Anthracene-fused isoxazolopyrrolo[2,1-a]isoquinolines via an endocyclic N-acyliminium ion cyclization: a joint experimental and theoretical study

A simple and efficient strategy is reported for the synthesis of anthracene-fused isoxazolopyrrolo[2,1-a]isoquinolines via an endocyclic N-acyliminium ion cyclization. The cyclization of 18-aryl-21-(2-arylethyl)-22-hydroxy-16-oxa-17,21-diazahexacyclo[6.6.5.315,19.02,7.09,14.015,19]docosa-2,4,6,9,11,13,17-heptaen-20-ones proceeds with high stereoselectivity, leading to 28-aryl-30-oxa-12,29-diazaoctacyclo[13.6.6.32,14.02,14.03,12.04,9.016,21.022,27]triaconta-4,6,8,16,18,20,22,24,26,28-decaen-13-ones. The N-acyliminium cyclization of 18-aryl-21-(2-arylethyl)-20-hydroxy-16-oxa-17,21-diazahexacyclo[6.6.5.315,19.02,7.09,14.015,19]docosa-2,4,6,9,11,13,17-heptaen-22-ones occurs only for substrates with electron-rich aromatic groups in the arylalkyl fragment. In these cases, cyclization also proceeds with a high stereoselectivity with the formation of anthracene-fused isoxazolopyrrolo[2,1-a]isoquinolines as single diastereomers. To understand the mechanisms that allow for cyclization of N-acyliminium ion a quantum chemical investigation was performed.