Axial shielding of Pd(II) complexes enables perfect stereoretention in Suzuki-Miyaura cross-coupling of Csp3 boronic acids

Abstract

Stereocontrolled Csp³ cross-coupling can fundamentally change the types of chemical structures that can be mined for molecular functions. Although considerable progress in achieving the targeted chemical reactivity has been made, controlling stereochemistry in Csp³ cross-coupling remains challenging. Here we report that ligand-based axial shielding of Pd(II) complexes enables Suzuki-Miyaura cross-coupling of unactivated Csp³ boronic acids with perfect stereoretention. This approach leverages key differences in spatial orientation between competing pathways for stereoretentive and stereoinvertive transmetalation of Csp³ boronic acids to Pd(II). We show that axial shielding enables perfectly stereoretentive cross-coupling with a range of unactivated secondary Csp³ boronic acids, as well as the stereocontrolled synthesis of xylarinic acid B and all of its Csp³ stereoisomers. We expect these ligand design principles will broadly enable the continued search for practical and effective methods for stereospecific Csp³ cross-coupling.

Despite the progress in C(sp³) cross-coupling reactions, full control over the stereochemistry remains a challenge. Here, the authors show that phosphine-containing axially shielded Pd(II) complexes enable Suzuki-Miyaura cross-couplings of unactivated C(sp³) boronic acids with perfect stereoretention.