTIs) and is under phase II clinical trials. This observation clearly demonstrates the importance of hyroxymethyne linkers in sugar-based drug design and discovery. Although several methods have been reported for the preparation of C-glycosides, there are very few reactions that deliver the hydroxymethyne C-glycosides. Hence, the development of novel synthetic methods is critical for the exploration of their biological activity. We recently reported an interesting method for the synthesis of 2,3-unsaturated hydroxymethyne C-glycosides involving Wittig rearrangement.1 As shown in scheme 1, 3-O-allyl glycal derivative 8, upon exposure to n-butyl lithium in THF, provided the hydroxymethyne C-glycoside 9 as a single diastereomer. This reaction prompted us to investigate the application of the Wittig rearrangement reaction for the facile synthesis of hydroxymethyne C-glycosides. The success of the present protocol will definitely provide an economic procedure to synthesise various alkyl, hydroxymethyne C-glycosides. It also gives a deep understanding of the Wittig rearrangement in carbohydrates. In addition, the synthetic technology will pave the way for the construction of various chiral carbocycles from chiral pool starting materials.