Comprehensive Stereochemical Models for Selectivity Prediction in Diverse Chiral Phosphate-Catalyzed Reaction Space

The
reactivity landscape of chiral phosphate catalysis is rapidly
expanding and currently ranges from the hydrogenation of enals to
the electrophilic activation of allenamides. Despite the importance
of such transformations for the stereocontrolled synthesis of a diverse
array of organic compounds, the preferred pathway and reasons for
stereocontrol have not been firmly established, making it difficult
to develop new reactions more generally. Here, we address this challenge
by integrating traditional transition state calculations with statistical
tools to rapidly connect and analyze several types of chiral phosphate-catalyzed
enantioselective transformations. Detailed density functional theory
(DFT) calculations of carefully selected case studies reveal that
this set of superficially unrelated reactions operate, in many cases,
through a single mechanism involving two hydrogen-bonding interactions
from the iminium intermediate and nucleophile to the catalyst. From
the transition state structures, we rationalize the different factors
on which the enantioselectivity depends, focusing on the orientation
of the reactants with respect to the catalyst. These theoretical analyses
led to the construction of stereochemical models that correlate the
magnitude and explain the sense of enantioselectivity for over 200
chemical reactions. We demonstrate how the resulting models can be
used to assist reaction application to include additional substrates
and develop related transformations. Ultimately, our findings represent
a framework for formulating mechanistically relevant correlations
driven by high-level transition state analysis, and this strategy
should be broadly applicable to other catalytic systems widely applied
in asymmetric synthesis.