Stereodivergent Construction of Tertiary Fluorides in Vicinal Stereogenic Pairs by Allylic Substitution with Iridium and Copper Catalysts

Although
much effort has been spent on the enantioselective synthesis
of tertiary alkyl fluorides, the synthesis of compounds containing
such a stereogenic center within an array of stereocenters, particularly
two vicinal ones, remains a synthetic challenge, and no method to
control the configuration of each stereogenic center independently
has been reported. We describe a strategy to achieve such a stereodivergent
synthesis of vicinal stereogenic centers, one containing a fluorine
atom, by forming the connecting carbon–carbon bond with a catalyst
system comprising an iridium complex that controls the configuration
at the electrophilic carbon and a copper catalyst that controls the
configuration at the nucleophilic fluorine-containing carbon. These
reactions occur with alkyl- and aryl-substituted allylic esters and
the unstabilized enolates of azaaryl ketones, esters, and amides in
high yield, diastereoselectivity, and enantioselectivity (generally
>90% yield, >20:1 dr, 97−99% ee). Access to all four
stereoisomers
of products demonstrates the precise control of the two configurations
independently. This methodology extends to the stereodivergent construction
of vicinal quaternary and tertiary stereocenters in similarly high
yield and selectivity. DFT calculations uncover the origin of stereoselectivity
of copper enolate in allylic substitution.