Stereocontrolled Construction of 1,2-cis-α-Glycosidic Linkages Using Glycosyl Diphenyl Phosphates and Synthesis of α-Galactosylceramide KRN7000

Abstract

The development of a general stereoselective method for 1,2-cis-α-glycosidations remains an important issue for synthesis in carbohydrate chemistry. Recently, we have achieved a highly stereocontrolled construction of 1,2-cis-α-glycosidic linkages using glycosyl diphenyl phosphates as glycosyl donors. The per-O-benzyl-protected glucosyl and galactosyl donors and the 3,4,6-tri-O-acetyl-2-azido-2-deoxygalactosyl donor each react with a range of acceptor alcohols in the presence of 0.05-0.2 equiv of HClO 4 in dioxane/Et 2 O (1:1) to afford glycosides in good yields with good to high α-selectivities. The synthetic utility of the present glycosidation method was demonstrated by a stereoselective synthesis of the α-galactosylceramide KRN7000, an activator of natural killer (NK) T cells through CD1d molecules.

Structure-Activity Relationship Studies of Novel Glycosphingolipids That Stimulate Natural Killer T-Cells

“…After the disclosure of the structure 1 by Kirin Brewery, 4) many reports on the synthesis of 1 were published from 1995 to 2011, [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] including practical synthesis of it by Kirin group. 25) As shown in Fig.…”

“…Hence the synthesis of 1 includes two key steps: -selective (or -specific) galactosylation, and the construction of three continuous asymmetric centers of the phytosphingosine chain. To connect a galactose part in -orientation, researchers have used 1-OH free garactopyranose (D), 30,33,44) thiogalactoside (E), 28,30,36,37,41) galactosyl trichloroacetimidate (F), [27][28][29][32][33][34]36,39,43) phosphite (G), 33) phosphate (H), 42) acetate (I), 37) or halide (J) as the galactose donor. 4,25,26,29,31,35,38,40) Hague, 31) and trichloroacetimidate (L) with trimethylsilyl triflate (60%) reported by Kimura et al, 32) gave the highest -stereoselectivity (exclusivity).…”