Overcoming Reversibility: Borrowing Hydrogen Enables Enantioselective Intermolecular Oxa-Michael Addition to α,β-Unsaturated Aldehydes

Abstract Chiral 1,3-dioxygenated motifs are key scaffolds in bioactive natural products, yet their synthesis via intermolecular oxa-Michael addition to α,β-unsaturated aldehydes remains challenging notably due to the high reversibility of the oxygenated nucleophile addition. This study presents a multicatalytic borrowing hydrogen (BH) strategy combining iridium-catalyzed reversible dehydrogenation/hydrogenation and enantioselective organocatalyzed iminium-type activation to overcome these limitations. Under mild conditions (25°C), the approach enables the enantioselective oxa-Michael addition of oxygenated nucleophiles (oximes and alcohols) to allylic alcohols, directly delivering key enantioenriched alcohols. Mechanistic studies confirm that the BH pathway displaces the equilibrium toward the alcohol product, limiting racemization at the aldehyde level occurring through rapid retro-oxa-Michael addition. This work demonstrates that BH catalysis can unlock otherwise inaccessible transformations starting directly from aldehydes, offering a sustainable and efficient route to complex chiral molecules.