Chiral <i>N</i>‑Hydroxyalkyl Pyrid-2-Ylidenes:\nA New Class of Ligands for Copper-Catalyzed Asymmetric Allylic Alkylation

A class of chiral <i>N</i>-heterocyclic carbenes\nderived\nfrom pyridine, namely <i>N</i>-hydroxyalkyl pyrid-2-ylidenes,\nwas developed. Capitalizing the remarkable steric and electronic features\nof the pyrid-2-ylidene core with the presence of a chiral hydroxyalkyl-chelating\narm on the nitrogen atom, these ligands demonstrated high performance\nin copper-catalyzed asymmetric allylic alkylation of dialkylzincs\nto various allylic or dienic phosphates with high γ-selectivity\n(>98%) and enantioselectivity (up to 95% ee). Importantly, the\ncatalyst\nloading can be decreased to below 0.5 mol% without any loss of catalyst\nefficiency, thus outperforming <i>N</i>-hydroxyalkyl imidazoline-2-ylidene\ncongeners. Moreover, thanks to the versatile post-transformation of\nthe resulting enantioenriched skipped 1,4-dienes, various relevant\nbuilding blocks were synthesized, notably a key intermediate in the\ntotal synthesis of (+)-Phorbasin C. Furthermore, by involving a transient\noxazolidine, which acts as a masked carbene before the insertion of\nthe metal center, a well-defined but air-sensitive <i>N</i>-hydroxyalkyl pyrid-2-ylidene copper(I) chloride complex was isolated.\nDeuteration experiments and computational studies provided valuable\ninsights into the formation of the oxazolidine and the corresponding\ncopper complex.