Regiocontrolled Direct C−H Arylation of Indoles at the C4 and C5 Positions

Yang, Youqing; Gao, Pan; Zhao, Yue; Shi, Zhuangzhi

doi:10.1002/ange.201612599

Cited by 44 publications

(12 citation statements)

References 71 publications

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“…However, this method suffers from low functional group tolerance and a limited substrate scope [ 14 – 22 ]. The few described methods for C5 and C6 indole functionalization provide limited functional group tolerance [ 19 , 23 ]. Recently, Baran et al developed a remarkable example of iridium-catalyzed ligand-controlled selective C6 tryptophan borylation;however, even this groundbreaking directing group-free method requires protecting groups and is unable to tolerate tryptophan containing cyclic dipeptides [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Indole C6 Functionalization of Tryprostatin B Using Prenyltransferase CdpNPT

et al. 2020

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Tryprostatin A and B are prenylated, tryptophan-containing, diketopiperazine natural products, displaying cytotoxic activity through different mechanisms of action. The presence of the 6-methoxy substituent on the indole moiety of tryprostatin A was shown to be essential for the dual inhibition of topoisomerase II and tubulin polymerization. However, the inability to perform late-stage modification of the indole ring has limited the structure–activity relationship studies of this class of natural products. Herein, we describe an efficient chemoenzymatic approach for the late-stage modification of tryprostatin B using a cyclic dipeptide N-prenyltransferase (CdpNPT) from Aspergillus fumigatus, which generates novel analogs functionalized with allylic, benzylic, heterocyclic, and diene moieties. Notably, this biocatalytic functionalizational study revealed high selectivity for the indole C6 position. Seven of the 11 structurally characterized analogs were exclusively C6-alkylated, and the remaining four contained predominant C6-regioisomers. Of the 24 accepted substrates, 10 provided >50% conversion and eight provided 20–50% conversion, with the remaining six giving <20% conversion under standard conditions. This study demonstrates that prenyltransferase-based late-stage diversification enables direct access to previously inaccessible natural product analogs.

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Section: Introductionmentioning

confidence: 99%

Indole C6 Functionalization of Tryprostatin B Using Prenyltransferase CdpNPT

et al. 2020

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“… 9 The Pd-catalyzed C4 arylation was studied by Zhi, and the acetyl-directing group has been removed in a separate step. 10 Recently, Miura et al reported the use of thiomethyl ether as an efficient directing group for C4 C–H functionalization. 11 In another study, You described a pivaloyl group-assisted C2/C4 heteroarylation of indoles by a controlled metalation tuning.…”

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confidence: 99%

Tandem Iridium-Catalyzed Decarbonylative C–H Activation of Indole: Sacrificial Electron-Rich Ketone-Assisted Bis-arylsulfenylation

2021

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Described herein is a decarbonylative tandem C–H bis-arylsulfenylation of indole at the C2 and C4 C–H bonds through the use of pentamethylcyclopentadienyl iridium dichloride dimer ([Cp*IrCl 2 ] 2 ) catalyst and disulfides. A new sacrificial electron-rich adamantoyl-directing group facilitates indole C–H bis-functionalization with a traceless in situ removal. Various differently substituted disulfides can be easily accommodated in this reaction by a coordination to Ir(III) through the formation of six- and five-membered iridacycles at the C2 and C4 positions, respectively. Mechanistic studies show that a C–H activation-induced C–C activation is involved in the catalytic cycle.

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“…We further examined the scope of using C3pivaloyl indoles as coupling partners with BBr 3 ; these compounds reacted with a high regioselectivity to produce C4-hydroxylated indoles (Fig. 3b) 59 . We first evaluated the influence of the N-H protection groups on the indoles.…”

Section: Resultsmentioning

confidence: 99%

Boron-mediated directed aromatic C–H hydroxylation

Lv¹,

Zhao²,

Yu³

et al. 2020

Nat Commun

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Transition metal-catalysed C-H hydroxylation is one of the most notable advances in synthetic chemistry during the past few decades and it has been widely employed in the preparation of alcohols and phenols. The site-selective hydroxylation of aromatic C-H bonds under mild conditions, especially in the context of substituted (hetero)arenes with diverse functional groups, remains a challenge. Here, we report a general and mild chelation-assisted C-H hydroxylation of (hetero)arenes mediated by boron species without the use of any transition metals. Diverse (hetero)arenes bearing amide directing groups can be utilized for ortho C-H hydroxylation under mild reaction conditions and with broad functional group compatibility. Additionally, this transition metal-free strategy can be extended to synthesize C7 and C4-hydroxylated indoles. By utilizing the present method, the formal synthesis of several phenol intermediates to bioactive molecules is demonstrated.

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Regiocontrolled Direct C−H Arylation of Indoles at the C4 and C5 Positions

Cited by 44 publications

References 71 publications

Indole C6 Functionalization of Tryprostatin B Using Prenyltransferase CdpNPT

Indole C6 Functionalization of Tryprostatin B Using Prenyltransferase CdpNPT

Tandem Iridium-Catalyzed Decarbonylative C–H Activation of Indole: Sacrificial Electron-Rich Ketone-Assisted Bis-arylsulfenylation

Boron-mediated directed aromatic C–H hydroxylation

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