Bioinspired Discovery of Chemical Reactions and Biological Probes

Griffiths, Brendan M.; Burl, Jessica D.; Wang, Xiang

doi:10.1055/s-0035-1561638

Cited by 11 publications

(2 citation statements)

References 18 publications

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“…52 On the other hand, as demonstrated through the chemoenzymatic synthesis of 9a, these regiodivergent carbene transferases can be leveraged to afford more complex, polycyclic indoline-based scaffolds akin to those found in various bioactive molecules. 3,[53][54][55] Regiodivergent selectivity is also of particular interest in the construction of compound libraries for drug discovery campaigns. [87][88] Our mechanistic studies provide valuable, first-time insights into the mechanism of hemoprotein-catalyzed carbene C(sp 3 )-H insertion, and collectively support the involvement of a radical, stepwise pathway, akin to the mechanism of native P450-catalyzed hydroxylation reactions 89 and non-native C-H amination reactions via nitrene transfer catalyzed by engineered P450s and other hemoproteins.…”

Section: Discussionmentioning

confidence: 99%

“…The synthetic utility of the present biocatalysts and methodology is further exemplified through the synthesis of a polycyclic indolinebased core structure akin to that found in many pharmacologically active molecules. 3,[53][54][55] Mechanistic studies provide first-time insights into the mechanism of the present reaction and hemoprotein-catalyzed C(sp3)-H carbene insertion.…”

Section: Introductionmentioning

confidence: 99%

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Radical-Mediated Regiodivergent C(sp3)–H Functionalization of N-Substituted Indolines via Enzymatic Carbene Transfer

Couture,

Cui,

Chu

et al. 2024

Preprint

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Indolines are ubiquitous structural motifs found in pharmaceuticals and natural products but modification of these scaffolds via selective C(sp3)–H functionalization represents a major challenge. Herein, we report the regio- and stereoselective C(sp3)–H functionalization of N-substituted indolines to produce both -and-functionalized indolines via carbene transfer chemistry with engineered iron-based CYP119 catalysts. These transformations are shown to proceed with high regio- (up to >99%) and enantioselectivity (up to 98% e.e.) as well as excellent catalytic efficiency (up to 99% yield and 8,900 TON), furnishing an efficient and regiodivergent route for diversification of this class of medicinally relevant molecules via direct C(sp3)–H functionalization. We further show that these catalysts can enable selective functionalization of exocyclic C(sp3)–H bond in N-methyl indolines and that enzyme-mediated a-and b-C(sp3)–H functionalization can be combined in a biocatalytic cascade to yield polycyclic indoline-containing scaffolds, which can be found in many drugs. Finally, computational and experimental mechanistic studies provide evidence for the occurrence of a radical-mediated C–H functionalization pathway, providing first insights into the mechanism of P450-catalyzed C(sp3)–H carbene insertion. Altogether, this work provides a direct and tunable strategy for the synthesis of functionalized indolines as key building blocks for medicinal chemistry and natural product synthesis and it sheds light into the mechanism of P450-catalyzed C(sp3)–H functionalization via carbene transfer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Radical-Mediated Regiodivergent C(sp3)–H Functionalization of N-Substituted Indolines via Enzymatic Carbene Transfer

Couture,

Cui,

Chu

et al. 2024

Preprint

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Vinyl‐/Furoindoles and Gold Catalysis: New Achievements and Future Perspectives for the Synthesis of Complex Indole Derivatives

Pirovano¹,

Abbiati²,

Brambilla³

et al. 2019

Eur J Inorg Chem

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The reactivity of vinyl‐/furoindole derivatives with gold‐activated π‐systems is the subject of extensive investigation. In the presence of these electrophilic partners, the realized transformations allow for the construction of different and fascinating architectures via cycloaddition and cyclization reactions often included in cascade processes. The reactions realized involving in these processes an external substituent at the indole moiety are the subject of the present minireview.

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Gold‐Catalyzed Synthesis of Spirofused Indoloquinuclidines

2018

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A novel series of spirofused indoloquinuclidines was obtained by a tandem Pictet–Spengler/AuI‐catalyzed cyclization sequence. By combining N‐propargyl tryptamine with aldehydes in the presence of acetic acid and a gold complex, the target indoloquinuclidines were obtained. The combination of a chiral phosphoric acid catalyst for the asymmetric Pictet–Spengler reaction with a gold complex furnished the target compounds with ee values up to 90 % in high diastereoselectivity.

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Bioinspired Discovery of Chemical Reactions and Biological Probes

Cited by 11 publications

References 18 publications

Radical-Mediated Regiodivergent C(sp3)–H Functionalization of N-Substituted Indolines via Enzymatic Carbene Transfer

Radical-Mediated Regiodivergent C(sp3)–H Functionalization of N-Substituted Indolines via Enzymatic Carbene Transfer

Vinyl‐/Furoindoles and Gold Catalysis: New Achievements and Future Perspectives for the Synthesis of Complex Indole Derivatives

Gold‐Catalyzed Synthesis of Spirofused Indoloquinuclidines

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