Tandem catalysis in domino olefin cross-metathesis/intramolecular oxa-conjugate cyclization: concise synthesis of 2,6-cis-substituted tetrahydropyran derivatives

Abstract

Herein, we describe the concise synthesis of 2,6-cis-substituted tetrahydropyran derivatives based on a domino olefin cross-metathesis/intramolecular oxa-conjugate cyclization (CM/IOCC) reaction. We have found that the domino CM/IOCC of δ-hydroxy olefins with α,β-unsaturated carbonyl compounds (e.g., trans-crotonaldehyde or N-acryloyl-2,5-dimethylpyrrole) could be efficiently achieved in the presence of the second-generation Hoveyda-Grubbs catalyst under elevated temperature conditions, directly affording 2,6-cis-substituted tetrahydropyrans in excellent yields with synthetically useful diastereoselectivity ("auto-tandem catalysis"). In addition, we have found that the domino CM/IOCC of δ-hydroxy olefins with α,β-unsaturated carbonyl compounds could be achieved simply by performing CM in the presence of a Brønsted acid in CH(2)Cl(2) at 25-35 °C, which delivered 2,6-cis-substituted tetrahydropyrans in good yields with excellent diastereoselectivity ("orthogonal-tandem catalysis"). To understand the mechanism of auto-tandem catalysis in the domino CM/IOCC reaction, we have investigated the role of ruthenium hydride complexes in the IOCC of a ζ-hydroxy α,β-unsaturated ketone as a model case.