Enantioselective Desymmetrization of Prochiral Cyclohexanones by Organocatalytic Intramolecular Michael Additions to α,β‐Unsaturated Esters

Yamagata, Adam D. Gammack; Datta, Sourav; Jackson, Kelvin E.; Stegbauer, Linus; Paton, Robert S.; Dixon, Darren J.

doi:10.1002/ange.201411924

Cited by 27 publications

(3 citation statements)

References 66 publications

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“…In collaboration with Dixon and colleagues, we described how the desymmetrization of a prochiral cyclohexanone through an intramolecular Michael addition to α,β-unsaturated esters can be catalyzed using a chiral primary amine (Figure ). Before consideration of the enantioselective reaction, it was discovered that small primary amines, such an n -butylamine, give rise to exclusive formation of the (contra-steric) endo diastereomer of the Michael adduct. We investigated the mechanistic origins of this selectivity by means of computations carried out at the M06-2X/6-311+G(d,p) level of theory with implicit (CPCM) solvation by CH 2 Cl 2 .…”

Section: Computational Catalyst Design For Asymmetric Cyclizationsmentioning

confidence: 99%

Catalytic Control in Cyclizations: From Computational Mechanistic Understanding to Selectivity Prediction

Peng

Paton

2016

Acc. Chem. Res.

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This Account describes the use of quantum-chemical calculations to elucidate mechanisms and develop catalysts to accomplish highly selective cyclization reactions. Chemistry is awash with cyclic molecules, and the creation of rings is central to organic synthesis. Cyclization reactions, the formation of rings by the reaction of two ends of a linear precursor, have been instrumental in the development of predictive models for chemical reactivity, from Baldwin's classification and rules for ring closure to the Woodward and Hoffmann rules based on the conservation of orbital symmetry and beyond. Ring formation provides a productive and fertile testing ground for the exploration of catalytic mechanisms and chemo-, regio-, diastereo-, and enantioselectivity using computational and experimental approaches. This Account is organized around case studies from our laboratory and illustrates the ways in which computations provide a deeper understanding of the mechanisms of catalysis in 5-endo cyclizations and how computational predictions can lead to the development of new catalysts for enhanced stereoselectivities in asymmetric cycloisomerizations. We have explored the extent to which several cation-directed 5-endo ring-closing reactions may be considered as electrocyclic and demonstrated that reaction pathways and magnetic parameters of transition structures computed using quantum chemistry are inconsistent with this notion, instead favoring a polar mechanism. A rare example of selectivity in favor of 5-endo-trig ring closure is shown to result from subtle substrate effects that bias the reactant conformation out-of-plane, limiting the involvement of cyclic conjugation. The mode of action of a chiral ammonium counterion was deduced via conformational sampling of the transition state assembly and involves coordination to the substrate via a series of nonclassical hydrogen bonds. We describe how computational mechanistic understanding has led directly to the discovery of new catalyst structures for enantioselective cycloisomerizations. Calculations have revealed that stepwise C-C bond formation and proton transfer dictate the exclusive endo diastereoselectivity of the intramolecular Michael addition to form 2-azabicyclo[3.3.1]nonane skeletons catalyzed by primary amines. These insights have led to development of a highly enantioselective catalyst with higher atom economy than previous generations. This Account also explores transition-metal-catalyzed cycloisomerizations, where our theoretical investigations have uncovered an unexpected reaction pathway in the [5 + 2] cycloisomerization of ynamides. This has led to the design of new phosphoramidite ligands to enable double-stereodifferentiating cycloisomerizations in both matched and mismatched catalyst-substrate settings. Computational understanding of the factors responsible for the regio-, enantio-, and diasterocontrol is shown to generate tangible predictions leading to an acceleration of catalyst development for selective cyclizations.

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Section: Computational Catalyst Design For Asymmetric Cyclizationsmentioning

confidence: 99%

Catalytic Control in Cyclizations: From Computational Mechanistic Understanding to Selectivity Prediction

Peng

Paton

2016

Acc. Chem. Res.

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“…From a computational perspective, understanding selectivity in kinetically controlled reactions relies on a comparison of competing transition structures and their relative stabilities. Developments in electronic structure theory have enabled us and others to describe challenging enantioselective reactions accurately, − but the application of computations to rational catalyst design is still very challenging . For example, to accelerate the discovery of the best catalyst for a desired reaction via computational support; it must be possible to make accurate computational predictions faster than the time taken to carry out reactions in real time.…”

Section: Introductionmentioning

confidence: 99%

Development of a True Transition State Force Field from Quantum Mechanical Calculations

Madarász

Berta

Paton

2016

J. Chem. Theory Comput.

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Transition state force fields (TSFF) treated the TS structure as an artificial minimum on the potential energy surface in the past decades. The necessary parameters were developed either manually or by the Quantum-to-molecular mechanics method (Q2MM). In contrast with these approaches, here we propose to model the TS structures as genuine saddle points at the molecular mechanics level. Different methods were tested on small model systems of general chemical reactions such as protonation, nucleophilic attack, and substitution, and the new procedure led to more accurate models than the Q2MM-type parametrization. To demonstrate the practicality of our approach, transferrable parameters have been developed for Mo-catalyzed olefin metathesis using quantum mechanical properties as reference data. Based on the proposed strategy, any force field can be extended with true transition state force field (TTSFF) parameters, and they can be readily applied in several molecular mechanics programs as well.

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“…The γ-bromo-crotonates 2a-2d, 2f, and 2n were known products. 2 The Characterization Data for γ-Bromo-crotonates…”

Section: Scheme S2 γ-Bromo-crotonates Used In the Reactionsmentioning

confidence: 99%

Relay Annulation of Ammonium Ylides with Oxindole-Derived ,-Unsaturated Ketimines: Catalytic Construction of Spiro-polycyclic Oxindoles

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Enantioselective Desymmetrization of Prochiral Cyclohexanones by Organocatalytic Intramolecular Michael Additions to α,β‐Unsaturated Esters

Cited by 27 publications

References 66 publications

Catalytic Control in Cyclizations: From Computational Mechanistic Understanding to Selectivity Prediction

Catalytic Control in Cyclizations: From Computational Mechanistic Understanding to Selectivity Prediction

Development of a True Transition State Force Field from Quantum Mechanical Calculations

Relay Annulation of Ammonium Ylides with Oxindole-Derived ,-Unsaturated Ketimines: Catalytic Construction of Spiro-polycyclic Oxindoles

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