Enantiodivergent Fluorination of Allylic Alcohols: Data Set Design Reveals Structural Interplay between Achiral Directing Group and Chiral Anion

Enantioselectivity values represent
relative rate measurements
that are sensitive to the structural features of the substrates and
catalysts interacting to produce them. Therefore, well-designed enantioselectivity
data sets are information rich and can provide key insights regarding
specific molecular interactions. However, if the mechanism for enantioselection
varies throughout a data set, these values cannot be easily compared.
This premise, which is the crux of free energy relationships, exposes
a challenging issue of identifying mechanistic breaks within multivariate
correlations. Herein, we describe an approach to addressing this problem
in the context of a chiral phosphoric acid catalyzed fluorination
of allylic alcohols using aryl boronic acids as transient directing
groups. By designing a data set in which both the phosphoric and boronic
acid structures were systematically varied, key enantioselectivity
outliers were identified and analyzed. A mechanistic study was executed
to reveal the structural origins of these outliers, which was consistent
with the presence of several mechanistic regimes within the data set.
While 2- and 4-substituted aryl boronic acids favored the (R)-enantiomer with most of the studied catalysts, meta-alkoxy substituted aryl boronic acids resulted in the
(S)-enantiomer when used in combination with certain
(R)-phosphoric acids. We propose that this selectivity
reversal is the result of a lone pair-π interaction between
the substrate ligated boronic acid and the phosphate. On the basis
of this proposal, a catalyst system was identified, capable of producing
either enantiomer in high enantioselectivity (77% (R)-2 to 92% (S)-2) using the same chiral catalyst by subtly changing the structure
of the achiral boronic acid.