| I. Nucleophilic additions to sterically unbiased ketones. It has long been known that small reagents attack cyclohexanone from its axial face. Although the origin of diastereoselectivity in such sterically unbiased systems is typically rationalized with a variety of stereoelectronic, electrostatic, and torsional arguments, another possibility is that subtle asymmetries in molecular geometry render the carbonyl groups inherently more reactive on one diastereoface through a phenomenon known as "orbital distortion." The validity of this idea is investigated computationally.;II. Intermolecular Michael additions. The union an enolate and an activated olefin often produces highly diastereoselective products under kinetic control. A number of mechanistic possibilities, such as O- vs. C-bound lithium enolates and open vs. closed transition states, are investigated computationally, and it is demonstrated that the reaction is consistent with O-bound lithium enolates reacting via closed, eight-membered transition states.;III. Intramolecular Michael additions. It is shown that intramolecular additions of beta-ketoester enolates to alpha,beta-unsaturated esters bearing adjacent stereogenic centers can often give highly diastereoselective Michael adducts. The reaction is investigated computationally and a dipole-minimized model based on six-membered chair transition states is presented. The role of beta-ketoester enolate geometry is also discussed. |
