Pd-catalyzed stereoselective enol ether coupling toward C2-branched carbohydrates: experimental and computational insights into glycal-controlled diastereoselectivity

Abstract

C2-branched glycal derivatives are key structural motifs in numerous pharmaceuticals and biologically active molecules. Herein, we report a ligand-free, palladium-catalyzed stereoselective cross-coupling of readily accessible iodo-glycals with cyclic enol ethers, enabling efficient access to C2-branched sugars. This strategy exploits the intrinsic stereoinductive properties of glycals, leading to highly diastereoselective sp²–sp³ bond formation (dr up to 1 : 0.05). A broad range of glycal substrates and cyclic enol ethers are well tolerated under the optimized reaction conditions. Computational studies show that the axial C4 substituent of the glycal plays a crucial role in controlling diastereoselectivity during the olefin insertion step, identified as the rate-determining step. Non-covalent interactions clearly reveal that interactions between the glycal moiety and dihydropyran substrates dictate stereocontrol in the C–C coupling, consistent with an interaction-controlled mechanism rather than a distortion-controlled mechanism.