Lithium Hexamethyldisilazide-Mediated Enolization of Highly Substituted Aryl Ketones: Structural and Mechanistic Basis of the <i>E</i>/<i>Z</i> Selectivities

Abstract

Enolizations of highly substituted acyclic ketones used in the syntheses of tetrasubstituted olefin-based anticancer agents are described. Lithium hexamethyldisilazide (LiHMDS)-mediated enolizations are moderately <i>Z</i>-selective in neat tetrahydrofuran (THF) and <i>E</i>-selective in 2.0 M THF/hexane. The results of NMR spectroscopy show the resulting enolates to be statistically distributed ensembles of <i>E</i>,<i>E</i>-, <i>E</i>,<i>Z</i>-, and <i>Z</i>,<i>Z</i>-enolate dimers with subunits that reflect the selectivities. The results of rate studies trace the preference for <i>E</i> and <i>Z</i> isomers to tetrasolvated- and pentasolvated-monomer-based transition structures, respectively. Enolization using LiHMDS in <i>N</i>,<i>N</i>-dimethylethylamine or triethylamine in toluene affords a 65:1 mixture of LiHMDS–lithium enolate mixed dimers containing <i>E</i> and <i>Z</i> isomers, respectively. Spectroscopic studies show that condition-dependent complexation of ketone to LiHMDS occurs in trialkylamine/toluene. Rate data attribute the high selectivity exclusively to monosolvated-dimer-based transition structures