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

Abstract

Described herein is our computational study to rationalize the stereoselective epimerization of alpha,alpha&apos;-cis-disubstituted oxolane and oxetane ketones 6 and 7 to the corresponding alpha,alpha&apos;-trans ketones 8 and 9 reported in our previous total syntheses of (+)-3-(Z)-isolaureatin (1) and (+)-3-(Z)-laureatin (2). Density functional theory (DFT) calculations using appropriately truncated models revealed that the alpha,alpha&apos;-trans ketones are more stable than the alpha,alpha&apos;-cis 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 7 compared to oxolane ketone 6 [0.25 & Aring; (trans only) vs 0.13 & Aring; (trans/cis = 4:1)]. © 2025 American Chemical Society