Henry condensations with 4 , 6 - O - benzylidenylated and non - protected D - glucose and L - fucose via DBU - catalysis

Mechanistic intermediates, and thermodynamically favored side products, in the Henry condensations of partially protected and non-protected pyranoses with a free anomeric hemiacetal function with nitromethane in various solvents for the kinetically controlled syntheses of C-glycopyranosides in the presence of DBU/molecular sieve catalyst system were identified. © 2003 Elsevier Science Ltd. All rights reserved. Carbohydrates play an important role in the biological activity of glycoconjugates such as glycolipids, bloodgroup antigens and complex glycoconjugates of plant, bacterial or viral origin. A particular class of carbohydrate derivatives, C-glycoside carbohydrate analogs are important enzyme inhibitors. Being structurally, chemically, and conformationally similar to O-glycosides but acidand enzymatically stable, aminomethyl C-glycosides are potentially more stable as mimetics and pseudo-substrates. They are obtainable from nitromethyl C-glycosides. One of the most common methods for the chain extension of carbohydrates is the Henry condensation of pentoses and hexoses with nitromethane in the presence of a strong base. In 1946 Sowden and Fisher condensed 4,6-O-benzylidene-D-glucose 1b with nitromethane in the presence of methoxide to give acyclic D-heptitol 2b and cyclic nitromethyl -D-glucopyranoside 3b in 21 and 5% yield, respectively. Later, Petrus et al. improved the total yields of unprotected nitromethyl D-hexopyranosides, but their approach is lengthy and complicated, requires careful workup, with adjustment of pH, and produces isomeric mixtures. Strong bases (HO, MeO) in these procedures in protic solvents lead to acyclic compounds (i.e. 2b, Scheme 1). Their hot dehydration ( S>0; G= H−T S) gives cyclic forms, reverting only very slowly to acyclics, at low temperatures. Presumably, acyclics, having more hydroxyl groups, are stabilized by solvation in protic solvents. We had synthesized directly cyclic compounds in aprotic solvents with a highly active bifunctional catalyst 2-hydroxypyridine and DBU/molecular sieve with an improved yield of 77%. We avoided protic solvents in view of the quoted (Scheme 3) pKa of DBU, which would provide just another way of creating RO, in ROH. The cyclic 3b was produced in a single step along with two minor byproducts 2b and 4b.