The Cyclization of β-(4-Carboxy-3-indole)-propionic Acids

Uhle, Frederick C.; McEwen, Charles M.; Schröter, H.; Yuan, Ching; Baker, Bryan W.

doi:10.1021/ja01490a042

Cited by 15 publications

(6 citation statements)

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“…Moreover, we found that indoles with a 4-carboxylic acid and methylene-bridged substituent at the 3-position are scarcely reported. To date, only one symmetrically 3,4-disubstituted indole has been described, harboring a 4-carboxylic acid and 3-acetic acid substituent, as well as its corresponding bis -methyl ester . However, their preparation requires a multistep route from 4-cyano-indole under harsh conditions that do not permit orthogonal functionalization of the 3,4-substituents.…”

Section: Resultsmentioning

confidence: 99%

Expanding the Chemical Space of Transforming Growth Factor-β (TGFβ) Receptor Type II Degraders with 3,4-Disubstituted Indole Derivatives

Längle,

Wojtowicz-Piotrowski,

Priegann

et al. 2024

ACS Pharmacol. Transl. Sci.

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The TGFβ type II receptor (TβRII) is a central player in all TGFβ signaling downstream events, has been linked to cancer progression, and thus, has emerged as an auspicious anti-TGFβ strategy. Especially its targeted degradation presents an excellent goal for effective TGFβ pathway inhibition. Here, cellular structure−activity relationship (SAR) data from the TβRII degrader chemotype 1 was successfully transformed into predictive ligand-based pharmacophore models that allowed scaffold hopping. Two distinct 3,4-disubstituted indoles were identified from virtual screening: tetrahydro-4-oxo-indole 2 and indole-3acetate 3. Design, synthesis, and screening of focused amide libraries confirmed 2r and 3n as potent TGFβ inhibitors. They were validated to fully recapitulate the ability of 1 to selectively degrade TβRII, without affecting TβRI. Consequently, 2r and 3n efficiently blocked endothelial-to-mesenchymal transition and cell migration in different cancer cell lines while not perturbing the microtubule network. Hence, 2 and 3 present novel TβRII degrader chemotypes that will (1) aid target deconvolution efforts and (2) accelerate proof-of-concept studies for small-molecule-driven TβRII degradation in vivo.

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Section: Resultsmentioning

confidence: 99%

Expanding the Chemical Space of Transforming Growth Factor-β (TGFβ) Receptor Type II Degraders with 3,4-Disubstituted Indole Derivatives

Längle,

Wojtowicz-Piotrowski,

Priegann

et al. 2024

ACS Pharmacol. Transl. Sci.

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“…The ubiquitous nature of the indole framework has stimulated the development of numerous methods for the synthesis of substituted indoles from benzenoid precursors. Among these, the Fischer, Reissert, and Batcho−Leimgruber indole syntheses have been widely utilized for the synthesis of 4-, 5-, 6-, and 7-substituted indoles. For the present project, we required an efficient synthesis of 6-bromotryptamine ( 7 ), which was a key precursor to β-carbolines 6 and 8 (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Enantioselective Total Syntheses of (+)-Arborescidine A, (−)-Arborescidine B, and (−)-Arborescidine C

2004

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Described are the first enantioselective total syntheses of (+)-arborescidine A ((+)-1), (-)-arborescidine B ((-)-2), and (-)-arborescidine C ((-)-3), via routes that proceeded in five steps and 50% overall yield, eight steps and 61% overall yield, and nine steps and 51% overall yield, respectively, from 6-bromotryptamine (7). The syntheses feature the use of the Noyori catalytic asymmetric hydrogen-transfer reaction to introduce chirality in dihydro-beta-carbolines 6 and 8. On the basis of an ample precedent from Noyori's work, the reduction produces dihydro-beta-carbolines, and ultimately the natural products, possessing the R absolute configuration. The synthetic arborescidines displayed optical rotations that were opposite in sign those of the natural products, thereby supporting the S configuration for natural arborescidines A (1) and B (2) and the (3S,17S) configuration for natural arborescidine C (3). Our results are in agreement with the initial stereochemical assignment by Païs and co-workers, and are counter to their recently revised assignment.

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“…The resulting 4-cyanoindole (6) was subjected to a Mannich reaction followed by substitution with diethylmalonate to give 8. Treatment with hydroxide produced (4-carboxy-3indole)-propionic acid (10), which was then reacted with acetic anhydride and a catalytic amount of potassium cyanide to afford crystals of Uhle's ketone (1) Cyclization reaction alternating vicissitudes and opened different discussions about the intermediate, the mechanism, and the applicability to other dicarboxylic acids. 10 Remarkably, at that time, the preparation of C4-substituted indoles like 6-10 were rarely reported in the literature, with only the Fischer indole synthesis available that produced a mixture of 4 and 6 regioisomers.…”

Section: Disconnection A: Cyclization Reaction Of the Opportune 34-dmentioning

confidence: 99%

“…Treatment with hydroxide produced (4-carboxy-3indole)-propionic acid (10), which was then reacted with acetic anhydride and a catalytic amount of potassium cyanide to afford crystals of Uhle's ketone (1) Cyclization reaction alternating vicissitudes and opened different discussions about the intermediate, the mechanism, and the applicability to other dicarboxylic acids. 10 Remarkably, at that time, the preparation of C4-substituted indoles like 6-10 were rarely reported in the literature, with only the Fischer indole synthesis available that produced a mixture of 4 and 6 regioisomers. As reported by Uhle himself in 1960, 11 a series of indole derivatives, all substituted in the 4-position and many with additional substitution in other positions, was shown to antagonize the action of 5hydroxytryptamine (5-HT) on the virgin rat uterus, thus launching a drug discovery program.…”

Section: Disconnection A: Cyclization Reaction Of the Opportune 34-dmentioning

confidence: 99%

“…Treatment with hydroxide produced 4-carboxyindole-3propanoic acid (10), which was then reacted with acetic anhydride and a catalytic amount of potassium cyanide to afford crystals of Uhle's ketone (1) in excellent yield. The latter transformation to tricyclic benzo[cd]indole derivatives had alternating vicissitudes and opened different discussions about the intermediate, the mechanism, and the applicability to other dicarboxylic acids.…”

Section: Disconnection A: Cyclization Reaction Of the Opportune 34-dmentioning

confidence: 99%

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Synthesis and Reactivity of Uhle’s Ketone and Its Derivatives

Bartoccini¹,

Piersanti²

2020

Synthesis

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Uhle’s ketone and its derivatives are highly versatile intermediates for the synthesis of a variety of 3,4-fused tricyclic indole frameworks, i.e. indole alkaloids of the ergot family, that are found in various bioactive natural products and pharmaceuticals. Therefore, the development of a convenient preparative method for this structural motif as well as its opportune/useful derivatization have been the subject of longstanding interest in the fields of synthetic organic chemistry and medicinal chemistry. Herein, we summarize recent and less recent methods for the preparation of Uhle’s ketone and its derivatives as well as its main reactivity towards the synthesis of bioactive substances. Regarding the preparation, it can be roughly classified into two categories: (a) using 4-unfunctionalized and 4-functionalized indole derivatives as starting materials to construct a fused six-member ring, and (b) constructing the indole ring through intramolecular cycloaddition. Principally, the reactivity of the cyclic Uhle’s ketone shown here is derived from the classical electrophilicity of the carbonyl carbon or the acidity of the α-hydrogen and, though less intensively investigated, chemical reactions that induce ring expansion to form novel ring skeletons.1 Introduction2 Synthesis2.1 Disconnection A: Cyclization Reaction of the Opportune 3,4-Disubstituted Indole2.2 Disconnection B: Intramolecular Friedel–Crafts Cyclization2.3 Disconnection B: Intramolecular Cyclization via Metal–Halogen Exchange2.4 Disconnection C: Intramolecular Diels–Alder Furan Cycloaddition2.5 Disconnection D: Intramolecular Dearomatizing [3 + 2] Annulation3 Reactivity3.1 Use of Uhle’s Ketone for Lysergic Acid3.2 Use of Uhle’s Ketone for Rearranged Clavines3.3 Use of Uhle’s Ketone for Medicinal Chemistry4 Conclusion and Outlook

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The Cyclization of β-(4-Carboxy-3-indole)-propionic Acids

Cited by 15 publications

References 0 publications

Expanding the Chemical Space of Transforming Growth Factor-β (TGFβ) Receptor Type II Degraders with 3,4-Disubstituted Indole Derivatives

Expanding the Chemical Space of Transforming Growth Factor-β (TGFβ) Receptor Type II Degraders with 3,4-Disubstituted Indole Derivatives

Enantioselective Total Syntheses of (+)-Arborescidine A, (−)-Arborescidine B, and (−)-Arborescidine C

Synthesis and Reactivity of Uhle’s Ketone and Its Derivatives

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