Ligand-controlled regiodivergence in Pd-catalyzed coupling of azlactones with isoprene

Transition-metal-catalyzed allylation of azlactones represents an elegant strategy for the synthesis of valuable α-quaternary amino acids. While much progress has been achieved, catalytic prenylation and reverse prenylation of azlactones have been less explored. Regiodivergent catalysis, aiming at attaining distinct regioisomers from the same starting materials through varying the catalyst, is an emerging strategy in synthetic chemistry. Herein, we present an atom-economical coupling of azlactones and isoprene with palladium catalysis in which ligand-controlled regiodivergence is achieved. With monophosphine PPhCy2 as ligand, reverse-prenylated azlactones are produced, while the selectivity switches to prenylation when varying to bisphosphine ligand dppe. The regiodivergence relies on tuning the coordination environment and steric effects. Initial rate kinetic analysis suggests a change in the rate-determining step induced by the optimal ligand. Furthermore, this protocol provides an expedient entry point to access quaternary-prenylated and reverse-prenylated amino acids, which have potential in the incorporation of peptides.