Theoretical study of the stereoselective additions of chiral alcohols to ketenes

In 1989, Larsen et al. at Merck discovered that the addition of chiral alcohols to ketenes provided enantiomerically enriched aryl propionic acids, compounds valued for their therapeutic antiinflammatory properties. The high 1,4-asymmetric induction observed (>99:1 dr in the addition, and up to 99% ee after hydrolysis to the acid) is rare. A quantitative model based on B3LYP density functional theory calculations accounts for the stereoselectivity in the addition of (S)-methyl lactate, (S)-3-methyl-2-butanol, and (S)-pantolactone to methylphenylketene. The conformational processes of the intermediates can impact the stereoselectivity of the process, and either the addition step, or the protonation of the enolate intermediate, may be stereoselectivity determining.