Asymmetric synthesis of chiral boronic esters featuring nonadjacent axial and flexible, acyclic central chirality

Nonadjacent chirality is prevalent in pharmaceuticals and bioactive molecules, but prior studies primarily focused on constructing noncontiguous stereocenters. However, the construction of nonadjacent axial and flexible, acyclic central chirality often involves highly flexible transition states, posing challenges in achieving precise control over enantio- and diastereoselectivity. Here, extensive ligand screening, followed by structural modification and optimization, identified a bulky <i>P</i>,<i>N</i>-phosphinooxazoline (<i>P</i>,<i>N</i>-phox) ligand derived from l-serine, enabling the direct asymmetric construction of atropisomers with axial and flexible, acyclic central chirality. The reaction demonstrates broad substrate scope, accommodating diverse aryl, alkyl, and natural product-derived boronic esters, and tolerates aryl trifluoromethanesulfonates (ArOTfs) with varying electronic and steric properties. Mechanistic studies indicate a palladium(II) intermediate, with 1,2-carbon migration as the rate-determining step. Furthermore, product derivatization introduces diverse functional groups, enhancing molecular complexity and facilitating downstream transformations.