Ir-Catalyzed Atroposelective Desymmetrization of Heterobiaryls: Hydroarylation of Vinyl Ethers and Bicycloalkenes

Abstract

A highly regio, diastereo-and enantioselective, scalable Ir-catalyzed hydroarylation of electron rich acyclic and tensioned cyclic olefins with heterobiaryls is described. The reaction of acyclic vinyl ethers, dihydrofuran and norbornenes with a variety of aryl isoquinoline, quinazoline, and picoline derivatives takes place with simultaneous installation of central and axial chirality, reaching complete branched/linear or exo/endo ratios and excellent diastereo-and enantiomeric excesses when in situ formed [Ir I /Tol-SDP] or [Ir I /Tol-BINAP] complexes are used as the catalysts. Kinetic isotope effect (KIE) analyses and a comprehensive computational study suggest that, despite fast double bond migratory insertion into Ir-H, the reaction proceeds through a modified Chalk-Harrod mechanism, starting with selectivity-determining insertion into Ir-CAryl. The regioselectivity is controlled by the electron donating alkoxy group, whereas diastereo-and enantioselectivity have a complex origin, that depend on the relative orientation of the alkoxy group and the establishment of adequate π-π interactions between the biaryl and the phosphine. ASSOCIATED CONTENT Supporting Information. Experimental procedures and characterization data for new compounds, crystallographic data for (Sa,R)-9b, (Ra,S)-7g and (Ra,R,R,S) 16h, and HPLC traces for compounds 7-11, 15-17. Additional computational details. XYZ coordinates of calculated species. This material is available free of charge via the Internet at http://pubs.acs.org.

Recent Developments in Enantioselective Transition Metal Catalysis Featuring Attractive Noncovalent Interactions between Ligand and Substrate

“…Very recently, an enantioselective iridium-catalyzed hydroarylation of vinyl ethers with heterobiaryl compounds was reported to form atropisomeric products ( Figure 42 a). 156 Biaryl spirodiphosphine ligand L15 or ( p -Tol)-BINAP L16 were optimal, depending on substrate class ( Figure 42 b), giving excellent yields and a good level of regio-, diastereo-, and enantioselectivity for both acyclic alkenes (using L15 ) and norbornenes (using L16 ). Migratory insertion of the iridium–carbon bond to the vinyl ether was proposed to be the selectivity-determining step, and detailed DFT calculations implicated several NCIs as possibly contributing to the high selectivity, although the precise interplay was complex.…”

Atroposelective transformation of axially chiral (hetero)biaryls. From desymmetrization to modern resolution strategies

“…Using [Ir I /Tol-SDP] complexes (SDP = spiro diphosphine), simultaneous generation of central and axial chirality was achieved with high regio-, diastereo-and enantioselectivity. 15 Deuterium labelling and computational evidences suggest that a modified Chalk-Harrod-type mechanism operates, and that the migratory insertion into the Ir-C Aryl bond is the selectivity-determining step.…”

Enantioselective Intermolecular Murai-Type Alkene Hydroarylation Reactions

“…In 2020, Lassaletta and co-workers reported a method for the installation of axial chirality by Ir(I)-catalyzed enantioselective hydroarylations with naphthylisoquinolines of type 42 (Scheme 13). 86 Here, using (S)-Tol-SDP or (R)-Tol-BINAP as the chiral ligand, hydroarylation of enol ethers or bicycloalkenes gave a range of demanding targets in high enantioselectivity and diastereopurity. For example, hydroarylation of acyclic vinyl ethers provided 43a-f in 70-96% yield and 94-99% e.e., whereas cyclic systems generated 43g-i in 46-76% yield and 92-97% e.e.…”