Diastereocontrolled Synthesis of Carbon Glycosides of N-Acetylneuraminic Acid via Glycosyl Samarium(III) Intermediates.

R-O-Glycosides of N-acetylneuraminic acid (Neu5Ac, 1, Scheme 1) are often found terminating the oligosaccharide component of cell-surface glycoproteins and glycolipids. Neu5Ac is involved in a number of important biological events: intercellular interactions such as adhesion, aggregation, and agglutination; masking of antigenic oligosaccharides and suppressing undesired immune reactions (antirecognition phenomena); influencing the cell membrane permeability for ions, amino acids, and proteins; and protection of glycoproteins against proteolysis.1 Terminal Neu5Ac is an attachment site of pathogens to the cells, and often catabolic and inflammatory processes are initiated on the removal of this carbohydrate group.2 In general the “right” life time of a cell is a reflection of a delicate balance between the introduction and removal of terminal Neu5Ac or other sialic acids. The glycosidic bond of Neu5Ac is cleaved in ViVo by hydrolase type enzymes, called neuraminidases.3 Therefore, designing nonhydrolyzable analogs of Neu5Ac-R-O-glycosides is an attractive approach to control, at the molecular level, events of crucial importance to glycobiology and immunology. The replacement of the interglycosidic oxygen atom by a methylene group, for example, generates a class of hydrolytically and metabolically inert isosteres, the Neu5Ac C-glycosides. Despite several elegant methods for direct carbon-carbon (C-C) bond formation at the anomeric center in aldoses and ketoses,4 no major advances have been reported in the synthesis of Neu5Ac C-glycosides.5 The major problem confounding their synthesis is the requirement that the C-C bond being formed results in a quaternary C-atom. Herewith, we report our findings of a general method for diastereocontrolled preparation of R-C-glycosides of Neu5Ac. This approach is tolerant of a wide variety of protecting groups. The reducing potential of SmI2 is exploited through the in situ generation of an N-acetylneuraminyl samarium(III) species and its coupling to carbonyl compounds under Barbier conditions.6 In model studies that led to this method, the SmI2-promoted generation of the anomeric capto-dative free radical 3 was attempted, employing an ester tethered Neu5Ac-sulfone 27 (Scheme 1). It was anticipated that 3 would collapse into a mixture of C-glycosides by cyclization through an exoand/or endo-mode.8 Surprisingly, instead of the anticipated cyclic C-glycosides (5 and/or 6), the 2-deoxy compound 79 was isolated in excellent yield and stereoselectivity. No trace of the C-2-epimer having an equatorial carboxy function was observed. This exceptional stereoselectivity suggested an intermediate second electron transfer providing the organosamarium(III) derivative 4, in which the bulky I2Sm(III)-substituent adopts the more thermodynamically stable equatorial position. A diastereocontrolled synthesis of R-linked C-disaccharides was designed using this C-2-samariated Neu5Ac derivative