Tertiary amines are important structural motifs in pharmaceutical therapeutics, natural products and agrochemicals. Lewis basic amines tend to bind to the metals and inhibit the catalyst making them challenging counterparts in metal catalysis. Herein, we report a broadly applicable methodology for the enantioselective synthesis of chiral α-trisubstituted α-tertiary allylic amines. This protocol utilizes chiral bicyclo[2.2.2]octadiene-ligated rhodium catalyst for regio- and enantioselective substitution of racemic tertiary allylic trichloroacetimidates with unactivated secondary amines nucleophiles. A series of chiral allylic tertiary amines were synthesized in good yields and excellent regio- and enatioselectivities.<br/>Mechanistic investigations revealed that allylic trichloroacetimidates undergo dynamic kinetic asymmetric transformation (DYKAT) in presence of diene-ligated rhodium catalyst enabling high asymmetric induction. The role of trichloroacetimidate is crucial as a leaving group, directing group and a ligand for promoting p-s-p interconversion, thereby leading to DYKAT process. Studies involving enantioenriched deuterated allylic substrates confirm that an <i>outer-sphere</i> nucleophilic attack is operative in enantioselective C−N bond formation. Density Functional Theory (DFT) calculations are being conducted to gain more insight into the reaction mechanism. This catalytic method features excellent selectivities, fast reaction times and operational simplicity. We anticipate that this method will facilitate post modification of existing drugs and discovery of novel small molecule pharmaceuticals.

Rhodium-catalyzed asymmetric allylic substitution for synthesis of chiral α-trisubstituted α-tertiary allylic amines

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