Origin of Diastereocontrol in the Oxy‐Michael Reactions of δ‐Lactol Anions: A Computational and Experimental Study

The diastereoselectivity in the alkylation and Michael addition of “naked” 6‐substituted δ‐lactolates has been studied by density functional (B3LYP) calculations with ab initio (MP2) energy refinements. The resulting proposed model for the origins of stereocontrol in this reaction has been tested by experiment. The reactions lead to a high cis diastereoselectivity across the THP ring due to the preference for both the alkoxide and the 6‐substituent to sit equatorial in the alkylation transition structure. In the oxy‐Michael addition of these lactolates to β‐substituted nitroolefins, we propose that the high diastereoselectivity β‐ to the nitro group is a result of a combination of steric, stereoelectronic and solvation factors. Controlling the lactols: DFT, ab initio and experimental techniques have been used to probe the stereocontrol in the alkylation and oxy‐Michael reactions of substituted δ‐lactols (see scheme).