A Noven Radical Ring-Enlargement Reaction : The Reaction Mechanism and the Medicinal Chemical Application

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We developed a regio-and stereoselective method for introducing 1-hydroxyethyl, 2-hydroxyethyl, and vinyl groups at the position β to a hydroxyl group in halohydrins or α-phenylselenoalkanols using an intramolecular radical cyclization reaction with a dimethyl-or diphenylvinylsilyl group as a temporary connecting radical-acceptor tether (Scheme 14). Thus, when a vinylsilyl ether of halohydrins or α-phenylselenoalkanols was subjected to the radical reaction with Bu_3SnH/AIBN, the selective introduction of both 1-hydroxyethyl and 2-hydroxyethyl groups can be achieved, depending on the concentration of Bu_3SnH in the reaction system, via a 5-exo-cyclization intermediate or a 6-endo-cyclization intermediate, respectively, after oxidative ring-cleavage by treating the cyclization products under Tamao oxidation conditions. A vinyl group can also be introduced by photo-irradiating the vinylsilyl ether in the presence of (Bu_3Sn)_2, and then treating the resulting atom-transfer 5-exo-cyclization product with fluoride ion. The mechanistic studies showed that the kinetically favored 5-exo-cyclized radical was trapped when the concentration of Bu_3SnH was high enough. At lower concentrations of Bu_3SnH and higher reaction temperatures, the 5-exo-cyclized radical rearranged into the more stable ring-enlarged 4-oxa-3-silacyclohexyl radical, which was then trapped with Bu_3SnH.The ring-enlarging rearrangement was experimentally proved to occur via a pentavalent-like silicon-bridging transition state. This radical reaction with a vinylsilyl tether has been successfully applied to the synthesis of 4'-branched-chain sugar nucleosides as a nucleoside unit for antisense studies and also for potent antiviral nucleosides. C-glycosides trisphosphates as potent IP_3-receptor ligands were also synthesized using the radical reaction as the key step.