Revisiting Stereocontrol through Ligand-Directed Non-Covalent Interactions in the Asymmetric Synthesis of Tetrahydrofuran Cores via Tsuji–Trost Asymmetric Allylic Alkylation

Five-membered oxygenated heterocycles, such as substituted tetrahydrofurans (THFs), are important structural motifs in bioactive compounds and can be efficiently accessed through palladium-catalyzed asymmetric allylic alkylation (AAA). In this context, the desymmetrization of mesodiols represents a powerful strategy for the stereocontrolled construction of chiral THF frameworks. Herein, we present a combined experimental and computational study aimed at elucidating the origin of an unusual diastereoselectivity inversion observed in this reaction. While ligands of the Trost family are generally considered interchangeable when sharing the same chiral information, experimental results show that switching between (S,S)-DACH-Ph (L1) and (R,R)-ANDEN-Ph (L2) leads to a reversal of the major diastereomer formed without significant loss of enantioselectivity. Density functional theory (DFT) calculations reveal that this behavior cannot be rationalized by the only classical Trost–Toste steric quadrant model. Instead, the selectivity is governed by a network of ligand-controlled noncovalent interactions, including hydrogen bonding between the ligand amide N–H, the acetate counteranion, and the substrate hydroxyl groups, which dictate the relative stability of the competing transition states. These findings provide a mechanistic framework that explains the observed disaster conversion and highlights the critical role of interaction patterns beyond steric effects, offering new predictive insights for the design of asymmetric AAA processes.