Tetrahydrofuran Formation through Intramolecular Iodoetherification: Mechanistic Insights into the Neighbouring-Group Participation of an Ester

During the iodoetherification of chiral and conformationally restricted 3-butenyl-carbinols to obtain 2,5-disubstituted THF rings, the presence of an ester in the side chain exerted a profound effect in the chemo- and diastereoselectivity of the reaction. When submitted to standard iodoetherification conditions, ester-containing substrates gave diastereomeric mixtures of THF rings, together with variable amounts of iodohydrins. Conversely, when the ester group is reduced to alcohol or ether, the corresponding trans-THF are obtained faster, with complete diastereoselectivity and without contamination of the iodohydrin. In this work, the mechanistic details of the iodoetherification of protected 3-butenyl-carbinols are unveiled. The results show that the carbonyl group reduces the nucleophilicity of the acetonide oxygen atoms and stabilizes the reactants by a carbonyl-iodonium through-space interaction. Additionally, it promotes the formation of a stable 7-membered carboxonium intermediate, causing an increment of the activation barriers and a decrease in the reaction diastereoselectivity with respect to the non-ester analogues.