Felkin-Anh Model from an Orbital Phase Perspective: Diastereoselectivity in Nucleophilic Addition to 2,3-bis(trifluoromethyl)bicyclo[2.2.1]heptan-7-One

To address the electronic effect in nucleophilic addition, we often use the Felkin-Anh model, in which the most s-electron-withdrawing group (sEWG) at the a-position of the carbonyl should be located anti to the nucleophile approach. The diastereoselectivity is often explained by the antiperiplanar effect of the sEWG. Reetz and Frenking reported that the FMO, the LUMO in the a-substituted ketone, has greater expansion anti the sEWG. Thus, the FMO theory can also apply to this diastereoselectivity. However, there is still no explanation for why the LUMO has greater expansion anti to the sEWG and toward the nucleophile approach with this conformation, as is suggested by the FMO theory. We show here that the phase-continuous cyclic orbital interaction among n_Nu:--p*_C=O-s*_C-A/vic-s*_CC/gem- controls the diastereoselectivity, which is confirmed with theoretical calculations and the bond model analysis using a conformationally-fixed bicyclic molecule, 2,3-bis(trifluoromethyl)bicyclo[2.2.1]heptan-7-one 1, as a model.