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

Described herein is our computational study to rationalize the stereoselective epimerization of α,α’-cis-disubstituted oxolane and oxetane ketones 6 and 7 to the corresponding α,α’-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 α,α’-trans ketones are more stable than the α,α’-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 Å (trans only) vs 0.13 Å (trans/cis = 4:1)].