Stereochemistry of the Reaction of Lithium Aluminum Hydride and of Methyllithium with Methyl-Substituted Cyclopentanones, Cyclohexanones, and Norbornanones. Evidence for a Linear Combination of Steric Strain and Product Stability Control in the Stereochemical Course of the Addition Reactions

Methyl-substituted cyclopentanones, cyclohexanones, and norbornanones were reacted with methyllithium in ether and with lithium aluminum hydride in tetrahydrofuran at 0 °C. The stereochemical course of these reactions is reported and analyzed. The stereochemistry is best explained by a linear combination of both steric strain and product stability controls, Δ(ΔG*) = Δσ + Δπ. While diastereomeric secondary alcohols show significant differences in thermodynamic stability (ΔG°H), tertiary diastereomeric 1-methylcycloalkyl alcohols show little difference in stability. Hence, the stereochemical course of the reaction of methyllithium with cyclic ketones is little affected by the product stability and Δπ = 0. In the case of lithium aluminum hydride reduction, however, the stereochemistry is dictated simultaneously and linearly by both steric strain and product stability controls. It was found that if product stability control can be cancelled, both methyllithium and lithium aluminum hydride have about equal steric demand in their transition state complexes. Accordingly, an empirical equation, Δ(ΔG*)H = Δ(ΔG*)_Me + 1.4(ΔG°)_H, was obtained. Here, Δ(ΔG*)_H and Δ(ΔG*)_Me, respectively, are the transition state energy differences leading to two diastereomers in the reactions of ketone with lithium aluminum hydride and with methyllithium. The equation provides a qualitative as well as a quantitative treatment of the stereochemical course of the reaction of lithium aluminum hydride with cyclic ketones.