Aza-[3 + 3] Annulations: A New Unified Strategy in Alkaloid Synthesis

An aza-[3 + 3] annulation or formal cycloaddition strategy for constructing complex heterocycles, chiefly alkaloids, is reviewed here. This annulation involves a Knoevenagel-type condensation of α,β-unsaturated iminium salts with vinylogous amides or urethanes followed by a 6π-electron electrocyclic ring-closure. Both the inter- and intramolecular aza-annulation pathways illustrated here constitute a stepwise formal [3 + 3] cycloaddition in which two σ-bonds are formed in addition to a new stereogenic center adjacent to the heteroatom. This review describes our total synthesis efforts in the last ten years to unequivocally demonstrate that this aza-[3 + 3] annulation can serve as a powerful approach and a unified strategy in alkaloid synthesis.