Atroposelective Construction of Nine‐Membered Carbonate‐Bridged Biaryls

Jia, Shiqi; Tian, Yuhong; Li, Xin; Wang, Pengfei; Lan, Yu; Yan, Hailong

doi:10.1002/anie.202206501

Cited by 48 publications

(23 citation statements)

References 120 publications

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“…A neutral nonaromatic representation, a zwitterionic structure, or a biradical resonance structure was proposed as the plausible canonical structure of VQMs (Scheme a). Even though indirect evidence for the existence of VQMs had been obtained by trapping experiments − and Freccero provided spectroscopic evidence for the generation of VQM in the solvent by laser flash photolysis (LFP), direct evidence for the presence of VQMs is scant. The isolation of VQMs was hindered mainly due to the generation of thermodynamically unfavorable VQMs.…”

Section: Discovery and Identification Of Vinylidene Ortho-quinone Met...mentioning

confidence: 99%

“…The enantioselective generation of tri-substituted VQM intermediates was achieved afterward by Irie, Yan, and Tan with a chiral proton shuttle (Scheme b), such as cinchona alkaloid derivates (Scheme c) or chiral phosphoric acid, through a prototropic rearrangement of VQMs precursors. Later, Yan and Zhao realized that the asymmetric incorporation of halogens, selenium, and sulfur in the allene motif led to tetra -substituted VQM intermediates, which profoundly modified the electronic properties (Scheme b). Additionally, some transition-metal catalytic approaches also implied that the processes proceeded via VQM-like intermediates .…”

Section: Introductionmentioning

confidence: 99%

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Enantioselective Synthesis of Atropisomers via Vinylidene ortho-Quinone Methides (VQMs)

2022

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Conspectus Atropisomers, arising from conformational restriction, are inherently chiral due to the intersecting dissymmetric planes. Since there are numerous applications of enantiopure atropisomers in catalyst design, drug discovery, and material science, the asymmetric preparation of these highly prized molecules has become a flourishing field in synthetic chemistry. A number of catalysts, synthetic procedures, and novel concepts have been developed for the manufacture of the atropisomeric molecules. However, due to the intrinsic properties of different types of atropisomers featuring biaryl, hetero-biaryl, or non-biaryl architectures, only very few methods pass the rigorous inspection and are considered generally applicable. The development of a broadly applicable synthetic strategy for various atropisomers is a challenge. In this Account, we summarize our recent studies on the enantioselective synthesis of atropisomers using the vinylidene ortho-quinone methides (VQMs) as pluripotent intermediates. The most appealing features of VQMs are the disturbed aromaticity and axial chirality of the allene fragment. At the outset, the applications of VQMs in organic synthesis have been neglected due to their principal liabilities: ephemeral nature, extraordinary reactivity, and multireaction sites. The domestication of this transient intermediate was demonstrated by in situ catalytic asymmetric generation of VQMs, and the reactivity and selectivity were fully explored by judiciously modifying precursors and tuning catalytic systems. A variety of axially chiral heterocycles were achieved through five-, six-, seven- and nine-membered ring formation of VQM intermediates with different kinds of branched nucleophilic functional groups. The axially chiral C–N axis could be constructed from VQM intermediates via N-annulation or desymmetrization of preformed C–N scaffolds. We take advantage of the high electrophilicity of VQMs toward a series of sulfur and carbon based nucleophiles leading to atropisomeric vinyl arenes. Furthermore, chiral helical compounds were realized by cycloaddition or consecutive annulation of VQM intermediates. These achievements demonstrated that the VQMs could work as a nuclear parent for the collective synthesis of distinct and complex optically active atropisomers. Recently, we have realized the isolation and structural characterization of the elusive VQMs, which were questioned as putative intermediates for decades. The successful isolation of VQMs provided direct evidence for their existence and an unprecedented opportunity to directly investigate their reactivity. The good thermal stability and reserved reactivity of the isolated VQMs demonstrated their great potential as synthetic reagents and expanded the border of VQM chemistry.

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Section: Discovery and Identification Of Vinylidene Ortho-quinone Met...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enantioselective Synthesis of Atropisomers via Vinylidene ortho-Quinone Methides (VQMs)

2022

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“…Recently, Yan and co-workers devised an organocatalytic asymmetric synthesis of atropisomers, nine-membered bridged carbonates, via a vinylidene ortho -quinone methide (VQM) intermediate. 44 Under the catalytic influence of chiral squaramide C-8 , the newly designed substrates 86 undergo the enantioselective bromination with N -bromo succinimide (NBS) to deliver VQM 88 , which by ring expansion generates the indole ring along with new nine-membered ring structures 87 containing the carbonate linkage (Scheme 22). This ring expansion can be attributed to the high reactivity of intermediate 88 that ultimately provides the product.…”

Section: Asymmetric Synthesis Of Nine-membered Bridged Biarylsmentioning

confidence: 99%

Catalytic asymmetric synthesis of medium-sized bridged biaryls

2022

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“…However, in sharp contrast to well-developed biaryl skeletons composed of all carbon aromatics, enantioselective synthesis of indolyl atropisomers remains a challenging task possibly due to the relatively low rotational barrier . In particular, the de novo construction of axially chiral indoles under mild conditions is underexplored compared with the asymmetric functionalization of indoles …”

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confidence: 99%

Silver-Catalyzed Direct Nucleophilic Cyclization: Enantioselective De Novo Synthesis of C–C Axially Chiral 2-Arylindoles

Liu

Xiang

et al. 2023

Org. Lett.

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Atropisomeric indoles widely exist in natural products, pharmaceuticals, functional materials, and catalysts for their featured biological activities, photoelectric properties, and catalytic activities, while facile and de novo construction of this motif remains underexplored. Herein, we report a chiral silver phosphatecatalyzed direct 5-endo-dig nucleophilic cyclization of 2-alkynylanilins under mild conditions, affording various C−C axially chiral 2arylindoles in high to excellent yields and enantioselectivities. Control experiments implied the cooperative catalysis of AgOAc and chiral phosphoric acid, wherein the former accelerated the desired transformation while the latter improved the enantioselectivity. In addition, as the first example of silver-catalyzed enantioselective de novo synthesis of C−C axially chiral indole skeletons, synthetic applications and products' thermal stability have been investigated.

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Atroposelective Construction of Nine‐Membered Carbonate‐Bridged Biaryls

Cited by 48 publications

References 120 publications

Enantioselective Synthesis of Atropisomers via Vinylidene ortho-Quinone Methides (VQMs)

Enantioselective Synthesis of Atropisomers via Vinylidene ortho-Quinone Methides (VQMs)

Catalytic asymmetric synthesis of medium-sized bridged biaryls

Silver-Catalyzed Direct Nucleophilic Cyclization: Enantioselective De Novo Synthesis of C–C Axially Chiral 2-Arylindoles

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