Computational Insights into “Lone Pair–Lone Pair Interaction-Controlled” Isomerization in the Asymmetric Total Syntheses of (+)-3-(<i>Z</i>)-Laureatin and (+)-3-(<i>Z</i>)-Isolaureatin

Described herein is our computational study to rationalize the stereoselective epimerization of α,α'-<i>cis</i>-disubstituted oxolane and oxetane ketones <b>6</b> and <b>7</b> to the corresponding α,α'-<i>trans</i> ketones <b>8</b> and <b>9</b> reported in our previous total syntheses of (+)-3-(<i>Z</i>)-isolaureatin (<b>1</b>) and (+)-3-(<i>Z</i>)-laureatin (<b>2</b>). Density functional theory (DFT) calculations using appropriately truncated models revealed that the α,α'-<i>trans</i> ketones are more stable than the α,α'-<i>cis</i> ketones, in very good agreement with experimental results. The computational results showed that the isomer with a longer interatomic distance between the two ring oxygen atoms was lower in energy, which suggested the presence of repulsive interactions between those oxygen atoms. Support for these distance-dependent repulsive interactions came from the observation that the energy differences between the two isomers correlated with the solvent polarity. Most importantly, a larger interoxygen distance difference could be responsible for the enhanced stereoselectivity for epimerization of oxetane ketone <b>7</b> compared to oxolane ketone <b>6</b> [0.25 Å (<i>trans</i> only) vs 0.13 Å (<i>trans</i>/<i>cis</i> = 4:1)].