Transition State Force Field for the Asymmetric Redox-Relay Heck Reaction

Abstract

A transition state force field (TSFF) was developed using the quantum-guided molecular mechanics (Q2MM) method to describe the stereodetermining migratory insertion step of the enantioselective redox-relay Heck reaction for a range of multisubstituted alkenes. We show that the TSFF is highly predictive through an external validation of the TSFF against 151 experimentally determined stereoselectivities resulting in an R 2 of 0.89 and MUE of 1.8 kJ/mol. In addition, limitations in the underlying force field were identified by comparison of the TSFF results to DFT level calculations. A novel application of the TSFF was demonstrated for 31 cases where the enantiomer predicted by the TSFF differed from the originally published values. Experimental determination of the absolute configuration demonstrated that the computational predictions were accurate, suggesting that TSFFs can be used for the rapid prediction of the absolute stereochemistry for a class of reactions. Finally, a virtual ligand screen was conducted utilizing both the TSFF and a simple molecular correlation method. Both methods were similarly predictive, but the TSFF was able to show greater utility through transferability, speed, and interpretability.

Microsecond timescale MD simulations at the transition state of PmHMGR predict remote allosteric residues

“…We developed the Quantum-Guided Molecular Mechanics (Q2MM) method 13,14 for the automated tting of TSFFs to highlevel electronic structure calculations and applied it to a variety of transition metal catalyzed reactions. 17,18 The details of adapting the Q2MM method to the parameterization of TSFFs for enzymes have also been described. 19 The general philosophy of the Q2MM approach as applied to enzymes, shown in Fig.…”

Proofreading Experimentally Assigned Stereochemistry Through Q2MM Predictions in Pd-Catalyzed Allylic Aminations

“…Overall, the R 2 values for the internal validation ranges from 0.988 to 0.998 for geometric and Hessian eigenvalues, respectively, and 0.822 for charges, which are typical values for internal validations of TSFFs. 29,35,36 The next step is the external validation by prediction of selectivities for ligand-substrate combinations from the literature that are not part of the training set. Using CatVS, 31 the libraries of TS structures can rapidly and automatically be prepared for conformational searches by merging substrate, ligand, and nucleophile sub-libraries onto a template.…”

“…26 Quantum Guided Molecular Mechanics (Q2MM) was developed to predict stereoselectivity, combining the speed of molecular mechanics (MM) with the accuracy of DFT. [27][28][29][30] It uses transition state force elds (TSFFs) that are trained on electronic structure calculations of simpli ed models of the stereoselecting transition state. Because no empirical data are used to t the force eld, the results are true predictions.…”

Stereoselective Remote Functionalization via Palladium‐Catalyzed Redox‐Relay Heck Methodologies

“…This is am ajor research focus, and efforts towards predictinge nantioselectivities have already been reported. [68] The potential scalability of this transformation has also yet to be thoroughly investigated, and detailed studies from this perspective may encourage industrial uptake of the methodology. [69] For the redox-relay Heck reaction, additional considerations need to be taken for the use of diazonium salts in palladium catalysis, [70] whilst there is added complexity in the redox-relay oxidative Heck reaction based on the greater number of additives, which could make it more challenging to understand the role of all reaction components.…”

“…In time, these discoveries should aid in making new, complex transformations more predictable and reliable. This is a major research focus, and efforts towards predicting enantioselectivities have already been reported [68] . The potential scalability of this transformation has also yet to be thoroughly investigated, and detailed studies from this perspective may encourage industrial uptake of the methodology [69] .…”