Empowering Diastereoselective Cyclopropanation of Unactivated Alkenes with Sulfur Ylides through Nucleopalladation

Regio- and stereoselective cyclopropanation of unactivated alkenes under mild conditions remains a challenging yet fundamental transformation. We present a versatile palladium(II)-catalyzed method for the diastereoselective cyclopropanation of alkenyl amines and alkenyl acids, which leverages the nucleopalladation mechanism and the unique ambiphilic reactivity of sulfur ylides. This Pd(II)/Pd(IV) catalytic protocol selectively delivers <i>anti-</i>cyclopropanes for allylamines with a removable isoquinoline-1-carboxamide auxiliary, while enabling excellent <i>syn</i>-selectivity for alkenyl acid derivatives containing a 2-(aminomethyl)pyridine derivative as a directing group. The protocol is operationally simple and scalable, features a wide substrate generality, and also remains effective in the presence of various medicinally relevant scaffolds. The cyclopropane products were further transformed into 1,2,3-trifunctionalized cyclopropanes and engaged in an aza-Piancatelli reaction, introducing additional molecular complexity. DFT studies were performed to shed light on the reaction mechanism and the origins of the observed stereoselectivity.