18 research outputs found
Goldilocks Catalysts: Computational Insights into the Role of the 3,3' Substituents on the Selectivity of BINOL-Derived Phosphoric Acid Catalysts.
BINOL-derived phosphoric acids provide effective asymmetric catalysis for many organic reactions. Catalysts based on this scaffold show a large structural diversity, especially in the 3,3' substituents, and little is known about the molecular requirements for high selectivity. As a result, selection of the best catalyst for a particular transformation requires a trial and error screening process, as the size of the 3,3' substituents is not simply related to their efficacy: the right choice is neither too large nor too small. We have developed an approach to identify and quantify structural features on the catalyst that determine selectivity. We show that the application of quantitative steric parameters (a new measure, AREA(θ), and rotation barrier) to an imine hydrogenation reaction allows the identification of catalyst features necessary for efficient stereoinduction, validated by QM/MM hybrid calculations.We thank EPSRC for funding.This is the final version of the article. It first appeared from the American Chemical Society via https://doi.org/ 10.1021/jacs.6b0282
A Practical Guide for Predicting the Stereochemistry of Bifunctional Phosphoric Acid Catalyzed Reactions of Imines.
Chiral phosphoric acids have become powerful catalysts for the stereocontrolled synthesis of a diverse array of organic compounds. Since the initial report, the development of phosphoric acids as catalysts has been rapid, demonstrating the tremendous generality of this catalyst system and advancing the use of phosphoric acids to catalyze a broad range of asymmetric transformations ranging from Mannich reactions to hydrogenations through complementary modes of activation. These powerful applications have been developed without a clear mechanistic understanding of the reasons for the high level of stereocontrol. This Account describes investigations into the mechanism of the phosphoric acid catalyzed addition of nucleophiles to imines, focusing on binaphthol-based systems. In many cases, the hydroxyl phosphoric acid can form a hydrogen bond to the imine while the PâO interacts with the nucleophile. The single catalyst, therefore, activates both the electrophile and the nucleophile, while holding both in the chiral pocket created by the binaphthol and constrained by substituents at the 3 and 3' positions. Detailed geometric and energetic information about the transition states can be gained from calculations using ONIOM methods that combine the advantages of DFT with some of the speed of force fields. These high-level calculations give a quantitative account of the selectivity in many cases, but require substantial computational resources. A simple qualitative model is a useful complement to this complex quantitative model. We summarize our calculations into a working model that can readily be sketched by hand and used to work out the likely sense of selectivity for each reaction. The steric demands of the different parts of the reactants determine how they fit into the chiral cavity and which of the competing pathways is favored. The preferred pathway can be found by considering the size of the substituents on the nitrogen and carbon atoms of the imine electrophile, and the position of the nucleophilic site on the nucleophile in relation to the hydrogen-bond which holds it in the catalyst active site. We present a guide to defining the pathway in operation allowing the fast and easy prediction of the stereochemical outcome and provide an overview of the breadth of reactions that can be explained by these models including the latest examples.We are grateful to the EPSRC for a DTA award (J.P.R.).This is the author final version of the article. It first appeared from the American Chemical Society via http://dx.doi.org/10.1021/acs.accounts.6b0005
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BINOPtimal: a web tool for optimal chiral phosphoric acid catalyst selection.
A catalyst selection program, BINOPtimal, has been developed. This interactive web tool selects the best performing chiral phosphoric acid catalysts from analysis of the starting materials, imine and nucleophile, on the basis of rules derived from the transformations within its database. This procedure has been applied to an example transformation demonstrating the potential to assist reaction design. The tool is available at www-mmm.ch.cam.ac.uk.EPSRC
Leverhulme
Isaac Newton trus
Base-mediated cascade rearrangements of aryl-substituted diallyl ethers.
Two base-mediated cascade rearrangement reactions of diallyl ethers were developed leading to selective [2,3]-Wittig-oxy-Cope and isomerization-Claisen rearrangements. Both diaryl and arylsilyl-substituted 1,3-substituted propenyl substrates were examined, and each exhibits unique reactivity and different reaction pathways. Detailed mechanistic and computational analysis was conducted, which demonstrated that the role of the base and solvent was key to the reactivity and selectivity observed. Crossover experiments also suggest that these reactions proceed with a certain degree of dissociation, and the mechanistic pathway is highly complex with multiple competing routes.We thank Eli Lilly (Dr Magnus Walter and Dr Maria Whatton) for a CASE
award to C.A.M. and Queenâs University Belfast for funding. We also thank Girton College, Cambridge
(Research Fellowship to M.N.G.) and Unilever for support.This is the accepted manuscript of a paper published in The Journal of Organic Chemistry, 2015, 80 (3), pp 1472â1498, DOI: 10.1021/jo502403n, Publication Date (Web): December 16, 201
Strategies for remote enantiocontrol in chiral gold( iii ) complexes applied to catalytic enantioselective Îł,δ-DielsâAlder reactions
Goldilocks Catalysts: Computational Insights into the Role of the 3,3 Substituents on the Selectivity of BINOL-Derived Phosphoric Acid Catalysts
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Goldilocks Catalysts: Computational Insights into the Role of the 3,3ⲠSubstituents on the Selectivity of BINOL-Derived Phosphoric Acid Catalysts
BINOL-derived
phosphoric acids provide effective asymmetric catalysis
for many organic reactions. Catalysts based on this scaffold show
a large structural diversity, especially in the 3,3Ⲡsubstituents,
and little is known about the molecular requirements for high selectivity.
As a result, selection of the best catalyst for a particular transformation
requires a trial and error screening process, as the size of the 3,3â˛
substituents is not simply related to their efficacy: the right choice
is neither too large nor too small. We have developed an approach
to identify and quantify structural features on the catalyst that
determine selectivity. We show that the application of quantitative
steric parameters (a new measure, AREAÂ(θ), and rotation barrier)
to an imine hydrogenation reaction allows the identification of catalyst
features necessary for efficient stereoinduction, validated by QM/MM
hybrid calculations
A Practical Guide for Predicting the Stereochemistry of Bifunctional Phosphoric Acid Catalyzed Reactions of Imines
Recommended from our members
Base-mediated cascade rearrangements of aryl-substituted diallyl ethers.
Two base-mediated cascade rearrangement reactions of diallyl ethers were developed leading to selective [2,3]-Wittig-oxy-Cope and isomerization-Claisen rearrangements. Both diaryl and arylsilyl-substituted 1,3-substituted propenyl substrates were examined, and each exhibits unique reactivity and different reaction pathways. Detailed mechanistic and computational analysis was conducted, which demonstrated that the role of the base and solvent was key to the reactivity and selectivity observed. Crossover experiments also suggest that these reactions proceed with a certain degree of dissociation, and the mechanistic pathway is highly complex with multiple competing routes.We thank Eli Lilly (Dr Magnus Walter and Dr Maria Whatton) for a CASE
award to C.A.M. and Queenâs University Belfast for funding. We also thank Girton College, Cambridge
(Research Fellowship to M.N.G.) and Unilever for support.This is the accepted manuscript of a paper published in The Journal of Organic Chemistry, 2015, 80 (3), pp 1472â1498, DOI: 10.1021/jo502403n, Publication Date (Web): December 16, 201
Models for Understanding Divergent Reactivity in Lewis Acid-Catalyzed Transformations of Carbonyls and Olefins
Carbonyl-ene, Prins and carbonyl-olefin metathesis reactions represent powerful strategies for carbon-carbon bond formation relying on Lewis acid catalysts. Although common Lewis acids are able to provide efficient activation, the reactions often proceed with low regio-, or chemoselectivity while high selectivity frequently requires the use of well-designed metal-ligand complexes. Here we demonstrate that simple Lewis acids including Me2AlCl, FeCl3, and SnCl4 can show remarkable selectivity in dif-ferentiating between distinct transformations of carbonyl and olefin functional groups resulting in either carbonyl-ene or carbonyl-olefin metathesis products. Specifically, we report the development of predictive multivariate linear regression models that rely on kinetic and thermodynamic information obtained in DFT calculations to gain important insights into the complex potential energy surfaces (PES) of these competing reaction paths. The presented results further our understanding of Lewis acid reactivity and suggest that even simple Lewis acids have the potential to function as highly selective catalysts.</div