Lithium ephedrate-mediated addition of a lithium acetylide to a ketone: Solution structures and relative reactivities of mixed aggregates underlying the high enantioselectivities

Addition of lithium cyclopropylacetylide (RLi) to ArCOCF3 mediated by 1(R),2(S)-R2NCH(CH3)CH(Ph)OLi (ROLi; R2N = pyrrolidino) occurs with 50:1 enantioselectivity (Thompson, A. S. et al. Tetrahedron. Lett. 1995, 36, 8937). Low-temperature Li-6 and C-13 NMR spectroscopies reveal lithium cyclopropylacetylide in THF to be a dimer-tetramer mixture and the lithium alkoxide to be a complex mixture of oligomers. Mixtures of RLi and ROLi in THF afford stoichiometry-dependent mixtures of 3:1, 2:2, and 1:3 mixed tetramers. The dramatic improvements in the stereochemistry of 1,2-additions caused by aging the reaction at ambient temperatures are shown to coincide with unusually slow aggregate equilibrations. ReactIR studies showed that the previously detected requirement for 2 equiv of lithium acetylide per ketone stems from autoinhibition rather than from a proton abstraction of an NH moiety in the substrate. Semiempirical (MNDO) computational studies support a stereochemical model based upon 1,2-addition via a C-2 symmetric 2:2 mixed tetramer.