Atroposelective construction of indole-fused diazocines via gold(I)-catalysed 8-endo-dig cyclisation

Abstract

Axially chiral N-bridged biaryls embedded in medium-sized rings remain largely unexplored because of the combined challenges associated with C–N axial chirality and medium-ring formation. Here we report a gold(I)-catalysed atroposelective intramolecular cyclisation of indole-derived aryl propiolamides that enables direct access to indole-fused diazocines combining a C–N stereogenic axis with a conformationally constrained diazocine core. The transformation proceeds through a stereocontrolled 8-endo-dig hydroarylation promoted by a cationic gold complex bearing a BINOL-derived phosphoramidite ligand, affording the target scaffolds in high yields and excellent enantioselectivities across a broad substrate scope. DFT and QTAIM analyses reveal that stereocontrol originates from differential non-covalent interactions in key cyclisation intermediates. The resulting diazocines exhibit high barriers to racemisation and can be further diversified through downstream functionalisation without erosion of enantiopurity. Preliminary spectroscopic and DNA-interaction studies indicate that these rigid atropisomeric frameworks may be relevant for applications in molecular recognition. Overall, this work establishes a general catalytic strategy for the construction of medium-sized N-bridged atropisomers and expands the scope of gold-catalysed asymmetric cyclisations.