The addition of malonates to glycals: A general and convenient method for the synthesis of 2-C-branched carbohydrates

A general and convenient synthesis of carbohydrate 2-C-analogs by addition of malonates to glycals is described. The method is applicable to glycals derived from hexoses and pentoses and is characterized by easily available precursors. The reactions are mediated by manganese(In) or cerium(IV) and proceed via intermediarily generated malonyl radicals. All additions exhibit a very high degree of regioselectivity, since only 2-C-branched sugars were obtained. This result can be best rationalized by favorable orbital interactions between the SOMO of the malonyl radical and the HOMO of the double bond. Variation of the steric demand of the malonate or the glycal allows the stereoselectivities to be increased up to >98%. Highest selectivities were obtained with tri-O-acetyl-D-galactal and di-O-acetyl-D-arabinal, where the attack occurs exclusively from one face of the carbohydrate. For all cerium(IV)-mediated reactions, methyl glycosides are formed as main products in 73-89% yield, which can be isolated in analytically pure form on a gram scale. Strong evidence was found for a ligand transfer rather than electron transfer during the formation of carbohydrate 1-nitrates, which sheds light on the mechanism of transition-metal-mediated radical reactions. In terms of starting materials, stereoselectivities, and yields, the herein described method for the synthesis of carbohydrate 2-C-analogs is superior to literature known procedures.