N‐Heterocyclic Carbene Catalyzed (5+1) Annulations Exploiting a Vinyl Dianion Synthon Strategy

Nguyen, Xuan B.; Nakano, Yuji; Duggan, Nisharnthi M.; Scott, Lydia; Breugst, Martin; Lupton, David W.

doi:10.1002/ange.201905475

Cited by 8 publications

(2 citation statements)

References 105 publications

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“…This species can then engage in either a 5- or 6- exo -trig cyclization via one of the two remaining conjugate acceptors to allow the second, and enantiodetermining, C–C bond-forming event to occur. In all cases (seven examples), we observed cyclization to form cyclohexanone products such as 30 …”

Section: Polarity Inversion Using N-heterocyclic Carbenesmentioning

confidence: 99%

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Enantioselective Catalysis by the Umpolung of Conjugate Acceptors Involving N-Heterocyclic Carbene or Organophosphine 1,4-Addition

2023

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Conspectus Conjugate acceptors are one of the most common electrophilic functional groups in organic synthesis. While useful in a diverse range of transformations, their applications are largely dominated by the reactions from which their name is derived (i.e., as an acceptor of nucleophiles in the conjugate position). In 2014, we commenced studies focused on their ability to undergo polarity inversion through the conjugate addition of Lewis base catalysts. The first step in this process provides an enolate, from which the well-developed Rauhut–Currier (RC) and Morita–Baylis–Hillman (MBH) reactions can occur; however, tautomerization to provide a species in which the β-carbon of the conjugate acceptor can now act as a donor is also possible. When we commenced studies on this topic, reaction designs with this type of species, particularly when accessed using N-heterocyclic carbenes (NHCs), had been reported on only a handful of occasions. Despite a lack of development, conceptually it was felt that reactions taking advantage of polarity switching by Lewis base conjugate addition have a number of desirable features. Perhaps the most significant is the potential to reimagine a ubiquitous functional group as an entirely new synthon, namely, a donor to electrophiles from the conjugate position. Our work has focused on catalysis with both simple conjugate acceptors and also those embedded within more complicated substrates; the latter has allowed a series of cycloisomerizations and annulation reactions to be achieved. In most cases, the reactions have been possible using enantioenriched chiral NHCs or organophosphines as the Lewis base catalysts thereby delivering enantioselective approaches to novel cyclic molecules. While related chemistry can be accessed with either family of catalyst, in all cases reactions have been designed to take advantage of one or the other. In addition, a fine balance exists between reactions that exploit the initially formed enolate and those that involve the polarity-inverted β-anion. In our studies, this balance is addressed through substrate design, although catalyst control may also be possible. We consider the chemistry discussed in this Account to be in its infancy. Significant challenges remain to be addressed before our broad aim of discovering a universal approach to the polarity inversion of all conjugate acceptors can be achieved. These challenges broadly relate to chemoselectivity with substrates bearing multiple electrophilic functionalities, reliance upon the use of conjugate acceptors, and catalyst efficiency. To address these challenges, advances in catalyst design and catalyst cooperativity are likely required.

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Section: Polarity Inversion Using N-heterocyclic Carbenesmentioning

confidence: 99%

“…Chem., Int. Ed.2019581148311490 Enantioselective N-Heterocyclic Carbene Catalyzed Bis(enoate) Rauhut–Currier ReactionBaeS.ZhangC.GillardR.…”

Section: Key Referencesmentioning

confidence: 99%

Enantioselective Catalysis by the Umpolung of Conjugate Acceptors Involving N-Heterocyclic Carbene or Organophosphine 1,4-Addition

2023

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Enantioselective N‐Heterocyclic Carbene Catalyzed Bis(enoate) Rauhut–Currier Reaction

et al. 2019

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While the enantioselective Rauhut-Currier reaction is established with bis(enone) substrates,itisyet to be reported with less electrophilic bis(enoate) substrates.B ye xploiting high-nucleophilicity N-heterocyclic carbenes,i ti sp ossible to achieve Rauhut-Currier reactions with these substrates.T he reaction is demonstrated with ar ange of intramolecular reactions (20 examples) and six esterification/RC reaction cascades,w hich all proceed with high enantioselectivity (most > 93:7 er).

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Enantioselective Synthesis of Cyclopentenes by (3+2) Annulation via a 2‐Carbon Phosphonium

Seitz,

Maddigan‐Wyatt,

Cao

et al. 2024

Angewandte Chemie

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Herein we report a catalytic enantioselective (3 + 2) annulation, in which a vinyl phosphonium intermediate serves as the 2‐carbon component. The reaction involves an α‐umpolung β‐umpolung coupling sequence, enabled by β‐haloacrylates and chiral enantioenriched phosphepine catalysts. The reaction shows good generality, providing access to an array of cyclopentenes, with mechanistic studies supporting stereospecific formation of the vinyl phosphonium intermediate which then undergoes annulation with turn over limiting catalyst elimination. Beyond defining a new approach to cyclopentenes, these studies demonstrate that β‐haloacrylates can replace ynoates in reaction designs that require exclusive umpolung coupling at the α‐ and β‐positions.

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N‐Heterocyclic Carbene Catalyzed (5+1) Annulations Exploiting a Vinyl Dianion Synthon Strategy

Cited by 8 publications

References 105 publications

Enantioselective Catalysis by the Umpolung of Conjugate Acceptors Involving N-Heterocyclic Carbene or Organophosphine 1,4-Addition

Enantioselective Catalysis by the Umpolung of Conjugate Acceptors Involving N-Heterocyclic Carbene or Organophosphine 1,4-Addition

Enantioselective N‐Heterocyclic Carbene Catalyzed Bis(enoate) Rauhut–Currier Reaction

Enantioselective Synthesis of Cyclopentenes by (3+2) Annulation via a 2‐Carbon Phosphonium

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