Divergent access to E- or Z-trisubstituted medium-sized cycloalkenes by Pd-catalysed cycloaddition

Despite their significance in nature, medium-sized rings (particularly 9-11 membered ones) are non-existent in commercial small-molecule drugs largely due to the lack of efficient syntheses. Even with the widespread presence of macrocyclic alkenes in therapeutic agents, stereoselective access to either E- or Z-alkenes remains a formidable challenge. The few available methods for stereoselective macrocyclic alkene synthesis necessitate the use of geometrically pure E- or Z-alkene starting materials. Here we report the construction of 11-membered heterocyclic alkenes through Pd-catalysed formal cycloaddition of two readily available building blocks. This catalytic method also achieves a ligand-induced catalytic divergent preparation of either E- or Z-trisubstituted cycloalkenes starting from common terminal alkene substrates. Density functional theory calculations establish that the key alkoxide-chelated Pd-π-allyl intermediate adopts η¹ or η³ coordination depending on the ligand used. This leads to allylic substitution using opposite π-allyl faces and in turn E- or Z-geometry in the cycloalkene products.