Transannular vs Intramolecular Insertion Reactions of Transition Metal Carbenes: Evaluation of a Transannular Approach to Cyclooctane Ring Synthesis

The efficacy of closing cyclooctane rings via transannular metal-stabilized carbene insertion reactions within an 11-membered macrocyclic lactone ring was explored. The impact of performing these reactions in a transannular fashion was evaluated via a comparative study of closely analogous intramolecular (but not transannular) processes. Closure of a γ-lactone ring via intramolecular cyclopropanation on a moderately electron-deficient alkene proceeded in good yield under Cu(acac)2 catalysis, whereas analogous transannular cyclopropanation was thwarted by competitive β-hydride migration. In contrast, use of a more electron-rich methoxy-substituted alkene resulted in successful transannular cyclopropanation to afford the desired cyclooctane ring-containing product.