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 give 2,5-disubstituted THFs, the presence of an ester in the side chain exerts a profound effect on the chemo-and diastereoselectivity of the reaction. When submitted to standard iodoetherification conditions, ester-containing substrates gave diastereomeric mixtures of THFs, together with variable amounts of iodohydrins. Conversely, when the ester group was reduced to an alcohol or ether, the corresponding trans-THFs were obtained more quickly, with complete diastereoselectivity and without contamination by the iodohydrin. In this paper, the mechanistic details of the iodoetherification of protected 3-butenyl carbinols are revealed. The results show that the carbonyl group decreases 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 seven-membered-ring carboxonium intermediate, causing an increase in the activation barriers and a decrease in the reaction diastereoselectivity compared to the non-ester analogues.