Intramolecular rhodium-catalysed [2 + 2 + 2] cycloaddition of linear chiral N-bridged triynes: straightforward access to fused tetrahydroisoquinoline core

Abstract

A route for the preparation of merged symmetrical tetrahydroisoquinolines with central chirality through a rhodium-catalyzed intramolecular [2 + 2 + 2] cycloaddition involving enantiopure triynes as substrates is described. The results show that linear triynes lacking a 3-atom tether can undergo efficient cyclisation. The N-tethered 1,7,13-triynes used in our approach were easily prepared from readily accessible chiral homopropargyl amides, the basic building blocks in our approach, which were efficiently obtained by diastereoselective addition of propargyl magnesium bromide to Ellman imines. Additional substitution at the benzene rings could be attained when substituted triynes at the terminal triple bonds were employed, giving access to more complex tetrahydroisoquinolines after the rhodium-catalyzed intramolecular [2 + 2 + 2] cycloaddition. Among the different transition-metal catalysts, the Wilkinson complex (RhCl(PPh₃)₃) afforded higher yields in the cyclisation of linear triynes; however, triynes bearing a Br substituent at the terminal positions underwent the cyclisation more efficiently in the presence of [RhCl(CO)₂]₂.