Palladium Catalyzed Enantioselective trans-C–H Functionalization of Piperidines Using a Catalytic BINOL Base Exhibiting Aggregation Driven Asymmetric Amplification

<jats:p> Piperidine is a crucial motif in pharmaceutical and agrochemical compounds and the most prevalent saturated heterocycle in FDA approved drugs. Despite this, the diversity of commercially available piperidine derivatives remains extremely limited and such building blocks are seldom enantioenriched. C–H functionalization of saturated N-heterocycles offers the potential to convert simple precursors to high value chiral materials in underexplored chemical space. Here we report the first <jats:italic toggle="yes">trans</jats:italic> -selective and highly enantioselective C–H arylation of piperidine substrates, using dual palladium and 3,3’-dibromo-BINOL catalysts. The method accommodates enantioselective desymmetrization, kinetic resolution, and diastereoselective processes on heterocycles with a variety of substitution patterns. Excellent enantio- (up to 99:1 e.r.) and diastereoselectivity is observed to yield difunctionalized N-Boc piperidines of high value to medicinal chemistry. Mechanistic investigations support an enantioselective outer sphere deprotonation mediated by a BINOLate base and reveal an asymmetric amplification arising from reactivity differences between racemic and enantiopure 3,3’-dibromo-BINOL catalysts. Leveraging mechanistic insights, a complementary racemic <jats:italic toggle="yes">trans</jats:italic> -arylation protocol was established, providing direct access to <jats:italic toggle="yes">trans</jats:italic> -arylated piperidines and contrasting with the <jats:italic toggle="yes">cis</jats:italic> -selectivity typically observed in directed C–H arylation processes. </jats:p>