A Transient Directing Group Strategy Enables Enantioselective Reductive Heck Hydroarylation of Alkenes

Abstract

Metal-coordinating directing groups have seen extensive use in the field of transition-metal-catalyzed alkene functionalization; however, their waste-generating installation and removal steps limit the efficiency and practicality of reactions that rely on their use. Inspired by developments in asymmetric organocatalysis, where reactions rely on reversible covalent interactions between an organic substrate and a chiral mediator, we have developed a transient-directing-group approach to reductive Heck hydroarylation of alkenyl benzaldehyde substrates that proceeds under mild conditions. Highly stereoselective migratory insertion is facilitated by in situ formation of an imine from catalytic amounts of a commercially available amino acid additive. Computational studies reveal an unusual mode of enantioinduction by the remote chiral center in the transient directing group.Among the foremost challenges in modern synthetic chemistry is forming carbon-carbon bonds to establish stereocenters remote from existing functional groups. Catalytic enantioselective alkene functionalization has emerged as an attractive strategy owing to the widespread accessibility and unique reactivity profile of alkenes. Within the contemporary alkene functionalization toolkit, palladium-catalyzed Heck-type arylations [1] constitute an especially powerful mode of reactivity as a result of their broad substrate scope and functional-group compatibility. Nevertheless, significant limitations in Heck-type chemistry remain, including controlling regioselectivity with multi-substituted, electronically neutral alkenes; suppressing b-hydride elimination to enable interception with additional reaction partners; and achieving stereoinduction during intermolecular migratory insertion. [2] The use of directing groups (DGs), functional motifs containing one or more binding sites that are capable of facilitating efficient intramolecular delivery of a reagent or catalyst, is a classical strategy in organic synthesis for controlling reactivity and selectivity. [3] In recent years, remov-able-DG strategies have been successfully applied to various alkene functionalization reactions, [4] including classical Mizoroki-Heck alkene arylations. [5] In the realm of difunctionalization and hydrofunctionalization of acyclic internal alkenes, removable bidentate DGs, such as 8-aminoquinoline-derived amides, have proven especially valuable due to their ability to suppress b-hydride elimination and allow subsequent transmetalation/ligand exchange. [6,7] While reactions involving removable DGs are intrinsically valuable, they are limited by the fact that the DG needs to be installed and cleaved, requiring a minimum of two concession steps (Scheme 1 A). Additionally, reactions using DGs are difficult to render enantioselective owing to a lack of available coordination sites on the metal for a chiral ligand. [8] Developing a strategy whereby a chiral directing moiety could condense with the substrate reversibly, promote the desired reaction, and then dissociate effectiv...