Organocatalytic Atroposelective Synthesis of N−N Axially Chiral Indoles and Pyrroles by De Novo Ring Formation

Chen, Ke-Wei; Chen, Zhi-Han; Yang, Shuang; Wu, Shufang; Zhang, Yuchen; Shi, Feng

doi:10.1002/anie.202116829

Cited by 131 publications

(42 citation statements)

References 158 publications

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“…Nevertheless, the highly atroposelective construction of indole frameworks bearing a N−N axis was not achieved until our recent work. 44 It should be noted that Lu's group established the first organocatalytic atroposelective synthesis of molecules bearing a N−N axis, 45 which led the development of this field. In our work (Scheme 19a), the strategy for synthesizing indole derivatives bearing a N−N axis involves the design of N-aminoindoles as platform molecules for de novo ring formation under asymmetric organocatalysis.…”

Section: N-aminoindoles As Platform Moleculesmentioning

confidence: 99%

“…The indole-based platform molecules introduced above are designed for the construction of atropisomeric indole frameworks bearing a C–C axis. Nevertheless, the highly atroposelective construction of indole frameworks bearing a N–N axis was not achieved until our recent work . It should be noted that Lu’s group established the first organocatalytic atroposelective synthesis of molecules bearing a N–N axis, which led the development of this field.…”

Section: Other Indole-derived Platform Molecules To Synthesize Axiall...mentioning

confidence: 99%

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Organocatalytic Atroposelective Synthesis of Indole Derivatives Bearing Axial Chirality: Strategies and Applications

2022

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Conspectus Catalytic atroposelective syntheses of axially chiral compounds have stimulated extensive interest in multiple communities, such as synthetic chemistry, biochemistry, and materials science, because of the intriguing characteristics of atropisomerism. In particular, atropisomeric indole derivatives, which contain a kind of five-membered heterocyclic framework, are widely distributed in a number of natural alkaloids, biologically relevant compounds, chiral ligands, and chiral organocatalysts. Hence, the catalytic atroposelective synthesis of indole derivatives bearing axial chirality is of considerable importance and has become an emerging focus of research. However, there are substantial challenges associated with the atroposelective synthesis of indole derivatives, including remote ortho-substituents around the chiral axis, a lower barrier for rotation, and a weaker configurational stability than that of atropisomeric six-membered biaryls. Therefore, the development of effective strategies toward the catalytic atroposelective synthesis of indole derivatives has become an urgent task. In order to tackle these challenges and to accomplish the task, our group devised a unique strategy of designing indole-derived platform molecules and developing organocatalytic enantioselective transformations of such platform molecules to synthesize atropisomeric indole derivatives; asymmetric organocatalysis has tremendous advantages and was the research area recognized by the Nobel Prize in Chemistry in 2021. This Account summarizes our endeavors in the organocatalytic atroposelective synthesis of indole derivatives bearing axial chirality. In brief, we devised and developed a series of indole-derived platform molecules, such as indolylmethanols, (hetero)aryl indoles, oxindole-based styrenes, N-aminoindoles, and indole-based homophthalic anhydrides, by introducing different functional groups onto the indole ring to achieve new reactivity and modulate the reactive site of the indole ring. As a result, these indole-derived platform molecules possess versatile and unique reactivity and are capable of undergoing a variety of organocatalytic enantioselective transformations for preparing structurally diversified indole derivatives with axial chirality. We used these strategies to accomplish the atroposelective synthesis of plenty of indole derivatives with axial chirality, including (hetero)aryl indoles, alkene-indoles, oxindole-based styrenes, N-pyrrolylindoles, and isochromenone-indoles. In addition, we gave a thorough and detailed understanding of the designed reaction by investigating the reaction pathway and activation mode. More importantly, we studied the biological activity of some products and performed catalyst design on the basis of atropisomeric indole moieties, which are helpful for disclosing more applications of indole derivatives bearing axial chirality. In the future, the organocatalytic atroposelective synthesis of indole derivatives bearing axial chirality will indubitably remain a frontier topic in the...

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Section: N-aminoindoles As Platform Moleculesmentioning

confidence: 99%

Section: Other Indole-derived Platform Molecules To Synthesize Axiall...mentioning

confidence: 99%

Organocatalytic Atroposelective Synthesis of Indole Derivatives Bearing Axial Chirality: Strategies and Applications

2022

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“…With the evolvement of asymmetric catalysis, over the past few decades, numerous transition-metal-catalyzed and organocatalyzed approaches have been developed for construction of enantiopure axially chiral biaryl and heterobiaryl atropisomers with structural diversity . A vast majority of these catalytic methods focus on four general ionic pathways (Figure a), including (1) stereoselective creation of (hetero)biaryl linkage by asymmetric cross-coupling or oxidative coupling, (2) enantioselective de novo ring construction by cycloadditions or cyclizations, (3) central-to-axial chirality transfer process, and (4) enantioselective functionalization of achiral or racemic (hetero)biaryl scaffolds (desymmetrization, kinetic resolution, etc.) .…”

Section: Introductionmentioning

confidence: 99%

Catalytic Asymmetric Construction of Axially and Centrally Chiral Heterobiaryls by Minisci Reaction

et al. 2022

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Axially chiral biaryls and heterobiaryls constitute the most represented subclass of atropisomers with prevalence in natural products, bioactive compounds, privileged chiral ligand/ catalysts, and optically pure materials. Despite many ionic protocols for their construction, radical-based variants represent another highly desirable and intriguing strategy but are far less developed. Moreover, efficient synthesis of axially chiral heterobiaryl molecules, especially ones having multiple heteroatoms and other types of chiral elements, through radical routes remains extremely limited. We herein disclose the first catalytic asymmetric, metal-free construction of axially and centrally chiral heterobiaryls by Minisci reaction of 5-arylpyrimidines and α-amino acid-derived redox-active esters. This is enabled by the use of 4CzIPN as an organic photoredox catalyst in conjunction with a chiral phosphoric acid catalyst. The reaction achieved a variety of interesting 5arylpyrimidines featuring the union of an axially chiral heterobiaryl and a centrally chiral α-branched amine with generally excellent regio-, diastereo-, and enantioselectivity (up to 82% yield; >19:1 dr; >99% ee). This finding also builds up a new platform for the development of desymmetrization methods via radical-involved atroposelective functionalization at heteroarene of prochiral heterobiaryls.

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“…Since the first report of atropisomeric compounds by Christie and Kenner in 1922, the synthesis and application of these compounds in catalysis, natural products, and pharmaceutics have been extensively studied with significant advances reported during the last decades. − However, highly atroposelective C–C bond formations, especially in the context of complex and highly substituted nitrogen-rich heterocycles, remain elusive to date (Scheme A). − Among the very limited number of reported examples, most involved atroposelective formation of a heterocycle containing noncoordinating nitrogen such as indole or carbazole. Similarly, atroposelective C–C bond formations via Negishi coupling are rare in the literature. − The few known examples focus on the synthesis of substituted biaryls, specifically binaphthalenes and biphenyls, with limited scope and moderate atroposelectivities (Scheme B).…”

Section: Introductionmentioning

confidence: 99%

Atroposelective Negishi Coupling Optimization Guided by Multivariate Linear Regression Analysis: Asymmetric Synthesis of KRAS G12C Covalent Inhibitor GDC-6036

Xu¹,

Grosslight

Mack³

et al. 2022

J. Am. Chem. Soc.

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An efficient asymmetric synthesis of a potent KRAS G12C covalent inhibitor, GDC-6036 (1), is reported. The synthesis features a highly atroposelective Negishi coupling to construct the key C–C bond between two highly functionalized pyridine and quinazoline moieties by employing a Pd/Walphos catalytic system. Statistical modeling by comparing computational descriptors of a range of Walphos chiral bisphosphine ligands to a training set of experimental results was used to inform the selection of the best ligand, W057-2, which afforded the desired Negishi coupling product ( R a )-3 in excellent selectivity. A subsequent telescoped reaction sequence of alkoxylation, global deprotection, and acrylamide formation, followed by a final adipate salt formation, furnished GDC-6036 (1) in 40% overall yield from starting materials pyridine 5 and quinazoline 6.

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Organocatalytic Atroposelective Synthesis of N−N Axially Chiral Indoles and Pyrroles by De Novo Ring Formation

Cited by 131 publications

References 158 publications

Organocatalytic Atroposelective Synthesis of Indole Derivatives Bearing Axial Chirality: Strategies and Applications

Organocatalytic Atroposelective Synthesis of Indole Derivatives Bearing Axial Chirality: Strategies and Applications

Catalytic Asymmetric Construction of Axially and Centrally Chiral Heterobiaryls by Minisci Reaction

Atroposelective Negishi Coupling Optimization Guided by Multivariate Linear Regression Analysis: Asymmetric Synthesis of KRAS G12C Covalent Inhibitor GDC-6036

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