Semiempirical MO approach to the mechanism of the NIS-mediated nucleophilic addition to glycals: multicomponent intermediates as models to tackle reactivity in organic chemistry

Abstract

A proposition for the nucleosidation mechanism of five-membered glycals promoted by N-iodo-succinimide (NIS), leading to 2'-deoxy-2'-iodo-beta-nucleosides, is presented herein supported by semiempirical MO calculations. The proposed mechanism goes through the formation of multicomponent molecular intermediates that drastically diminish the total energy values when compared to charged intermediates (via iodonium species). The nucleosidation step was performed establishing either bicomponent (dihydrofuran-NIS) or tricomponent (dihydrofuran-NIS-silylated nucleobase) intermediates. The latter possibility has been shown to be the most likely (according also to DFT calculations), and suggests that the mechanism should take place in a concerted fashion. According to the tricomponent pathway, we have studied the stereoselectivity of the process, finding that the activation energy for the beta-nucleosidation step is between similar to 6 kcal/mol (AM1) and similar to 10 kcal/mol (PM3) more favorable than that of the corresponding alpha-anomer, in agreement with the experimental results. The final step consists in an intramolecular silyl-transfer process accompanied by the NIS cleavage (in a different way depending on the calculation method employed), giving rise to the ultimate formation of N-silyl-succinimide. (C) 2005 Elsevier Ltd. All rights reserved.