Three Groups Good, Four Groups Bad? Atropisomerism in <i>ortho</i>‐Substituted Diaryl Ethers

Betson, Mark S.; Clayden, Jonathan; Worrall, Christopher P.; Peace, Simon

doi:10.1002/ange.200601866

Cited by 23 publications

(15 citation statements)

References 36 publications

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“…To achieve this distinction, we added an aldehyde group to key synthetic intermediate 13. The aryl-O-aryl bonds in the DHDG and valoneoyl groups are tri-ortho substituted, and their formation through cross-coupling catalysed by transition metals has been difficult 30,31 . Furthermore, the bond in the tergalloyl group is tetra-ortho substituted.…”

Section: Strategymentioning

confidence: 99%

“…Furthermore, the bond in the tergalloyl group is tetra-ortho substituted. For construction of multiortho-substituted aryl-O-aryl bonds, nucleophilic aromatic substitution (S N Ar) has been effective 29,30 The C-O digallate-containing motifs Oxa-Michael addition of phenols 8-11 to key building block 7 and subsequent elimination formed the C-O bond of the digallates. The design of building block 7 was critical.…”

Section: Strategymentioning

confidence: 99%

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A unified strategy for the synthesis of highly oxygenated diaryl ethers featured in ellagitannins

et al. 2014

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Ellagitannins are a family of polyphenols containing more than 1,000 natural products. Nearly 40% of these compounds contain a highly oxygenated diaryl ether that is one of the most critical elements to their structural diversity. Here, we report a unified strategy for the synthesis of highly oxygenated diaryl ethers featured in ellagitannins. The strategy involves oxa-Michael addition of phenols to an orthoquinone building block, with subsequent elimination and reductive aromatization. The design of the building block-a halogenated orthoquinone monoketal of gallal-reduces the usual instability of orthoquinone and controls addition/elimination. Reductive aromatization is achieved with perfect chemoselectivity in the presence of other reducible functional groups. This strategy enables the synthesis of different diaryl ethers. The first total synthesis of a natural ellagitannin bearing a diaryl ethers is performed to demonstrate that the strategy increases the number of synthetically available ellagitannins.

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Section: Strategymentioning

confidence: 99%

Section: Strategymentioning

confidence: 99%

A unified strategy for the synthesis of highly oxygenated diaryl ethers featured in ellagitannins

et al. 2014

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“…Well-studied biaryls, along with several classes of atropisomeric compounds including ortho-substituted anilides, N-arylimides, and diaryl ethers have been identified and their stereoselective synthesis has been explored. [1,2] In particular, axially chiral biaryls have been well studied because they provide an effective chiral environment for asymmetric reaction when they act as chiral ligands of metal catalysts or organocatalysts. Moreover, axially chiral anilides are utilized as useful chiral building blocks for N-heterocycles with axial-to-center chirality transfer.…”

mentioning

confidence: 99%

Atropisomerism of α,β‐Unsaturated Amidines: Stereoselective Synthesis by Catalytic Cascade Reaction and Optical Resolution

Shindo

Takemoto

Takasu

2009

Chemistry A European J

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Atropisomerism, a stereochemical property resulting from restricted rotation around a single bond where the steric strain barrier is high enough, has been the subject of much attention in organic chemistry. Well-studied biaryls, along with several classes of atropisomeric compounds including ortho-substituted anilides, N-arylimides, and diaryl ethers have been identified and their stereoselective synthesis has been explored. [1,2] In particular, axially chiral biaryls have been well studied because they provide an effective chiral environment for asymmetric reaction when they act as chiral ligands of metal catalysts or organocatalysts. Moreover, axially chiral anilides are utilized as useful chiral building blocks for N-heterocycles with axial-to-center chirality transfer.[3] In contrast to the above atropisomers whose rotationally-restricted single bond is directly connected to one or two aryl group(s), atropisomerism in acyclic p-systems such as 1,3-dienes [4] and a,b-unsaturated carbonyl derivatives have rarely been studied. To the best of our knowledge, there is only one example of the optical resolution of a,b-unsaturated carboxylic acid derivatives. Mannschreck and his co-workers reported the optical property of atropoisomeric thioamide derivatives of acrylic acid.[5] However, atropisomerism of a,b-unsaturated amidine derivatives, which would be potential synthetic precursors for heterocyclic compounds, is unexplored. We envisioned that highly substituted amidines 1 would provide a comparable stable atropisomer on axial chirality around a C2ÀC3 single bond (Figure 1). Herein, we report the optical resolution of atropisomeric a,b-unsaturated amidines and a novel stereoselective synthetic method of a,b-unsaturated amidines with bulky substituents.At the outset of this study, we considered the preparation of steric hindered a,b-unsaturated amidines. We thought that efficient synthesis of 1 by a coupling reaction to make a C2ÀC3 single bond or direct addition or substitution reaction to introduce a bulky substituent would be difficult. To achieve stereoselective synthesis of a,b-unsaturated amidines, we focused on the cascade reaction, consisting of [2+2] cycloaddition and successive electrocyclic ring-opening reaction (cycloreversion) of nitrogen-substituted alkynes and imines (Scheme 1).[6] The cascade reaction corresponds to formal aza-enyne metathesis. In the [2+2] cycloaddition, the repulsive steric interaction of bulky substituents on both substrates would decrease owing to the linear geometry of the alkyne substrate. We expected that cycloreversion of the resulting azetine intermediate 2 would proceed in a geometrical selective manner. As a related study, cycloreversion of cyclobutenes has been well explored to give the corresponding 1,3-butadienes. [7,8] In the thermal cycloreversion of fourmembered rings, the geometry of the product is ruled out by conrotatory rotation of the s-orbital of the central single bond and torquoselectivity (inward vs outward rotation in the conrotatory rotation). The torquos...

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“…Atropisomeric diaryl ethers9 form part of the structure of vancomycin10 and are promising scaffolds for the construction for new chiral ligands 11. Dialdehyde 3 and diol 1 were made by our published route 9. In an initial screen, we attempted enantioselective acetylation by incubating diol 1 with Candida antarctica lipase B and vinyl acetate.…”

Section: Methodsmentioning

confidence: 99%

Biocatalytic Desymmetrization of an Atropisomer with both an Enantioselective Oxidase and Ketoreductases

Yuan¹,

Page²,

Worrall³

et al. 2010

Angewandte Chemie

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Atropisomeric ligands have found numerous powerful applications in catalysis, [1] and the atropisomeric biaryl bisphosphine binap played an important role in the award of a Nobel Prize to Noyori in 2001.[2] Enantiomerically pure atropisomers commonly employed as chiral ligands are generally made by resolution: there are still relatively few effective methods for direct asymmetric coupling to form single enantiomers. [3] Kinetic resolution [4] and dynamic resolution [5] under kinetic [5a] or thermodynamic [5b] control are particularly appealing given the possibility offered by atropisomerism for thermal racemization of the less reactive enantiomer. The use of desymmetrization for the synthesis of single atropisomers is rare. [6] Following the early example of enantioselective lithiation reported by Raston and co-workers, [6b] the research groups of Hayashi [6c] and Harada [6d] also reported chemical methods for desymmetrizing biphenyl compounds. A single example of the enzymatic desymmetrization of a biaryl compound with a lipase was reported by Matsumoto et al.[6e]Herein, we report two novel and complementary biocatalytic approaches to the enantioselective synthesis of atropisomers by the desymmetrization of appropriate achiral substrates containing a pair of enantiotopic functional groups. The atropisomer in question is the diaryl ether 2, which may be formed either by enantioselective oxidation of the symmetrical diol 1 or by the corresponding reduction of the symmetrical dialdehyde 3 (Scheme 1). The enzymes we employed for these transformations were 1) a variant of galactose oxidase (GOase) which had been previously evolved to accept chiral benzylic alcohols as substrates with high enantioselectivity (1!2) [7] and 2) a family of ketoreductases that are known to possess good activity and enantioselectivity for the asymmetric reduction of benzylic ketones (3!2). [8] Atropisomeric diaryl ethers [9] form part of the structure of vancomycin [10] and are promising scaffolds for the construction for new chiral ligands.[11] Dialdehyde 3 and diol 1 were made by our published route. [9] In an initial screen, we attempted enantioselective acetylation by incubating diol 1 with Candida antarctica lipase B and vinyl acetate. Slow acylation of 1 was observed with approximately 50 % conversion after 24 h to the monoacetate 4 and modest enantioselectivity (60 % ee). In contrast, when diol 1 was incubated with the previously reported M 3-5 variant of GOase, [7] rapid oxidation to the monoaldehyde (P)-2 resulted in 80 % conversion after 24 h to material with 94 % ee.During the oxidation of 1 to 2, rapid formation of the product (P)-2 with approximately 88 % ee (see below for assignment of the absolute configuration) was observed after 1 h, followed by a slower increase in enantiomeric purity to a maximum ee value of 94 % (Figure 1). This increase in the ee value, along with the formation of the dialdehyde 3 (14 % after 24 h), suggested that the minor enantiomer (M)-2 produced in the enantioselective oxidation of 1 was ...

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Three Groups Good, Four Groups Bad? Atropisomerism in ortho‐Substituted Diaryl Ethers

Cited by 23 publications

References 36 publications

A unified strategy for the synthesis of highly oxygenated diaryl ethers featured in ellagitannins

A unified strategy for the synthesis of highly oxygenated diaryl ethers featured in ellagitannins

Atropisomerism of α,β‐Unsaturated Amidines: Stereoselective Synthesis by Catalytic Cascade Reaction and Optical Resolution

Biocatalytic Desymmetrization of an Atropisomer with both an Enantioselective Oxidase and Ketoreductases

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