Spiroketal Synthesis Via Uncatalyzed Inverse Electron-Demand Hetero-Diels-Alder Reactions at Ambient Temperature.
- 1Department of Chemistry and Biochemistry, University of California, Los Angeles, 607 Charles E. Young Dr., Los Angeles, California90095, United States.
Abstract
Vinyl vicinal tricarbonyl reagents have been used as flexible bis-electrophiles in a variety of condensation reactions. Here, we show the enone component of the molecule participates in uncatalyzed inverse electron-demand hetero-Diels-Alder reactions with α-methylidene furans, pyrans and oxepanes. This previously unrecognized reactivity mode enables direct, diastereoselective access to 5,6-, 6,6- and 7,6- spiroketal substructures using stoichiometric reactants at ambient temperature - and without the use of Lewis acidic additives or catalysts. Broad substrate scope is demonstrated using diverse cyclic enol ethers, with substrate-dependent competition between Diels-Alder and carbonyl-ene pathways occurring for specific ring systems. Density functional theory calculations reveal that both pathways proceed through polar, stepwise mechanisms involving zwitterionic intermediates, with subtle energetic differences governing pathway selectivity. The unsaturated α-keto ester present in cycloaddition products can be manipulated in a variety of useful ways. A selection of enabling transformations is demonstrated, as is a concise synthesis of a reveromycin B subunit.
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BibTeX
@article{greene2026spiroketal,
title = {{Spiroketal Synthesis Via Uncatalyzed Inverse Electron-Demand Hetero-Diels-Alder Reactions at Ambient Temperature.}},
author = {Emma J Greene and Matthew C Raeside and Marcelo A Mazariego and Andy Y Song and K N Houk and Patrick G Harran},
journal = {Journal of the American Chemical Society},
year = {2026},
month = sep,
doi = {10.1021/jacs.6c09678},
url = {https://europepmc.org/article/MED/42937878},
note = {CC BY},
}
RIS
TY - JOUR
TI - Spiroketal Synthesis Via Uncatalyzed Inverse Electron-Demand Hetero-Diels-Alder Reactions at Ambient Temperature.
AU - Emma J Greene
AU - Matthew C Raeside
AU - Marcelo A Mazariego
AU - Andy Y Song
AU - K N Houk
AU - Patrick G Harran
PY - 2026
DA - 2026/09/01
JO - Journal of the American Chemical Society
DO - 10.1021/jacs.6c09678
UR - https://europepmc.org/article/MED/42937878
AB - Vinyl vicinal tricarbonyl reagents have been used as flexible bis-electrophiles in a variety of condensation reactions. Here, we show the enone component of the molecule participates in uncatalyzed inverse electron-demand hetero-Diels-Alder reactions with α-methylidene furans, pyrans and oxepanes. This previously unrecognized reactivity mode enables direct, diastereoselective access to 5,6-, 6,6- and 7,6- spiroketal substructures using stoichiometric reactants at ambient temperature - and without the use of Lewis acidic additives or catalysts. Broad substrate scope is demonstrated using diverse cyclic enol ethers, with substrate-dependent competition between Diels-Alder and carbonyl-ene pathways occurring for specific ring systems. Density functional theory calculations reveal that both pathways proceed through polar, stepwise mechanisms involving zwitterionic intermediates, with subtle energetic differences governing pathway selectivity. The unsaturated α-keto ester present in cycloaddition products can be manipulated in a variety of useful ways. A selection of enabling transformations is demonstrated, as is a concise synthesis of a reveromycin B subunit.
SN - 0002-7863
SN - 1520-5126
ER -