Catalytic control in cyclizations: from computational mechanistic understanding to selectivity prediction
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 formatio...
| Main Authors: | , |
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| Format: | Journal article |
| Language: | English |
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American Chemical Society
2016
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| _version_ | 1797093226501373952 |
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| author | Peng, Q Paton, R |
| author_facet | Peng, Q Paton, R |
| author_sort | Peng, Q |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T03:57:15Z |
| format | Journal article |
| id | oxford-uuid:c34a213b-37dc-4fc0-8718-a2b5f0c25a69 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:57:15Z |
| publishDate | 2016 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:c34a213b-37dc-4fc0-8718-a2b5f0c25a692022-03-27T06:15:19ZCatalytic control in cyclizations: from computational mechanistic understanding to selectivity predictionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:c34a213b-37dc-4fc0-8718-a2b5f0c25a69EnglishSymplectic Elements at OxfordAmerican Chemical Society2016Peng, QPaton, RThis 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. |
| spellingShingle | Peng, Q Paton, R Catalytic control in cyclizations: from computational mechanistic understanding to selectivity prediction |
| title | Catalytic control in cyclizations: from computational mechanistic understanding to selectivity prediction |
| title_full | Catalytic control in cyclizations: from computational mechanistic understanding to selectivity prediction |
| title_fullStr | Catalytic control in cyclizations: from computational mechanistic understanding to selectivity prediction |
| title_full_unstemmed | Catalytic control in cyclizations: from computational mechanistic understanding to selectivity prediction |
| title_short | Catalytic control in cyclizations: from computational mechanistic understanding to selectivity prediction |
| title_sort | catalytic control in cyclizations from computational mechanistic understanding to selectivity prediction |
| work_keys_str_mv | AT pengq catalyticcontrolincyclizationsfromcomputationalmechanisticunderstandingtoselectivityprediction AT patonr catalyticcontrolincyclizationsfromcomputationalmechanisticunderstandingtoselectivityprediction |