Computational Insights into Privileged Stereocontrolling Interactions Involving Chiral Phosphates and Iminium Intermediates

Abstract

The precise design of a catalyst for a given reaction is extremely difficult, often requiring a significant empirical screening campaign to afford products in high yields and enantiomeric excess. Design becomes even more challenging if one requires a catalyst that performs well for a diverse range of substrates. Such "privileged" catalysts exist, but little is known why they operate so generally. We report the results of computations which show that when substrate and catalyst features are conserved between significantly different mechanistic regimes, similar modes of activation can be invoked. As a validating case study, we explored a Hantzsch ester hydrogenation of α,β-unsaturated iminiums involving BINOL-derived chiral phosphates and find they impart asymmetric induction in an analogous fashion to their acid counterpart. Specifically, DFT calculations at the IEFPCM(1,4-dioxane)-B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level predicted enantioselectivity to be close to the experimental value (82% ee calculated, 96% ee experimental) and showed that the reaction proceeds via a transition state involving two hydrogen-bonding interactions from the iminium intermediate and nucleophile to the catalyst. These interactions lower the energy of the transition structure and provide extra rigidity to the system. This new model invokes "privileged" noncovalent interactions and leads to a new explanation for the enantioselectivity outcome, ultimately providing the basis for the development of general catalyst design principles and the translation of mechanistically disparate reaction profiles for the prediction of enantioselectivity outcomes using statistical models.

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

“…However, recent density functional theory (DFT) calculations have shown these pathways can lead to catalyst deactivation, and this reaction event would also explain the experimental data . In our computational study of the Hantzsch ester hydrogenation of α,β-unsaturated iminiums, we showed that the reaction proceeds via a transition state (TS) involving two hydrogen-bonding (H-bond) contacts with both reactants . Steric interactions between reasonably large groups on the catalyst and substrate in addition to the iminium H-bond control the product outcome (Figure B, Mechanism C).…”

“…Further, simple models that can be sketched by hand are qualitative and do not provide a quantitative prediction of the enantioselectivity output . Accordingly, we deployed statistical modeling tools, which could greatly enhance the application and predictive power of our reaction models. − To connect these nine disparate reaction types, a comprehensive multivariate linear regression (cMLR) model that relates the features of all of the reaction components to the experimentally obtained enantioselectivity outcomes conveyed as ΔΔ G ‡ would be required (see SI for full details on workflow, statistical models considered, and additional validation tests) . These tools have been used recently in other contexts but often without the guidance of TS calculations, , which are valuable for formalizing mechanistic principles that enable the prediction of product stereochemistry and are required to carefully consider the limits of model generality.…”

“…Polarizability, highest occupied molecular orbital (HOMO), and lowest unoccupied molecular orbital (LUMO) energies, which do not rely on common substructures, were also collected. Lastly, this set was expanded to include descriptors like IR vibrations, bond distances, and angles that have proven well-equipped to describe similar reaction components. , Solvent effects were described by topological, two-dimensional descriptors typically employed for QSAR modeling of structurally disparate molecules (e.g., molecular shape, size, and the number of heteroatoms). To generate mechanistically meaningful relationships between the descriptors and the experimentally determined enantioselectivity, the data set was categorized by iminium (Type I, +ve ee or Type II, −ve ee) and nucleophile orientation (nucleophile carbon to the right +ve ee or left −ve).…”

“…16 In our computational study of the Hantzsch ester hydrogenation of α,β-unsaturated iminiums, we showed that the reaction proceeds via a transition state (TS) involving two hydrogen-bonding (H-bond) contacts with both reactants. 17 Steric interactions between reasonably large groups on the catalyst and substrate in addition to the iminium H-bond control the product outcome (Figure 1B, Mechanism C). This analysis could also be applied to explain the experimental results for the epoxidation of enals.…”

H-Bonded Counterion-Directed Enantioselective Au(I) Catalysis

“…Therefore, in the vast majority of cases, the noncovalent interactions required for enantioinduction 11 are not built into the catalytic system a priori but rather selected during optimization by a lengthy trial-and-error approach and rationalized only a posteriori . 12 Alternatively, the chiral anion can be precisely positioned by a rigid covalent linkage to the ligand, as in the “tethered counterion-directed catalysis” strategy recently disclosed by Marinetti, Guinchard, and co-workers for the enantioselective Au(I)-catalyzed tandem cycloisomerization–nucleophile addition to 2-alkynyl enones. 13 However, despite its elegance, this latter approach becomes akin to using a chiral ligand, so it is devoid of the flexibility and combinatorial potential offered by the original two-component ACDC.…”