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Cyclometalated Iridium–PhanePhos Complexes Are Active Catalysts in Enantioselective Allene–Fluoral Reductive Coupling and Related Alcohol-Mediated Carbonyl Additions That Form Acyclic Quaternary Carbon Stereocenters

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journal contribution
posted on 25.01.2019, 17:36 by Leyah A. Schwartz, Michael Holmes, Gilmar A. Brito, Théo P. Gonçalves, Jeffery Richardson, J. Craig Ruble, Kuo-Wei Huang, Michael J. Krische
Iridium complexes modified by the chiral phosphine ligand PhanePhos catalyze the 2-propanol-mediated reductive coupling of diverse 1,1-disubstituted allenes 1a1u with fluoral hydrate 2a to form CF3-substituted secondary alcohols 3a3u that incorporate acyclic quaternary carbon-containing stereo­diads. By exploiting concentration-dependent stereo­selectivity effects related to the interconversion of kinetic (Z)- and thermodynamic (E)-σ-allyl­iridium isomers, adducts 3a3u are formed with complete levels of branched regio­selectivity and high levels of anti-diastereo- and enantio­selectivity. The utility of this method for construction of CF3-oxetanes and CF3-azetidines is illustrated by the formation of 4a and 6a, respectively. Studies of the reaction mechanism aimed at illuminating the singular effectiveness of PhanePhos as a supporting ligand in this and related transformations have led to the identification of a chromatographically stable cyclometalated iridium–(R)-PhanePhos complex, Ir-PP-I, that is catalytically competent for allene–fluoral reductive coupling and previously reported transfer hydrogenative C–C couplings of dienes or CF3-allenes with methanol. Deuterium labeling studies, reaction progress kinetic analysis (RPKA) and computational studies corroborate a catalytic mechanism involving rapid allene hydrometalation followed by turnover-limiting carbonyl addition. A computationally determined stereo­chemical model shows that the ortho-CH2 group of the cyclometalated iridium–PhanePhos complex plays a key role in directing diastereo- and enantio­selectivity. The collective data provide key insights into the structural–interactional features of allyl­iridium complexes required to enforce nucleophilic character, which should inform the design of related cyclometalated catalysts for umpoled allylation.