Using Theory and Experiment to Discover Catalysts for Electrocyclizations

Tantillo, Dean J.

doi:10.1002/anie.200804908

Cited by 35 publications

(11 citation statements)

References 24 publications

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“…For 5-endo-trig cyclizations Alabugin has discovered the presence of a 5-center, 6-electron σ-aromatic orbital array involving the nucleophilic lone pair, the target alkene π bond and a σCC bridge can result in TS aromaticity. 29 This has further led to the classification of such cyclizations as ''aborted'' [2,3]-sigmatropic shifts. This would give rise to in-plane TS aromaticity, while an electrocyclic mechanism would show out-ofplane TS aromaticity.…”

Section: -Endo-trig Selective 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: -Endo-trig Selective Cyclizationsmentioning

confidence: 99%

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

Peng

Paton

2016

Acc. Chem. Res.

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“…Tantillo has discussed the challenges inherent in catalyzing reactions that involve highly delocalized, nonpolar transition‐state structures . It is therefore not surprising that attempts to develop catalytic triene 6π electrocyclizations have met with limited success . Two fundamentally different catalytic strategies have been described in the literature: a) acceleration by interaction of a triene substituent with a Lewis acid promoter ( I , Figure b); and b) acceleration by metal–π‐electron interaction(s) .…”

Section: Introductionmentioning

confidence: 99%

Transition‐Metal Catalysis of Triene 6π Electrocyclization: The π‐Complexation Strategy Realized

et al. 2020

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Triene 6π electrocyclization, wherein a conjugated triene undergoes a concerted stereospecific cycloisomerization to a cyclohexadiene, is a reaction of great historical and practical significance. In order to circumvent limitations imposed by the normally harsh reaction conditions, chemists have long sought to develop catalytic variants based upon the activating power of metal–alkene coordination. Herein, we demonstrate the first successful implementation of such a strategy by utilizing [(C5H5)Ru(NCMe)3]PF6 as a precatalyst for the disrotatory 6π electrocyclization of highly substituted trienes that are resistant to thermal cyclization. Mechanistic and computational studies implicate hexahapto transition‐metal coordination as responsible for lowering the energetic barrier to ring closure. This work establishes a foundation for the development of new catalysts for stereoselective electrocyclizations.

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“…[9] Tantillo has discussed the challenges inherent in catalyzing reactions that involve highly delocalized, nonpolar transition-state structures. [12] It is therefore not surprising that attempts to develop catalytic triene 6p electrocyclizations have met with limited success. [10][11][12] Tw o fundamentally different catalytic strategies have been described in the literature:a )acceleration by interaction of at riene substituent with aL ewis acid promoter (I,F igure 1b); [10][11][12] and b) acceleration by metal-p-electron interaction(s).…”

Section: Introductionmentioning

confidence: 99%

“…[12] It is therefore not surprising that attempts to develop catalytic triene 6p electrocyclizations have met with limited success. [10][11][12] Tw o fundamentally different catalytic strategies have been described in the literature:a )acceleration by interaction of at riene substituent with aL ewis acid promoter (I,F igure 1b); [10][11][12] and b) acceleration by metal-p-electron interaction(s). [13][14][15] Thef ormer approach was first realized in 2008 when Bergman and Tr auner described the use of Lewis acid catalysts for accelerating electrocyclization of trienes bearing ester or ketone substituents at the 2-position ( Figure 1b).…”

Section: Introductionmentioning

confidence: 99%

“…The synthetic power of 6π electrocyclization has been demonstrated through applications for the synthesis of complex cyclohexadienes, aromatics, and natural products; however, the high energetic barrier to ring closure has prevented this atom economical transformation from reaching its full potential due to competitive thermal rearrangements and decomposition pathways for both starting trienes and cyclohexadiene products . Tantillo has discussed the challenges inherent in catalyzing reactions that involve highly delocalized, nonpolar transition‐state structures . It is therefore not surprising that attempts to develop catalytic triene 6π electrocyclizations have met with limited success .…”

Section: Introductionmentioning

confidence: 99%

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Transition‐Metal Catalysis of Triene 6π Electrocyclization: The π‐Complexation Strategy Realized

et al. 2020

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Using Theory and Experiment to Discover Catalysts for Electrocyclizations

Cited by 35 publications

References 24 publications

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

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

Transition‐Metal Catalysis of Triene 6π Electrocyclization: The π‐Complexation Strategy Realized

Transition‐Metal Catalysis of Triene 6π Electrocyclization: The π‐Complexation Strategy Realized

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