Correction to “Cyclization Cascades Initiated by 1,6-Conjugate Addition”

Brooks, Joshua L.; Frontier, Alison J.

doi:10.1021/ja4118363

Cited by 4 publications

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“…In a different study, we found that generating pentadienyl cations of type 82 (3-alkyl or -aryl) is possible from the 1,6-addition of a nucleophile to a dienyl diketone (Scheme ). − Activation of the dienyl diketone with a Lewis acid facilitates addition of nucleophiles to generate intermediate 82 . This intermediate presumably forms in the S-conformation but can then isomerize (through σ-bond rotation) to the U-shape necessary for cyclization.…”

Section: Resultsmentioning

confidence: 99%

“…Cyclization generates 5-hydroxyketone products 83 as single diastereoisomers. Cyclizations triggered by 1,6-addition of amine and malonate nucleophiles have been demonstrated with both unsubstituted (R 3 = H, 86 – 94 ) and substituted (R 3 = methyl, 95 and 96 ) , dienones (Scheme ). Strangely, if R 3 is any larger than methyl, electrocyclization is thwarted and a different reaction pathway is observed (vide infra).…”

Section: Resultsmentioning

confidence: 99%

“…In unsubstituted dienones (R 3 = H), exo -methylene enones 97 are obtained (Scheme a) . Having established that trisubstituted amines do promote the cyclization, we carried on with addition of DABCO to substituted dienones (R 3 = Me) and found that these reactions do not produce cyclopentenones at all, but rather dihydropyrans 98 (Scheme b). , …”

Section: Resultsmentioning

confidence: 99%

“…In these cases, with tertiary amine nucleophiles, the usual conjugate addition/cyclization is unproductive and indeed must be reversible. This reversibility was unanticipated and led us to misassign structures at first. , Later experiments designed to explore the feasibility of this pathway provided strong support for this hypothesis (Scheme a). Methylation of the amine in Nazarov product 124 leads to quaternary ammonium intermediate 124 , which is analogous to the zwitterion 117 formed when a tertiary amine is used.…”

Section: Resultsmentioning

confidence: 99%

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New Twists in Nazarov Cyclization Chemistry

Frontier

Hernandez

2020

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS:The defining feature of the Nazarov cyclization is a 4πconrotatory electrocyclization, resulting in the stereospecific formation of functionalized cyclopentanones. The reaction provides access to structural motifs that are found in many natural products and drug targets. Harnessing the full potential of the Nazarov cyclization broadens its utility by enabling the development of new methodologies and synthetic strategies. To achieve these goals through efficient cyclization design, it is helpful to think of the reaction as a two-stage process. The first stage involves a 4π-electrocyclization leading to the formation of an allylic cation, and the second stage corresponds to the fate of this cationic intermediate. With a complete understanding of the discrete events that characterize the overall process, one can optimize reactivity and control the selectivity of the different Stage 2 pathways.In this Account, we describe the development of methods that render the Nazarov cyclization catalytic and chemoselective, focusing specifically on advances made in our lab between 2002 and 2015. The initial discovery made in our lab involved reactions of electronically asymmetric ("polarized") substrates, which cyclize efficiently in the catalytic regime using mild Lewis acidic reagents. These cyclizations also exhibit selective eliminative behavior, increasing their synthetic utility. Research directed toward catalytic asymmetric Nazarov cyclization led to the serendipitous discovery of a 4π-cyclization coupled to a well-behaved Wagner−Meerwein rearrangement, representing an underexplored Stage 2 process. With careful choice of promoter and loading, it is possible to access either the rearrangement or the elimination pathway. Additional experimental and computational studies provided an effective model for anticipating the migratory behavior of substiutents in the rearrangements. Problem-solving efforts prompted investigation of alternative methods for generating pentadienyl cation intermediates, including oxidation of allenol ethers and addition of nucleophiles to dienyl diketones. These Nazarov cyclization variants afford cyclopentenone products with vicinal stereogenic centers and a different arrangement of substituents around the ring. A nucleophilic addition/cyclization/elimination sequence can be executed enantioselectively using catalytic amounts of a nonracemic chiral tertiary amine. In summary, the discovery and development of several new variations on the Nazarov electrocyclization are described, along with synthetic applications. This work illustrates how strongly substitution patterns can impact the efficiency of the 4π-electrocyclization (Stage 1), allowing for mild Lewis acid catalysis. Over the course of these studies, we have also identified new ways to access the critical pentadienyl cation intermediates and demonstrated strategies that exploit and control the different cationic pathways available post-electrocyclization (Stage 2 processes). These advances in Na...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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New Twists in Nazarov Cyclization Chemistry

Frontier

Hernandez

2020

Acc. Chem. Res.

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“…We previously described a Lewis acid that promoted 1,6-conjugate addition to initiate Nazarov cyclization. 6 For example, treatment of dienyl diketones 1 (R 3 ≠ H) with catalytic Lewis acid, lithium chloride, and triethylamine as a base, and in the presence of a nucleophile, results in their smooth conversion to cyclopentenones 2 (eq 1 ). However, treatment of the same dienyl diketones 1 with the nucleophilic tertiary amine DABCO (1,4-diazabicyclo[2.2.2]octane) leads to two different types of cyclization products: either 2 H -pyrans 3 (eq 2 ) 7 or 4-methylene cyclopentenones 4 (eq 3 ), depending upon the R 3 substituent on the dienone.…”

Section: Introductionmentioning

confidence: 99%

No Acid Required: 4π and 6π Electrocyclization Reactions of Dienyl Diketones for the Synthesis of Cyclopentenones and 2H-Pyrans

2014

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The 1,6-conjugate addition of nucleophiles to dienyl diketones produces either cyclopentenone or 2H-pyran products with high selectivity through either Nazarov (4π) or 6π electrocyclization, respectively. The outcome of the reaction is dependent upon the nature of the nucleophile used. Nucleophiles that are anionic or easily deprotonated exclusively produce cyclopentenones via Nazarov cyclization, whereas the neutral nucleophile DABCO promotes 6π cyclization to afford 2H-pyrans. Experimental evidence is presented for both retro-4π and -6π electrocyclization in these systems, lending support to the bifurcated mechanistic hypothesis proposed for these cyclizations.

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Enantioselective Nazarov cyclization catalyzed by a cinchona alkaloid derivative

Huang

Frontier

2015

Tetrahedron Letters

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Nucleophilic catalysts for a 1,6 addition/Nazarov cyclization/elimination sequence were evaluated for their ability to induce enantioselectivity in the electrocyclization step. Of the tertiary amines examined, it was found that a cinchona alkaloid derivative was able to generate substituted 5-hydroxy γ-methylene cyclopentenones with excellent enantioselectivity. The study results suggest that successful cyclization depends upon the ability of the dienyl diketone substrate to readily adopt an s-cis conformation.

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Correction to “Cyclization Cascades Initiated by 1,6-Conjugate Addition”

Cited by 4 publications

References 0 publications

New Twists in Nazarov Cyclization Chemistry

New Twists in Nazarov Cyclization Chemistry

No Acid Required: 4π and 6π Electrocyclization Reactions of Dienyl Diketones for the Synthesis of Cyclopentenones and 2H-Pyrans

Enantioselective Nazarov cyclization catalyzed by a cinchona alkaloid derivative

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