Concise Synthesis of a Pentasaccharide Related to the Anti-Leishmanial Triterpenoid Saponin Isolated from Maesa balansae † Vishal Kumar Rajput and Balaram Mukhopadhyay* Indian Institute of Science Education and Research-Kolkata (IISER-K), HC-7, Sector-III, Salt Lake City, Kolkata 700 106, India sugarnet73@hotmail.com ReceiVed May 31, 2008 Concise synthesis of the glycone part (a pentasaccharide) of the anti-leishmanial triterpenoid saponin isolated from Maesa balansae is reported. A late-stage TEMPO-mediated oxida- tion of a primary hydroxyl group to carboxylic acid has been achieved under phase-transfer conditions. Glycosylations were performed either by thioglycoside or glycosyl trichlo- roacetimidate activation using sulfuric acid immobilized on silica (H 2 SO 4 -silica) in conjunction with N-iodosuccinimide and alone, respectively. H 2 SO 4 -silica was proved to be a better choice as promoter than conventional Lewis acid promoters such as TfOH or TMSOTf. Saponins, glycosylated secondary metabolites in plants, 1 are synthesized routinely during their normal program of growth and development. Because of their intense antifungal properties, it is believed that these molecules act as natural chemical barriers in plants against fungal attack. 2 In addition to their natural protective activity, many of them are exploited as sources for drugs, e.g., ginseng and liquorice, or food crops such as legumes and oats. 3 Therefore, this class of compounds is commercially attractive for diverse reasons. However, the detailed genetic machinery responsible for the elaboration of this important family is largely uncharacterized till date. Although a broad range of architectural diversity is observed in the saponin family, one common feature shared by all saponins is the presence of a sugar chain attached to the 3-position of the aglycon moiety. Sugar chains differ substantially from saponin to saponin; they are often branched and consist of up to five sugar units (usually selected from glucose, rhamnose, arabinose, xylose, or glucu- ronic acid). 4 The glycosylation step is believed to happen at the final stage of the saponin biosynthesis, and the saponin bioactivity largely depends on the glycosylation pattern. 5 Therefore, a clear elucidation of the biosynthetic formation of the glycone chain as well as the enzymes involved in the whole process is of absolute necessity. Moreover, to explore the medicinal activities associated with many of the saponins, chemical synthesis of the saccharide fragments will be useful. Recently, De Kimpe et al. 6 reported the isolation and characterization of six triterpenoid saponins (maesabalides I-IV) 7 isolated from the Vietnamese medicinal plant Maesa balansae that showed intense in vitro and in vivo anti- leishmanial activity against intracellular Leishmania infantum amastigotes. 8 To determine the structure-activity relationship for the saponins, they have evaluated some semisynthetic analogs of the same. However, they focused on the modification of the aglycon part only. As Leishmaniasis is a growing threat to the public health with about 350 million people living in endemic areas and an annual incidence of about 2 million cases. 9 Inadequate resources are available to tackle this disease, with treatment options limited to pentavalent antimonials as first- line chemotherapeutics and to amphotericin and pentamidine as second-line chemotherapeutics, and novel drug leads are highly needed 10 to combat this deadly disease. In order to exploit the scopes arisen from the identification of anti-leishmanial saponins from Maesa balansae, here we report the concise chemical synthesis of the pentasaccharide side chain (Figure 1), aiming for the elucidation of the biosynthetic pathway of † Dedicated to Prof. Sushanta Dattagupta, Director, IISER-K on the occasion of his 60th birthday. (1) Price, K. R.; Johnson, I. T.; Fenwick, G. R. CRC Crit. ReV. Food Sci. Nutr. 1987, 26, 27–133. (2) Papadopoulou, K.; Melton, R. E.; Legget, M.; Daniels, M. J.; Osbourn, A. E Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 12923–12928. (3) Haralampidis, K.; Trojanowska, M.; Osbourn, A. E. AdV. Biochem. Eng. Biotechnol. 2002, 75, 31–49. (4) Hostettmann, K. A.; Marston, A. Saponins. Chemistry and Pharmacology of Natural Products; Cambridge University Press: Cambridge, UK, 1995. (5) (a) Paczkowski, C.; Wojciechowski, Z. A. Phytochemistry 1994, 35, 1429– 1434. (b) Wojciechowski, Z. A. Phytochemistry 1975, 14, 1749–1753. (6) Germonprez, N.; Maes, L.; Van Puyvelde, L.; Van Tri, M.; Tuan, D. A.; De Kimpe, N. J. Med. Chem. 2005, 48, 32–37. (7) Germonprez, N.; Van Puyvelde, L.; Maes, L.; De Kimpe, N. Tetrahedron 2004, 60, 219–228. (8) Maes, L.; Vanden Berghe, D.; Germonprez, N.; Quirijnen, L.; Cos, P.; De Kimpe, N.; Van Puyvelde, L. Antimicrob. Agents Chemother. 2004, 48, 130– 136. (9) Desjeux, P Trans. R. Soc. Trop. Med. Hyg. 2001, 95, 239–243. (10) Guerin, P.; Olliaro, J. P.; Sundar, S.; Boelaert, M.; Croft, S. L.; Desjeux, P.; Wasunna, M. K.; Bryceson, A. D. Lancet Infect. Dis. 2002, 2, 494–501. FIGURE 1. Structure of maesabalide I and synthetic target. 10.1021/jo801171f CCC: $40.75  2008 American Chemical Society 6924 J. Org. Chem. 2008, 73, 6924–6927 Published on Web 08/02/2008