Stereoselective preparation of deuterium-labeled sugars:: (6R)-(6-2H1)-N-acetylglucosamine derivatives

The preparation of methyl (6R)-(6-H-2(1))-2-deoxy-2-N-acetamido-alpha-D-glucose (8 alpha-d) and methyl (6R)-(6-H-2(1))-2-deoxy-2-N-acetamido-beta-D-glucose (8 beta-d) is described. The key step in the synthesis was the stereoselective reduction of a C6-aldehydo-GlcNAc derivative with (R)-(+)-Alpine-Borane-d. Reduction of either methyl 6-aldehydo-3,4-di-O-benzyl-alpha-GlcNAc (6 alpha) or methyl 6-aldehydo-3,4-di-O-benzyl-beta-GlcNAc (6 beta) using (R)-(+)-Alpine-Borane-d in CH2Cl2 was significantly more stereoselective (>15:1 stereoselectivity for both anomers) than was reduction with NaBD4 in MeOH. The absolute stereochemistry at C6 of the deuterated GlcNAc derivatives was determined from H-1 NMR analysis of the conformationally locked sugars, methyl (6R)-(6-H-2(1))-4,6-O-benzylidene-2-deoxy-2 N-acetamido-alpha-D-glucose (9 alpha-d) and methyl (6R)-(6-H-2(1))-4,6-O-benzylidene-2-deoxy-2- beta-D-glucose (9 beta-d). Comparison of (3)J(H5,H6) values and H-1-H-1 NOEs for the nondeuterated and deuterated benzylidene derivatives showed that reduction with (R)-(+)-Alpine-Borane-d gave the (6R)-(6-H-2(1)) epimer as the major product for both the GlcNAc alpha and beta methyl glycosides. This stereoselective reduction enabled the H-1 NMR signals for the prochiral H6 and H6' protons in a series of GlcNAc derivatives to be assigned.