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

• Published in: Journal of the American Chemical Society Vol. 139; no. 35; pp. 12182 - 12189
• Main Authors: Mack, Kyle A, McClory, Andrew, Zhang, Haiming, Gosselin, Francis, Collum, David B
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06.09.2017
• Subjects: Ketones - chemistry; Kinetics; Lithium Compounds - chemistry; Magnetic Resonance Spectroscopy; Molecular Structure; Silanes - chemistry
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.7b05057

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 Z-selective in neat tetrahydrofuran (THF) and E-selective in 2.0 M THF/hexane. The results of NMR spectroscopy show the resulting enolates to be statistically distributed ensembles of E,E-, E,Z-, and Z,Z-enolate dimers with subunits that reflect the selectivities. The results of rate studies trace the preference for E and Z isomers to tetrasolvated- and pentasolvated-monomer-based transition structures, respectively. Enolization using LiHMDS in N,N-dimethylethylamine or triethylamine in toluene affords a 65:1 mixture of LiHMDS–lithium enolate mixed dimers containing E and Z 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.