Silver(I)‐ or Copper(II)‐Mediated Dearomatization of Aromatic Ynones: Direct Access to Spirocyclic Scaffolds

James, Michael J.; Cuthbertson, James D.; O’Brien, Peter; Taylor, Richard J. K.; Unsworth, William P.

doi:10.1002/ange.201501812

Cited by 40 publications

(8 citation statements)

References 40 publications

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“…For the majority of substrates only a single regioisomer was observed. Enzymatic halogenation could be seen to be mediated on several less reactive or challenging substrates, including (poly)heterocycles (5) 20 , azaspirocycles (14) 21 or bathophenanthroline (30), that were not readily iodinated using synthetic conditions at room temperature. Fourteen of these products were selected, based on both structural interest and conversion level, for further analysis including spectroscopic structural characterisation.…”

Section: Resultsmentioning

confidence: 99%

A marine viral halogenase that iodinates diverse substrates

et al. 2019

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Oceanic cyanobacteria are the most abundant oxygen-generating phototrophs on our planet, and therefore, important to life. These organisms are infected by viruses called cyanophages, recently shown to encode metabolic genes that modulate host photosynthesis, phosphorus cycling and nucleotide metabolism. Herein, we report the characterisation of a wild type flavin-dependent viral halogenase (VirX1) from a cyanophage. Notably, halogenases have been previously associated 2 with secondary metabolism, tailoring natural products. Exploration of this viral halogenase reveals it capable of regioselective halogenation of a diverse range of substrates, with a preference for forming aryl iodide species; this has potential implications for the metabolism of the infected host. Until recently, a flavin-dependent halogenase (FDH) capable of iodination in vitro had not been reported. VirX1 is interesting from a biocatalytic perspective showing strikingly broad substrate flexibility, and a clear preference for iodination, as illustrated by kinetic analysis. These factors together render it an attractive tool for synthesis. The selective formation of carbon-halogen (C-X) bonds is of great importance to the pharmaceutical and agrochemical industries 1,2. The introduction of a halogen (X) into a molecule can be used to modulate bioactivity, bioavailability and metabolic stability 1-3. Traditional chemical methodologies of halogenating aromatic substrates generally employ highly reactive reagents and generate harmful waste. As traditional reagents lack components that enable the tuning of product selectivity, they oftentimes generate products in which either only the most nucleophilic position is halogenated or mixtures of products are produced. Conversely, biosynthetic (enzymatic) halogenation is mild, highly selective and utilises simple salts such as NaCl or NH 4 Br as the source of halide while oxygen serves as the oxidant 1-3. Consequently, the discovery and structural characterisation of flavin-dependent halogenases (FDHs) capable of selectively forming C-Cl and C-Br bonds 4,5 and the discovery of a S-adenosylmethionine (SAM)-dependent fluorinase 6 , able to mediate nucleophilic C-F bond formation, attracted considerable attention. Until recently, a FDH capable of generating C-I bonds remained to be discovered and characterised 7 .

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Section: Resultsmentioning

confidence: 99%

A marine viral halogenase that iodinates diverse substrates

et al. 2019

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“…Most of the compounds studied have an indol-3-yl group attached to C-1, and when they are treated with Brønsted, Lewis, and π acids to activate the carbon−carbon triple bond and facilitate conjugate addition, the most effective catalysts screened were Ph 3 PAuNTf 2 , Cu(OTf) 2 , AgNO 3 , and AgOTf while triflic acid was ineffective. 321,322 The final product appeared to be catalyst dependent. Thus, the copper and silver catalysts produced 3,3-disubstituted spirocyclic indolenines 271 in excellent yields via intermediate I (Scheme 125).…”

Section: Conjugate Additionsmentioning

confidence: 99%

“…Optimization using 1-(indol-3-yl)-4-(4-methoxyphenyl)but-3yn-2-one 270 showed that the bulkiest CPA gave the highest enantiomeric excess, and when the conditions detailed in Scheme 128 were applied, ee up to 78% was obtained. 321 X-ray structure determination proved that the Ag-CPA 276 catalyst gave predominantly spirocycles 271 with S configuration.…”

Section: Conjugate Additionsmentioning

confidence: 99%

Conjugated Ynones in Organic Synthesis

2019

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This review article will consider the preparation and application of ynones in synthetic organic chemistry. Concerning the preparation of these bifunctional compounds, several methodologies starting from propargyl alcohols, acyl derivatives, both by using alkynylmetal reagents or by transition metal (mainly palladium and copper) catalyzed alkynylations, carbon monoxide (carbonylation of terminal alkynes and alkenes), and other substrates will be discussed. The reactivity and synthetic applications of ynones will be focused on conjugate additions with boron-, carbon-, nitrogen-, oxygen-, and other heteroatom-containing nucleophiles, as well as radicals. Then, cycloaddition processes will include [2 + 2] cycloadditions, [3 + 2] 1,3-dipolar cycloadditions (with azides, nitrones, azomethine imines and ylides, nitrile oxides, diazo compounds, and other dipoles), and [4 + 2] cycloadditions (mainly Diels–Alder-type reactions). The reduction of the triple bond, addition to the carbonyl group (using carbon- and heteronucleophiles and reductions), and other not so commonly used processes (such as aldol reactions, cyclizations, and isomerizations) will be considered at the end.

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“…The Unsworth group and the Van der Eycken group have respectively reported the syntheses of spirocyclic scaffolds. Using Ag(I) salts as catalyst and chiral phosphoric acids (CPAs) as ligand, an asymmetric variant furnished spirocyclic indolenines in up to 89:11 er [Eq.…”

Section: Carbon‐containing Nucleophilesmentioning

confidence: 99%

“…Using Ag(I) salts as catalyst and chiral phosphoric acids (CPAs) as ligand, an asymmetric variant furnished spirocyclic indolenines in up to 89:11 er [Eq. (55‐1)] . Moreover, this kind of cyclization could also be achieved with the aid of NIS [Eq.…”

Section: Carbon‐containing Nucleophilesmentioning

confidence: 99%

Tandem Reactions of Ynones: via Conjugate Addition of Nitrogen‐, Carbon‐, Oxygen‐, Boron‐, Silicon‐, Phosphorus‐, and Sulfur‐Containing Nucleophiles

et al. 2019

Adv Synth Catal

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Scheme 12. Enamines:T BAF-catalyzed cyclization.Scheme 13. Intramolecular cyclization.Scheme14. Intramolecular cyclizations.Scheme15. CÀNa nd OÀNb ond cleavage. Scheme 16. Applications of RNH-Nu. Scheme 17. NH-sulfoximines and NH-sulfondiimines. Scheme18. Radical cyclizationf or the synthesis of indoles. Scheme 22. 2H-Azirines:[3 + +2] cycloadditions. Scheme 23. Visible light-induced cycloaddition for pyrrole synthesis. Scheme24. Cyclization and sulfonyl migration. Scheme 25. NR 2 -E strategy analysis. Scheme 57. Several arenes for annulations. Scheme 58. Conjugateaddition. Scheme 59. Asymmetric conjugate addition.Scheme60. Conjugatea ddition andcyclization.

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Silver(I)‐ or Copper(II)‐Mediated Dearomatization of Aromatic Ynones: Direct Access to Spirocyclic Scaffolds

Cited by 40 publications

References 40 publications

A marine viral halogenase that iodinates diverse substrates

A marine viral halogenase that iodinates diverse substrates

Conjugated Ynones in Organic Synthesis

Tandem Reactions of Ynones: via Conjugate Addition of Nitrogen‐, Carbon‐, Oxygen‐, Boron‐, Silicon‐, Phosphorus‐, and Sulfur‐Containing Nucleophiles

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