Automated Quantum Mechanical Predictions of Enantioselectivity in a Rhodium‐Catalyzed Asymmetric Hydrogenation

Guan, Yanfei; Wheeler, Steven E.

doi:10.1002/anie.201704663

Cited by 47 publications

(41 citation statements)

References 70 publications

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“…However, it was unclear what further modifications could lead to additional reactivity enhancement. 19,27 Although successful predictions of new transition metal catalysts from computational results alone are still rare, 28 several examples have recently been described wherein a combination of computational and experimental evaluations has led to the discovery of catalysts with improved reactivity and selectivity. 19,21 Such synergetic efforts effectively utilize the predictive power of computation, while the experimental verification helps resolve the uncertainty of calculated energies and issues that cannot be readily addressed by computations alone, such as catalyst decomposition.…”

Section: Introductionmentioning

confidence: 99%

Mechanistically Guided Design of Ligands That Significantly Improve the Efficiency of CuH-Catalyzed Hydroamination Reactions

et al. 2018

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Using a mechanistically guided ligand design approach, a new ligand (SEGFAST) for the CuHcatalyzed hydroamination reaction of unactivated terminal olefins has been developed, providing a 62-fold rate increase over reactions compared to DTBM-SEGPHOS, the previous optimal ligand. Combining the respective strengths of computational chemistry and experimental kinetic measurements, we were able to quickly identify potential modifications that lead to more effective ligands, thus avoiding synthesizing and testing a large library of ligands. By optimizing the combination of attractive, non-covalent ligand-substrate interactions and the stability of the catalyst under the reaction conditions, we were able to identify a finely-tuned hybrid ligand that greatly enables accelerated hydrocupration rates with unactivated alkenes. Moreover, a modular and robust synthetic sequence was devised, which allowed for practical, gram-scale synthesis of these novel hybrid ligand structures.

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Section: Introductionmentioning

confidence: 99%

Mechanistically Guided Design of Ligands That Significantly Improve the Efficiency of CuH-Catalyzed Hydroamination Reactions

et al. 2018

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“…Moreover, especially when very high levels of enantioselectivity are required, it is unlikely that a better catalyst can be found by chance through screening of a chiral catalyst library or structural modifications of the state-of-the-art catalyst without any rational guidance for the improvement of the selectivity. Recent developments of density functional theory (DFT) calculations have enabled scientists to acquire information on possible reaction paths, including intermediates and transition-state structures, and these modern methods, which enclose long-range dispersion correlations, have reached a high level of accuracy with respect to the prediction of the stereoselectivity in organic reactions 5 – 10 . Meanwhile, multidimensional analysis methods based on steric parameters and properties of organic compounds for asymmetric reactions have been developed 11 , 12 .…”

Section: Introductionmentioning

confidence: 99%

Computational design of high-performance ligand for enantioselective Markovnikov hydroboration of aliphatic terminal alkenes

2018

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Finding optimal chiral ligands for transition-metal-catalyzed asymmetric reactions using trial-and-error methods is often time-consuming and costly, even if the details of the reaction mechanism are already known. Although modern computational analyses allow the prediction of the stereoselectivity, there are only very few examples for the attempted design of chiral ligands using a computational approach for the improvement of the stereoselectivity. Herein, we report a systematic method for the design of chiral ligands for the enantioselective Markovnikov hydroboration of aliphatic terminal alkenes based on a computational and experimental evaluation sequence. We developed a three-hindered-quadrant P-chirogenic bisphosphine ligand that was designed in accordance with the design guidelines derived from this method, which allowed the Markovnikov hydroboration to proceed with high enantioselectivity (up to 99% ee).

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“…Automation of descriptor generation will also certainly play an important role in order to simplify routine computational design. 25 Also, we envisage that an automated, easy-to-use and transparent approach to monitor and Boltzmann-weight (if appropriate) conformational effects will be of great use and may help to bring these approaches to a broader section of the organic community.…”

Section: Introductionmentioning

confidence: 99%

Conformational Effects on Physical-Organic Descriptors – the Case of Sterimol Steric Parameters

Brethomé¹,

Fletcher²,

Paton

2018

Preprint

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<div> <div> <div> <p>Mathematical relationships which relate chemical structure with selectivity have provided quantitative insights underlying catalyst design and informing mechanistic studies. Flexible compounds, however, can adopt several distinct geometries and so can be challenging to describe using a single structure-based descriptor. How best to quantify the structural characteristics of an ensemble of structure poses both practical and technical difficulties. In this work we introduce an automated computational workflow which can be used to obtain multidimensional Sterimol parameters for a conformational ensemble of a given substituent from a single command. The Boltzmann-weighted Sterimol parameters obtained from this approach are shown to be useful in multivariate models of enantioselectivity, while the range of values from conformers within 3 kcal/mol of the most stable structure provides a visual way to capture a possible source of uncertainty arising in the resulting models. Implementing our approach requires no programming expertise and can be executed from within a graphical user interface using open-source programs. </p> </div> </div> </div>

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Automated Quantum Mechanical Predictions of Enantioselectivity in a Rhodium‐Catalyzed Asymmetric Hydrogenation

Cited by 47 publications

References 70 publications

Mechanistically Guided Design of Ligands That Significantly Improve the Efficiency of CuH-Catalyzed Hydroamination Reactions

Mechanistically Guided Design of Ligands That Significantly Improve the Efficiency of CuH-Catalyzed Hydroamination Reactions

Computational design of high-performance ligand for enantioselective Markovnikov hydroboration of aliphatic terminal alkenes

Conformational Effects on Physical-Organic Descriptors – the Case of Sterimol Steric Parameters

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