Diastereodivergent access of spiro(pyrroloquinoline-pyrazolone) and oxa-azabicyclo[3.2.1]octane scaffolds via cascade approaches

Abstract

Owing to the increased interest in the biological activity and reactivity of indole-fused heterocycles, they, in particular, 1,7-fused motifs (pyrroloquinolines), have received growing attention over the last few decades. Alternatively, bicyclo[3.2.1]octanes (BCOs) have extensive applications in medicinal chemistry. However, the easy synthesis of 1,7-fused indole scaffolds from easily accessible precursors has remained a challenging goal. Herein, we developed base- and solvent-controlled diastereodivergent (4 + 2) annulations between enone-tethered indoles and alkylidene pyrazolones, enabling two distinct diastereomers of spiro(pyrroloquinoline-pyrazolone) frameworks having three contiguous chiral centres, including one chiral quaternary spiro centre (54 examples, up to 98%). Moreover, the use of indole acceptors allows the synthesis of hitherto unknown indole-fused oxa-azabicyclo[3.2.1]octanes in high yields (20 examples, up to 93%). The current protocols feature operational simplicity, high atom economy, gram-scale synthesis, and post-synthetic modifications. Furthermore, these annulations could be applicable in the synthesis of drug-relevant molecules. Additionally, mechanistic studies on the reaction pathways of these annulations are included.