Structure–Reactivity Relationships in Lithiated Evans Enolates: Influence of Aggregation and Solvation on the Stereochemistry and Mechanism of Aldol Additions

Aldol
additions to isobutyraldehyde and cyclohexanone with lithium
enolates derived from acylated oxazolidinones (Evans enolates) are
described. Previously characterized trisolvated dimeric enolates undergo
rapid addition to isobutyraldehyde to give a 12:1 syn:syn selectivity
in high yield along with small amounts of one anti isomer. The efficacy
of the addition depends critically on aging effects and the reaction
quench. Unsolvated tetrameric enolates that form on warming the solutions
are unreactive toward isobutyraldehyde and undergo retroaldol reaction
under forcing conditions. Additions to cyclohexanone are relatively
slow but form a single isomeric adduct in >80% yield. The ketone-derived
aldolates are robust. All attempts to control stereoselectivity by
controlling aggregation failed. Rate studies of addition to cyclohexanone
trace the lack of aggregation-dependent selectivities to a monomer-based
mechanism. The synthetic implications and possible utility of lithium
enolates in Evans aldol additions are discussed.