Enantioselective Synthesis of Spiro-bis-N-heterocyclic Lactams via Formal (3+2) Cycloaddition of 3-Methylene Isoindolinones with C3-Substituted 2-Indolylmethanols

A stereoselective formal (3+2) cycloaddition protocol between 3-methylene isoindolinones and C3-substituted 2-indolylmethanols has been developed. The reactions afforded a wide range of chiral spiro-bis-N-heterocyclic lactams bearing nonadjacent stereocenters, including a quaternary carbon spiro chiral center in good yields (up to 98%) and excellent enantio- and diastereoselectivities (up to >99% ee, >20:1 dr) by chiral phosphoric acid organocatalysis (0.5 mol %). Gram-scale reactions and diversified synthetic transformations of the desired spiro-lactams without loss of stereochemical purity further substantiate their potential utility.