Diastereo- and Enantioselective Synthesis of Bi- and Tricyclic N‑Heterocycle-Fused β‑Lactones

The utility of the nucleophile-catalyzed (Lewis base) aldol lactonization (NCAL) process for the diastereo- and enantioselective synthesis of N-heterocycle-fused-β-lactones from N-linked ketoacids is described. A series of bi- and tricyclic, N-heterocycle-fused, β-lactones were first synthesized in racemic fashion via the NCAL process with excellent diastereoselectivity (>19:1) utilizing 4-pyrrolidinopyridine as an effective achiral Lewis base. A catalytic, enantioselective version of this NCAL process using isothiourea catalysts provided access to bicyclic β-lactone-fused, N-heterocycles in moderate to good yields (up to 80%) with high enantiocontrol (up to >99:1 er). An unusual diastereodivergent NCAL process was discovered that leads to two different products; a tricyclic N-heterocycle-fused β-lactone and a bicyclic enamine derived from in situ decarboxylation of the diastereomeric tricyclic β-lactone. The reactivity of these adducts was briefly explored.