The applications of <i>β</i>‐keto amides for heterocycle synthesis

Wu, Xiaoqiang; Li, Wanfang

doi:10.1002/jhet.4497

Cited by 14 publications

(2 citation statements)

References 296 publications

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“…Finally we note the N-terminal β-keto amide and γ-keto amide peptides generated are suitable substrates for many other macrocyclization or late-stage diversification reactions 44 . Potential reactions of N-terminal β-and γ-keto amides include those that generate pyridines (Hantzsch reaction 87 ), pyrazoles (Knorr 88 ), pyrroles (Hantzsch, Knorr, Paal-Knorr 89 ), dihydropyrimidinones (Biginelli 90 ), and carbocycles (Conia-Ene 91 ), in addition to Michael additions, alkylations, acylations, and arylations.…”

Section: Discussionmentioning

confidence: 99%

“…Friedländer reactions of β-keto amides proceed readily under mild aqueous conditions β-and γ-keto carbonyl groups participate in an array of chemical transformations that generate carbocyclic and heterocyclic frameworks, often with elements of stereocontrol [43][44][45] . One classic transformation is the Friedländer reaction 46 , a double condensation of a 2-aminoarylcarbonyl and an aldehyde or ketone to form a quinoline, a fused [6,6] heterocyclic aromatic ring.…”

Section: Introduction Of a Reactive 13-dicarbonyl Motif At The N-term...mentioning

confidence: 99%

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Chemo-ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines

Knudson,

Dover,

Dilworth

et al. 2024

Preprint

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Expanding the chemical and structural complexity of genetically encoded peptides remains a challenge in peptide therapeutics discovery. Here we report that linear peptides with a reactive β- or γ-keto amide at their N-termini can be synthesized ribosomally using in vitro translation methods. We show that peptides carrying an N-terminal β-keto amide can be converted into diverse heterocyclic quinoline-peptide hybrids via Friedländer reactions with a variety of 2-aminoarylcarbonyl co-substrates. Reactions with appropriately substituted 2-aminobenzophenones generated quinoline-peptide hybrids with stable biaryl atropisomeric axes. In vitro-translated peptides carrying both an N-terminal β-keto amide and an internal 2-aminoacetophenone motif undergo intramolecular Friedländer macrocyclization reactions that embed a quinoline pharmacophore directly within the macrocyclic backbone. The introduction of N-terminal ketide building blocks into genetically encoded materials and their post-translational derivatization with carbonyl chemistry simultaneously expands the chemical diversity and structural complexity of genetically encoded materials and provides a paradigm for the programmed synthesis of peptide-derived materials that more closely resemble complex natural products.

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Section: Discussionmentioning

confidence: 99%

Section: Introduction Of a Reactive 13-dicarbonyl Motif At The N-term...mentioning

confidence: 99%

Chemo-ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines

Knudson,

Dover,

Dilworth

et al. 2024

Preprint

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Allenamides as a Powerful Tool to Incorporate Diversity: Thia‐Michael Lipidation of Semisynthetic Peptides and Access to β‐Keto Amides

Na,

Sander,

Davidson

et al. 2024

Angewandte Chemie

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Lipopeptides are an important class of biomolecules for drug development. Compared with conventional acylation, a chemoselective lipidation strategy offers a more efficient strategy for late‐stage structural derivatisation of a peptide scaffold. It provides access to chemically diverse compounds possessing intriguing and non‐native moieties. Utilising an allenamide, we report the first semi‐synthesis of antimicrobial lipopeptides leveraging a highly efficient thia‐Michael addition of chemically diverse lipophilic thiols. Using chemoenzymatically prepared polymyxin B nonapeptide (PMBN) as a model scaffold, an optimised allenamide‐mediated thia‐Michael addition effected rapid and near quantitative lipidation, affording vinyl sulfide‐linked lipopeptide derivatives. Harnessing the utility of this new methodology, 22 lipophilic thiols of unprecedented chemical diversity were introduced to the PMBN framework. These included alkyl thiols, substituted aromatic thiols, heterocyclic thiols and those bearing additional functional groups (e.g., amines), ultimately yielding analogues with potent Gram‐negative antimicrobial activity and substantially attenuated nephrotoxicity. Furthermore, we report facile routes to transform the allenamide into a β‐keto amide on unprotected peptides, offering a powerful “jack‐of‐all‐trades” synthetic intermediate to enable further peptide modification.

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Asymmetrische Synthese von β‐Ketoamiden durch eine Sulfoniumumlagerung

Porte,

Nascimento,

Sirvent

et al. 2024

Angewandte Chemie

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The synthesis of enantioenriched α‐substituted 1,3‑dicarbonyls remains a contemporary challenge in synthesis due to their tendency to undergo racemization via keto‐enol tautomerization. Herein, we report a method to access enantioenriched β‐ketoamides by a chiral sulfinimine‐mediated [3,3]‐sigmatropic sulfonium rearrangement. The transformation displays good chirality transfer, as well as excellent chemoselectivity and functional group tolerance. Diastereoselective reduction of the ketone moiety, also achievable in one‐pot fashion, affords enantioenriched β‑hydroxyamides.

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The applications of β‐keto amides for heterocycle synthesis

Cited by 14 publications

References 296 publications

Chemo-ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines

Chemo-ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines

Allenamides as a Powerful Tool to Incorporate Diversity: Thia‐Michael Lipidation of Semisynthetic Peptides and Access to β‐Keto Amides

Asymmetrische Synthese von β‐Ketoamiden durch eine Sulfoniumumlagerung

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