Designing the Secondary Coordination Sphere in Small-Molecule Catalysis

Zak, Inbal L.; Gadekar, Santosh C.; Milo, Anat

doi:10.1055/s-0040-1707326

Cited by 8 publications

(10 citation statements)

References 42 publications

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“…192−194 In 2019, we reported that the catalytic activity of N-heterocyclic carbene (NHC) triazolium salts bearing a hydroxy handle could be fine tuned by the in situ addition of boronic acids as second-sphere modifiers. 194,195 This strategy also enabled more rapid data collection because the catalyst structure was modified without the need to synthesize libraries of catalysts. In this work, we investigated the effect of second-sphere modifications on benzoin reactions with a focus on electron-deficient aldehydes, which were notoriously challenging because of facile racemization.…”

Section: ■ Enhanced Data Visualizationmentioning

confidence: 99%

Mechanistic Inference from Statistical Models at Different Data-Size Regimes

Lustosa

Milo

2022

ACS Catal.

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The chemical sciences are witnessing an influx of statistics into the catalysis literature. These developments are propelled by modern technological advancements that are leading to fast and reliable data production, mining, and management. In organic chemistry, models encoded with information-rich parameters have facilitated the formulation of mechanistic hypotheses across different data-size regimes. Herein, we aim to demonstrate through selected examples that the integration of statistical principles into homogeneous catalysis can streamline not only reaction optimization protocols but also mechanistic investigation procedures. Namely, we highlight how different aspects of molecular modeling, data set design, data visualization, and nuanced data restructuring can contribute to improving chemical reactivity and selectivity, while furthering our understanding of reaction mechanisms. By mapping out these techniques at different data set sizes, we hope to encourage the broad application of data-driven approaches for mechanistic studies regardless of the accessible amount of data.

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Section: ■ Enhanced Data Visualizationmentioning

confidence: 99%

Mechanistic Inference from Statistical Models at Different Data-Size Regimes

Lustosa

Milo

2022

ACS Catal.

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“…As part of our ongoing program on secondary sphere modified organocatalysts, 18 we recently reported the application of amino catalysts in an aldol reaction between aromatic aldehydes and cyclopentanone ( Figure 2 .a). 19 By modifying proline with boronic acids in situ we were able to rapidly access different organocatalyst derivatives without any synthetic effort.…”

Section: Introductionmentioning

confidence: 99%

Effect of Solvents on Proline Modified at the Secondary Sphere: A Multivariate Exploration

et al. 2022

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The critical influence of solvent effects on proline-catalyzed aldol reactions has been extensively described. Herein, we apply multivariate regression strategies to probe the influence of different solvents on an aldol reaction catalyzed by proline modified at its secondary sphere with boronic acids. In this system, both in situ binding of the boronic acid to proline and the outcome of the aldol reaction are impacted by the solvent-controlled microenvironment. Thus, with the aim of uncovering mechanistic insight and an ancillary aim of identifying methodological improvements, we designed a set of experiments, spanning 15 boronic acids in five different solvents. Based on hypothesized intermediates or interactions that could be responsible for the selectivity in these reactions, we proposed several structural configurations for the library of boronic acids. Subsequently, we compared the statistical models correlating the outcome of the reaction in different solvents with molecular descriptors produced for each of these proposed configurations. The models allude to the importance of different interactions in controlling selectivity in each of the studied solvents. As a proof-of-concept for the practicality of our approach, the models in chloroform ultimately led to lowering the ketone loading to only two equivalents while retaining excellent yield and enantio- and diastereo-selectivity.

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“…Supramolecular recognition may represent a versatile tool to overcome the synthetic challenges of tuning the second coordination sphere of a catalyst,[ 5j , 15 , 16 ] and test the validity of this approach (Figure 1 C). In particular, catalysts CR M and CR,X M (Figure 2 , M=Fe, Mn) bearing two or one 18‐benzo‐crown‐6‐ether (CR) receptors, respectively, strongly bind protonated primary amines, promoting their selective C−H oxidation.…”

Section: Introductionmentioning

confidence: 99%

Remote Amino Acid Recognition Enables Effective Hydrogen Peroxide Activation at a Manganese Oxidation Catalyst

2021

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Precise delivery of a proton plays a key role in O 2 activation at iron oxygenases, enabling the crucial OÀ O cleavage step that generates the oxidizing high-valent metaloxo species. Such a proton is delivered by acidic residues that may either directly bind the iron center or lie in its second coordination sphere. Herein, a supramolecular strategy for enzyme-like H 2 O 2 activation at a biologically inspired manganese catalyst, with a nearly stoichiometric amount (1-1.5 equiv) of a carboxylic acid is disclosed. Key for this strategy is the incorporation of an α,ω-amino acid in the second coordination sphere of a chiral catalyst via remote ammonium-crown ether recognition. The properly positioned carboxylic acid function enables effective activation of hydrogen peroxide, leading to catalytic asymmetric epoxidation. Modulation of both amino acid and catalyst structure can tune the efficiency and the enantioselectivity of the reaction, and a study on the oxidative degradation pathway of the system is presented.

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Designing the Secondary Coordination Sphere in Small-Molecule Catalysis

Cited by 8 publications

References 42 publications

Mechanistic Inference from Statistical Models at Different Data-Size Regimes

Mechanistic Inference from Statistical Models at Different Data-Size Regimes

Effect of Solvents on Proline Modified at the Secondary Sphere: A Multivariate Exploration

Remote Amino Acid Recognition Enables Effective Hydrogen Peroxide Activation at a Manganese Oxidation Catalyst

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