Palladium-Catalyzed, Enantioselective (3 + 2)-Cycloannulation of β-Keto Esters with Alkylidene 2H-Indoles toward Complex Indole-Based Heterocycles

A cooperative approach toward biologically important N-fused polycyclic indoles with synthetically challenging tetracyclic [6–5–5–6] and [6–5–5–5] core structures has been developed. The concept is based on a highly stereoselective (3 + 2)-cycloannulation of chiral metal enolates with a reactive vinylogous iminium ion, both generated in situ via dual activation with a single chiral Pd catalyst (5 mol %). Densely functionalized pyrrolo[1,2-a]indoles with three contiguous chiral centers were constructed with high stereoselectivities (>95:5 d.r. and up to >99% ee) and excellent yields (up to 99%). ESI-MS studies and additional control experiments provided a clear mechanistic picture of the cycloannulation event. The products were readily transformed into an array of valuable, indole-based, highly complex heterocycles.