Investigations on Transition-State Geometry in the Aldol Condensation

Model compounds 1 and 2 have been studied to elucidate the relative orientation of enolate and carbonyl moieties in the aldol reaction. The syntheses of these compounds have been achieved from a common precursor derived from fragmentation of adamantane. Models of the limiting transition structures reveal that the cyclization must proceed through either a synclinal or antiperiplanar orientation of the aldehyde with respect to the enolate. Cyclizations of 1 were unexpectedly sluggish due to slow deprotonation of the tertiary center. The cyclization of 2 was very rapid and was studied as a function of enolate type (metal counterion), base type, solvent, and additive. The reactions of metal enolates showed an increasing preference for the syn product 5 with increasing cation coordinating ability (K⁺ < Na⁺ < Li⁺ < MgBr⁺). Attempted cyclization via boron and stannous enolates failed. The type of base and the choice of solvent had negligible effects on the selectivity. However, in the presence of strong cation-complexing agents, the model showed a strong preference for reaction via an antiperiplanar orientation of reactants giving the anti product 6 with high selectivity. The origin of the selectivities and the implication for enolate and transition structures are discussed.