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J Org Chem. 2017 Jan 6;82(1):57-75. doi: 10.1021/acs.joc.6b02053. Epub 2016 Dec 22.

Diastereoselective Synthesis of Highly Substituted Tetrahydrofurans by Pd-Catalyzed Tandem Oxidative Cyclization-Redox Relay Reactions Controlled by Intramolecular Hydrogen Bonding.

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Chemical Biology Program , Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 422, New York, New York 10065, United States
School of Chemical Engineering, Shandong University of Technology , Zibo 255049, China.
Lab of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School , Shenzhen 518055, China.
Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 422, New York, New York 10065, United States


Palladium-catalyzed oxidative cyclization of alkenols provides a convenient entry into cyclic ethers but typically proceeds with little or no diastereoselectivity for cyclization of trisubstituted olefins to form tetrahydrofurans due to the similar energies of competing 5-membered transition-state conformations. Herein, a new variant of this reaction has been developed in which a PdCl2/1,4-benzoquinone catalyst system coupled with introduction of a hydrogen-bond acceptor in the substrate enhances both diastereoselectivity and reactivity. Cyclization occurs with 5-exo Markovnikov regioselectivity. Mechanistic and computational studies support an anti-oxypalladation pathway in which intramolecular hydrogen bonding increases the nucleophilicity of the alcohol and enforces conformational constraints that enhance diastereoselectivity. The cyclization is followed by a tandem redox-relay process that provides versatile side-chain functionalities for further derivatization.

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