Spiroketal Synthesis Via Uncatalyzed Inverse Electron-Demand Hetero-Diels-Alder Reactions at Ambient Temperature

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.