Cascade Michael Addition/Cycloketalization of Cyclic 1,3-Dicarbonyl Compounds: Important Role of the Tethered Alcohol of α,β-Unsaturated Carbonyl Compounds on Reaction Rate and Regioselectivity

Reactions
of α,β-unsaturated aldehydes and cyclic 1,3-dicarbonyl
compounds proceed primarily by cascade Knoevenagel condensation/six-π-electron
electrocyclization (K6EC, formal [3 + 3] cycloaddition), while α,β-unsaturated
ketones usually react with cyclic 1,3-dicarbonyl compounds in a 1,4-addition
manner. This paper discloses our findings that under acidic conditions,
α,β-unsaturated carbonyl compounds (ketones and aldehydes)
with a tethered alcohol react with cyclic 1,3-dicarbonyl compounds
in a highly regioselective 1,4-addition fashion via in situ generation
of a hypothetical α-methylene cyclic oxonium ion as the reactive
Michael acceptor. Our studies uncovered the important effect of the
tethered alcohol on the reaction rate and/or efficiency and some new
mechanistic aspects of the cascade Michael addition/cycloketalization.
Finally, the substrate scope was examined, and 43 analogues of penicipyrone
and tenuipyrone were prepared in good to excellent yields.