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. 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

Joshua L Brooks  1 , Liping Xu  2   3 , Olaf Wiest  3   4 , Derek S Tan  1   5
Affiliations

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

Joshua L Brooks et al. J Org Chem. .

Abstract

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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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Natural products containing 1,1,4-trisubstituted tetrahydrofuran motifs.
Figure 2
Figure 2
Models of diastereocontrol in intramolecular oxypalladations of alkenols to form 1,1,4-trisubstituted tetrahydrofurans.
Figure 3
Figure 3
Deuterium-labeling experiment to probe mechanism of side-chain carbonyl formation.
Figure 4
Figure 4
Deuterium-labeling experiments to differentiate between syn- and anti-oxypalladation mechanisms.
Figure 5
Figure 5
Proposed models for organization of anti-oxypalladation transition state by intramolecular hydrogen bonding (pathway A) or Pd chelation (pathway B) by the distal (noncyclizing) alcohol followed by tandem redox-relay reaction to generate an aldehyde side-chain functionality.
Figure 6
Figure 6
Stereodifferentiating transition structures 25a and 25b for the cyclization of 4a (Ln = Cl2(BQ)) with bond distances in Å.
See this image and copyright information in PMC

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