Unveiling a key catalytic pocket for the ruthenium NHC-catalysed asymmetric heteroarene hydrogenation.

The chiral ruthenium(ii)bis-SINpEt complex is a versatile and powerful catalyst for the hydrogenation of a broad range of heteroarenes. This study aims to provide understanding of the active form of this privileged catalyst as well as the reaction mechanism, and to identify the factors which control enantioselectivity. To this end we used computational methods and in situ NMR spectroscopy to study the hydrogenation of 2-methylbenzofuran promoted by this system. The high flexibility and conformational freedom of the carbene ligands in this complex lead to the formation of a chiral pocket interacting with the substrate in a "lock-and-key" fashion. The non-covalent stabilization of the substrate in this particular pocket is an exclusive feature of the major enantiomeric pathway and is preserved throughout the mechanism. Substrate coordination leading to the minor enantiomer inside this pocket is inhibited by steric repulsion. Rather, the catalyst exhibits a "flat" interaction surface with the substrate in the minor enantiomer pathway. We probe this concept by computing transition states of the rate determining step of this reaction for a series of different substrates. Our findings open up a new approach for the rational design of chiral catalysts.