Benzenoid Ring Functionalization of Indoles and Tryptophols via Combined Directed Ortho Metalation-Cross Coupling Methodology

Griffen, Edward J.; Roe, David G.; Snieckus, Victor

doi:10.1021/jo00111a003

Cited by 48 publications

(22 citation statements)

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“…The combined EtOH washings were concentrated to afford a brown solid that was recrystallized from cold hexane to give 10b (1.94 g, 88%) as a beige powder; mp 96-97 °C (hexane) (Lit. 22 98-99 °C).…”

Section: -(Tert-butyldimethylsilyl)-5-hydroxyindole (10b)mentioning

confidence: 99%

The Directed ortho Metalation (DoM)–Cross-Coupling Connection: Synthesis of Polyfunctional Biaryls

Quesnelle¹,

Snieckus²

2018

Synthesis

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A comparative evaluation of the combined directed ortho metalation (DoM)–Suzuki–Miyaura and DoM–Negishi cross-coupling reactions with aryl triflates for the synthesis of substituted biaryls is described. Both ortho-zinc and ortho-boron aryl directed metalation group (DMG = CON(i-Pr)2, OCONEt2, OMOM, NHBoc) substrates were evaluated. The superiority of the DoM–Negishi over the DoM–Suzuki–Miyaura reaction in operational convenience and mild reaction conditions is noted. Orthogonal Negishi and Suzuki–Miyaura with Corriu–Kumada reactions for the synthesis of a teraryl derivative is also reported.

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Section: -(Tert-butyldimethylsilyl)-5-hydroxyindole (10b)mentioning

confidence: 99%

The Directed ortho Metalation (DoM)–Cross-Coupling Connection: Synthesis of Polyfunctional Biaryls

Quesnelle¹,

Snieckus²

2018

Synthesis

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“…This time, the total synthesis commenced by TIPS-protection of 5methoxyindole (9) following a literature procedure forming indole 10 (see SI). [17][18][19] Selective bromination of 10 (Scheme 1) by directed ortho metalation 20 proved to be difficult and several approaches including temporary introduction of a TMS group on C-3 21,22 to induce steric hindrance, 22 use of TBS instead of TIPS as protection group and the use of different lithiation reagents failed to give 6-bromoindole 11 selectively. Eventually we found that using sec-BuLi/TMEDA followed by a reaction with 1,2-bromoethane gave a 2:3 mixture of 6-bromoindole 11 and 4-bromoindole 12 in 67% combined yield.…”

Section: Isolation and Structural Elucidationmentioning

confidence: 99%

Kinase Chemodiversity from the Arctic: The Breitfussins

et al. 2019

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In this work, we demonstrate that the indole-oxazole-pyrrole framework of the breitfussin family of natural products is a promising scaffold for kinase inhibition. Six new halogenated natural products, breitfussin C-H (3-8) were isolated and characterized from the Arctic, marine hydrozoan Thuiaria breitfussi. The structures of two of the new natural products were also confirmed by total synthesis. Two of the breitfussins (3 and 4) were found to selectively inhibit the survival of several cancer cell lines, with the lowest IC50 value of 340 nM measured against the drug-resistant triple negative breast cancer cell line MDA-MB-468, while leaving the majority of the tested cell lines not or significantly less affected. When tested against panels of protein kinases, 3 gave IC50 and Kd values as low as 200 and 390 nM against the PIM1 and DRAK1 kinases, respectively. The activity was confirmed to be mediated through ATP competitive binding in the ATP binding pocket of the kinases. Furthermore, evaluation of potential off-target and toxicological effects, as well as relevant in vitro ADME parameters for 3 revealed that the breitfussin scaffold holds promise for the development of selective kinase inhibitors.

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“…N-Silyl-protected 5-(diethylcarbamoyloxy)indole was reported, without comment nor explanation, to undergo metalation also at the 4-position. [48] What kind of phenomenon does provide extra acidification to the 4-position but not to the 6-position? Our tentative explanation focuses, for one thing, on the natural tendency of the nonbonding carbanionic electrons to seek stabilization by expanding beyond their ordinary confinements.…”

Section: Halofluoroindolesmentioning

confidence: 99%

In Search of Simplicity and Flexibility: A Rational Access to Twelve Fluoroindolecarboxylic Acids

2006

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All twelve indolecarboxylic acids 1-12 carrying both a fluorine substituent and a carboxy group at the benzo ring have been prepared either directly from the corresponding fluoroindoles 13-16 or from the chlorinated derivatives 22, 23 and 25 by hydrogen/metal permutation ("metalation"), or from the bromo-or iodofluoroindoles 17-20 and 26, 27, 29 and 30 by halogen/metal permutation, the organometallic intermediate being each time trapped with carbon dioxide. In most, though not all cases, the nitrogen atom in the fivemembered ring had to be protected by a trialkylsilyl group. Some of the bromo-or iodofluoroindoles (26 and 27) were successfully subjected to a basicity gradient-driven selective migration of the heavy halogen. An unexpected finding on the way to the target compounds were the rigorously site-

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Benzenoid Ring Functionalization of Indoles and Tryptophols via Combined Directed Ortho Metalation-Cross Coupling Methodology

Cited by 48 publications

References 0 publications

The Directed ortho Metalation (DoM)–Cross-Coupling Connection: Synthesis of Polyfunctional Biaryls

The Directed ortho Metalation (DoM)–Cross-Coupling Connection: Synthesis of Polyfunctional Biaryls

Kinase Chemodiversity from the Arctic: The Breitfussins

In Search of Simplicity and Flexibility: A Rational Access to Twelve Fluoroindolecarboxylic Acids

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