Diastereoselective Radical 1,4-Ester Migration: Radical Cyclizations of Acyclic Esters with SmI2

Reductive cyclizations of carbonyl compounds, mediated by samarium(II) diiodide (SmI2, Kagan's reagent), represent an invaluable platform to generate molecular complexity in a stereocontrolled manner. In addition to classical ketone and aldehyde substrates, recent advances in radical chemistry allow the cyclization of lactone and lactam-type substrates using SmI2. In contrast, acyclic esters are considered to be unreactive to SmI2 and their participation in reductive cyclizations is unprecedented. Here, we report a diastereoselective radical 1,4-ester migration process, mediated by SmI2, that delivers stereodefined alkene hydrocarboxylation products via radical cyclization of acyclic ester groups in alpha-carbomethoxy delta-lactones. Isotopic labeling experiments and computational studies have been used to probe the mechanism of the migration. We propose that a switch in conformation redirects single electron transfer from SmI2 to the acyclic ester group, rather than the more reactive lactone carbonyl. Our study paves the way for the use of elusive ketyl radicals, derived from acyclic esters, in SmI2-mediated reductive cyclizations.

Automated summary

Reductive cyclizations of carbonyl compounds mediated by SmI2 provide a stereocontrolled approach to generate molecular complexity. While previous studies mainly focused on ketone and aldehyde substrates, this research demonstrates the successful cyclization of lactone and lactam-type substrates as well. Additionally, the study presents a novel diastereoselective radical 1,4-ester migration process mediated by SmI2, allowing the formation of stereodefined alkene hydrocarboxylation products via radical cyclization of acyclic ester groups.