Catalytic endo-stereoselective [2+2] cycloaddition of norbornadienes with internal alkynes

Facial stereoselective transformations of bicyclic compounds offer streamlined access to conformationally constrained scaffolds that are valuable in catalysis, materials science and drug discovery. Owing to the higher electron density of the highest occupied molecular orbital on the exo-face, norbornadiene (NBD), a typical bicyclic molecule, undergoes most reactions on its more accessible exo-face, whereas reactions on the endo-face remain underdeveloped. Here we report a nickel(0)-catalysed endo-stereoselective [2+2] cycloaddition of NBDs with unactivated internal alkynes, enabled by ligand-mediated facial differentiation of NBDs and nickel-controlled configuration of a key intermediate. This method provides an expedient pathway to important scaffolds, including endo-tricyclononadienes and substituted homocubanes, with excellent atom economy. The utility of this scalable reaction is demonstrated through applications of the products in asymmetric catalysis and in the synthesis of drug analogues.