Effect of Solvents on Proline Modified at the Secondary Sphere: A Multivariate Exploration

The critical influence of solvent
effects on proline-catalyzed
aldol reactions has been extensively described. Herein, we apply multivariate
regression strategies to probe the influence of different solvents
on an aldol reaction catalyzed by proline modified at its secondary
sphere with boronic acids. In this system, both in situ binding of the boronic acid to proline and the outcome of the aldol
reaction are impacted by the solvent-controlled microenvironment.
Thus, with the aim of uncovering mechanistic insight and an ancillary
aim of identifying methodological improvements, we designed a set
of experiments, spanning 15 boronic acids in five different solvents.
Based on hypothesized intermediates or interactions that could be
responsible for the selectivity in these reactions, we proposed several
structural configurations for the library of boronic acids. Subsequently,
we compared the statistical models correlating the outcome of the
reaction in different solvents with molecular descriptors produced
for each of these proposed configurations. The models allude to the
importance of different interactions in controlling selectivity in
each of the studied solvents. As a proof-of-concept for the practicality
of our approach, the models in chloroform ultimately led to lowering
the ketone loading to only two equivalents while retaining excellent
yield and enantio- and diastereo-selectivity.