Enantioselective Synthesis of N–N Indole-PyrroleAtropisomers via Palladium/Chiral Phosphonic Acid Relay Catalysis

Abstract

N–N atropisomers have emerged as indispensable structural motifs in natural products, medicinal chemistry, and asymmetric catalysis due to their unique stereochemical properties. Herein, we introduce an innovative synthetic methodology for the enantioselective construction of N–N indole-pyrrole atropisomers through palladium/chiral phosphonic acid (CPA) relay catalysis. This process involves allylic alkylation, condensation, and dehydration between vinyl methylene cyclic carbonates and N-amino-indoles, enabling the efficient synthesis of structurally diverse N–N atropisomers with excellent yields (up to 92%) and exceptional enantiocontrol (up to 99% ee). Furthermore, biological evaluation revealed that compounds 3ta, 3sa, 3ca, 3bd, and 3bi demonstrate potent anti-inflammatory activity, significantly inhibiting nitric oxide (NO) production in LPS-stimulated RAW264.7 macrophages.