Interrupting Associative π-σ-π Isomerization Enables Z-Retentive Asymmetric Tsuji-Trost Reaction

The asymmetric Tsuji-Trost reaction has been extensively studied due to its importance in establishing stereogenic centers, often adjacent to an E-olefin moiety in organic molecules. The generally preferential formation of chiral E-olefin products is believed to result from the thermodynamically more stable syn-pi-allylpalladium intermediate. The rapid associative pi-sigma-pi isomerization makes it challenging to synthesize chiral Z-olefin products via the transient anti-pi-allylpalladium intermediate. Herein, we report a strategy for regulating associative pi-sigma-pi isomerization by tuning the steric bulkiness of the ligands, allylic leaving groups, and counteranions. The utilization of a Pd catalyst derived from chiral phosphoramidite ligands interrupts the associative pi-sigma-pi isomerization, enabling a highly efficient Z-retentive asymmetric Tsuji-Trost reaction toward an array of alpha-amino acid derivatives bearing a Z-olefin motif in high yields (up to 95%) and excellent stereoselectivity (up to 99% ee and >19:1 Z/E) with low catalyst loading (0.1 mol %). The mechanistic insights and the design strategy reported in this work pave the way for rational developments of Z-retentive asymmetric Tsuji-Trost-type reactions.