Theoretical Prediction of Selectivity in Kinetic Resolution
of Secondary Alcohols Catalyzed by Chiral DMAP Derivatives
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Abstract
The mechanism of esterification of the secondary alcohol
1-(1-naphthyl)ethanol <b>9</b> by isobutyric anhydride catalyzed
by 4-pyrrolidinopyridine
(PPY, <b>11</b>) and a series of single enantiomer atropisomeric
4-dialkylaminopyridines <b>8a</b>–<b>g</b> has
been studied computationally at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d)
level. Comparison of the levels of enantioselectivity predicted computationally
with the results obtained experimentally allowed the method to be
validated. The value of the approach is demonstrated by the successful
prediction that a structural modification of an aryl group within
the catalyst from phenyl to 3,5-dimethylphenyl would lead to improved
levels of selectivity in this type of kinetic resolution (KR) reaction,
as was subsequently verified following synthesis and evaluation of
this catalyst (<b>8d</b>). Experimentally, the selectivity of
this type of KR is found to exhibit a significant deuterium isotope
effect (for <b>9</b> vs <b><i>d</i><sub>1</sub></b>-<b>9</b>)