Unprecedented MsOH-promoted diastereoselective cascade dimerization and intramolecular lactonization of readily accessible alpha,beta-unsaturated gamma-ketoesters are presented. The results obtained in this work, control experiments, and density functional theory (DFT) calculations suggested that the initial enolization and E to Z isomerization/equilibration of olefin (C=C) of substrate alpha,beta-unsaturated gamma-ketoesters give a Z-isomer preferentially over an E-isomer. Subsequently, the Z-isomer undergoes intermolecular annulation with alpha,beta-unsaturated gamma-ketoesters via domino Michael addition/ketalization/lactonization steps to furnish fused tetracyclic pyrano-ketal-lactone. However, the Z-isomer prefers intramolecular trans-esterification in a competing pathway and gives bicyclic gamma-ylidene-butenolide. The key features of this work include simple Br & oslash;nsted acid catalysis, the formation of three bonds, two rings, and three contiguous stereogenic centers in a single step, DFT calculations, and the assignment of relative stereochemistry through X-ray diffraction (XRD) and two-dimensional (2D) nuclear magnetic resonance (NMR) analyses.

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