Active, selective, and stable single-component precatalysts for asymmetric allylic alkylation

The stereoselective construction of new carbon-element bonds is a crucial aspect of organic synthesis. Among the many strategies developed to date, palladium-catalysed asymmetric allylic alkylation is commonly used to access chiral molecules in natural product and active pharmaceutical ingredient synthesis. The use of modular Trost-type ligands and phosphinooxazoline (PHOX) ligands results in generally high stereoselectivity for a wide range of transformations. However, these reactions nearly always require relatively high catalyst loadings (5-10 mol%), reaction-specific catalyst preactivation protocols, and excess chiral ligand to ensure high yield and selectivity. Here we report the isolation and catalytic evaluation of a series of chiral palladium(0) single-component precatalysts that are active for a variety of asymmetric allylic alkylation reactions. The four Trost-type precatalysts in this work are the first characterized examples of stable, isolable Pd complexes with the diphosphines coordinated in the desired κ2-P,P fashion. All of the palladium(0) complexes are stable for >12 months when stored under nitrogen, and can be handled as solids and even in solution under air for hours without decomposition. A catalytic evaluation of these single-component precatalysts across 9 distinct asymmetric allylic alkylation reactions reveals excellent performance in terms of reactivity, selectivity, practicality, and minimizing palladium and chiral ligand loading. This enables both small-scale multivariate screening studies and preparative scale synthesis of key chiral building blocks, exemplified with the unprecedented enantioselective allylation of hydantoins. The optimized reaction achieves high yield and enantioselectivity with only 0.2 mol% of catalyst (turnover number of 465). These precatalysts will enable development of more efficient and robust asymmetric allylic alkylation reactions toward complex target molecules.