ConspectusThe standard method of screening ligands for selectivity in asymmetric,
transition metal-catalyzed reactions requires experimental testing
of hundreds of ligands from ligand libraries. This “trial and
error” process is costly in terms of time as well as resources
and, in general, is scientifically and intellectually unsatisfying
as it reveals little about the underlying mechanism behind the selectivity.
The accurate computational prediction of stereoselectivity in enantioselective
catalysis requires adequate conformational sampling of the selectivity-determining
transition state but has to be fast enough to compete with experimental
screening techniques to be useful for the synthetic chemist. Although
electronic structure calculations are accurate and general, they are
too slow to allow for sampling or fast screening of ligand libraries.
The combined requirements can be fulfilled by using appropriately
fitted transition state force fields (TSFFs) that represent the transition
state as a minimum and allow fast conformational sampling using Monte
Carlo.Quantum-guided molecular mechanics (Q2MM) is an automated
force
field parametrization method that generates accurate, reaction-specific
TSFFs by fitting the functional form of an arbitrary force field using
only electronic structure calculations by minimization of an objective
function. A key feature that distinguishes the Q2MM method from many
other automated parametrization procedures is the use of the Hessian
matrix in addition to geometric parameters and relative energies.
This alleviates the known problems of overfitting of TSFFs. After
validation of the TSFF by comparison to electronic structure results
for a test set and available experimental data, the stereoselectivity
of a reaction can be calculated by summation over the Boltzman-averaged
relative energies of the conformations leading to the different stereoisomers.The Q2MM method has been applied successfully to perform virtual
ligand screens on a range of transition metal-catalyzed reactions
that are important from both an industrial and an academic perspective.
In this Account, we provide an overview of the continued improvement
of the prediction of stereochemistry using Q2MM-derived TSFFs using
four examples from different stages of development: (i) Pd-catalyzed
allylation, (ii) OsO4-catalyzed asymmetric dihydroxylation
(AD) of alkenes, (iii) Rh-catalyzed hydrogenation of enamides, and
(iv) Ru-catalyzed hydrogenation of ketones. In the current form, correlation
coefficients of 0.8–0.9 between calculated and experimental
ee values are typical for a wide range of substrate–ligand
combinations, and suitable ligands can be predicted for a given substrate
with ∼80% accuracy. Although the generation of a TSFF requires
an initial effort and will therefore be most useful for widely used
reactions that require frequent screening campaigns, the method allows
for a rapid virtual screen of large ligand libraries to focus experimental
efforts on the most promising substrate–ligand combinations.