Secondary-sphere modification in proline catalysis: old friend, new connection

Domb, Ido; Lustosa, Danilo M.; Milo, Anat

doi:10.1039/d1cc05589e

Cited by 5 publications

(15 citation statements)

References 30 publications

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“…Gratifyingly, the excellent experimental results obtained using CHCl 3 or ACN as solvents with only 6.8 equiv of cyclopentanone already surpassed our previously optimized neat conditions. 19 Given these results, we wondered whether the models could provide an indication as to which of these systems could withstand further reduction in the amount of ketone without an erosion of selectivity. For the reaction in CHCl 3 the bound boronic acid–proline structure provided the best fit ( Figure 4 .h), whereas in ACN it was the boronic acid–aldehyde π interaction structure that led to the best fit ( Figure 4 .g).…”

Section: Resultsmentioning

confidence: 99%

“…It was also known that water had a marked effect on the diastereoselectivity and reactivity of these reaction. 19 Thus, all the reactions were performed with the addition of 0.9 μL of water. In an attempt to address the effect of water, we also planned an additional set of reactions without water.…”

Section: Methodsmentioning

confidence: 99%

“…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. Taking advantage of the broad spread of data stemming from our secondary-sphere modification, we set out to study the influence of solvent effects on the aldol reaction.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…109,188 Recently, we reported a catalytic method based on the in situ second-sphere modification of proline with boronic acids. 200 This method was applied in an intermolecular aldol reaction between cyclopentanone as aldol donor and benzaldehydes as aldol acceptors. A combination of proline and 2-fluoro-boronic acid were initially identified to deliver excellent levels of diastereoselectivity (dr), along with short reaction times and a broad scope.…”

Section: ■ Enhanced Data Visualizationmentioning

confidence: 99%

“…203−218 Pioneering work by the Fey group established libraries mostly specializing in phosphine ligands, motivated by their prevalence in cross-coupling reactions. 86,87,[193][194][195][196][197]200 More recently, a new library of monodentate phosphines, extended by ML techniques, was reported by the Aspuru-Guzik and Sigman groups. 211 The library is incorporated in an online platform named Kraken, and 200 descriptors are available for each ligand in the database.…”

Section: ■ Reaction Cliffsmentioning

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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