Differential reactivity of carbohydrate hydroxyls in glycosylations. I. Intramolecular interaction of the 5′-hydroxyl group with the heteroaromatic base in a model compound of 2′-deoxycytidine

Abstract

It is a well-recognized conjecture that the unusual reactivity of certain carbohydrate hydroxyls in glycosylation reactions is due to non-covalent intramolecular bonding interactions involving that hydroxyl. A model compound 1-[β-D-2′,3′-dideoxyribofuranosyl]-2-(1H)-pyrimidinone, which is related to the poor glycosyl acceptor 2′-deoxy-3′-O,4-N-diacetylcytidine (1), has been studied in order to assess the effects of hydrogen bonding involving 05′—H and the heteroaromatic system present in the molecule. The conformational potential energy surfaces of the model compound (lacking only the acetoxy at C3′ and the acetamido at C4) were calculated, using semiempirical (PM3) and abinitio (STO-3G) methods. The [Formula: see text] intramolecular hydrogen-bonded syn conformation of the model compound is the global minimum at the abinitio level of theory. The existence of this intramolecular hydrogen bonding was confirmed, theoretically, by Bader-type topological analysis of charge distribution at the 3-21G**//STO-3G level of theory. Such a conformation of the model compound strongly resembles that found for 1 by NMR in CD2Cl2 solution. The complex formation between this model compound and BF3 was also studied at the STO-3G, 3-21G**//STO-3G, and 6-31G**//STO-3G levels of theory. The results explain why glycosylation of hydrogen-bonded substrates succeeds when promoted by Lewis acids.