Synthetic fermentation of β-peptide macrocycles by thiadiazole-forming ring-closing reactions

Hubert, Jonathan G.; Stepek, Iain A.; Noda, Hidetoshi; Bode, Jeffrey W.

doi:10.1039/c7sc05057g

Cited by 10 publications

(4 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S1). Notably, the reaction proceeds in aqueous buffer without additional reagents or catalysts and yields benign byproducts, allowing direct-to-biology screens (6,13). We curated a building block collection initially comprising 78 initiators, 74 monomers, and 41 terminators (fig.…”

Section: Reaction Development and Automationmentioning

confidence: 99%

Predicting Three-Component Reaction Outcomes from 40k Miniaturized Reactant Combinations

Götz,

Richards,

Stepek

et al. 2024

Preprint

View full text Add to dashboard Cite

Efficient drug discovery relies on accessing diverse small molecules expediently and reliably. Improvements to reliability through machine learning predictions are hampered by poor availability of high-quality reaction data. Here, we introduce an on-demand synthesis platform based on a three-component reaction that delivers drug-like molecules overnight. Miniaturization and automation enable the execution and analysis of 50,000 reactions on a 3 microliter scale with distinct substrates, producing the largest public reaction outcome dataset. With machine learning, we accurately predict the result of unknown reactions and analyze the impact of data set size on model training. This study advances the on-demand synthesis of drug-like molecules through concatenating chemoselective reactions and provides a sufficiently large data set to critically evaluate emerging machine learning approaches to predicting chemical reactivity.

show abstract

Section: Reaction Development and Automationmentioning

confidence: 99%

Predicting Three-Component Reaction Outcomes from 40k Miniaturized Reactant Combinations

Götz,

Richards,

Stepek

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…In 2018, the synthesis of cyclic peptides based on β-amino acids containing a thiadiazole fragment was published. 454 In the reported approach, macrocyclization and heterocycle formation were conducted in a one-pot procedure (Scheme 225). The building block in this reaction is an α-keto acid comprising N′-Boc thiohydrazide fragment 1177 and elongation monomers 1178, whose synthesis is detailed in the article.…”

Section: Oxa -And Thiadiazoles In Macrocyclic Peptide Scaffoldsmentioning

confidence: 99%

“…In 2018, the synthesis of cyclic peptides based on β-amino acids containing a thiadiazole fragment was published . In the reported approach, macrocyclization and heterocycle formation were conducted in a one-pot procedure (Scheme ).…”

Section: Oxa - and Thiadiazoles In Macrocyclic Peptide Scaffoldsmentioning

confidence: 99%

Heteroaryl Rings in Peptide Macrocycles

2019

View full text Add to dashboard Cite

This Review is devoted to the chemistry of macrocyclic peptides having heterocyclic fragments in their structure. These motifs are present in many natural products and synthetic macrocycles designed against a particular biochemical target. Thiazole and oxazole are particularly common constituents of naturally occurring macrocyclic peptide molecules. This frequency of occurrence is because the thiazole and oxazole rings originate from cysteine, serine, and threonine residues. Whereas other heteroaryl groups are found less frequently, they offer many insightful lessons that range from conformational control to receptor/ligand interactions. Many options to develop new and improved technologies to prepare natural products have appeared in recent years, and the synthetic community has been pursuing synthetic macrocycles that have no precedent in nature. This Review attempts to summarize progress in this area.

show abstract

“…They are considered as privileged scaffolds in drug design and synthesis. 7,[12][13][14][15][16][17][18] Furthermore, these structures are found in a number of natural products. 1,[19][20][21] Over the last two decades, our research group and others have been interested in the nucleophilic addition of bis(trimethylsilyl)ketene acetals to different activated heterocyclic substrates 22 such as pyridine, [23][24][25][26][27][28] pyrazine, [29][30][31] quinoline, 32,33 imidazole, 34 4-azabenzimidazole 35 and 4,5-dihydrooxazole 36 derivatives.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel isoxazoline and isoxazolidine derivatives: carboxylic acids and delta bicyclic lactones via the nucleophilic addition of bis(trimethylsilyl)ketene acetals to isoxazoles

Rosales-Amezcua¹,

Ballinas-Indilí²,

López‐Reyes³

et al. 2021

Arkivoc

View full text Add to dashboard Cite

Bis(trimethylsilyl)ketene acetals readily react with activated N-triflyl isoxazoles to selectively afford novel isoxazoline or isoxazolidine derivatives. The regioselectivity of the reaction strongly depends on the substrate substituents. When the isoxazole is substituted at the 5-position by a methyl or phenyl group, the lactonization product, i.e., the isoxazolidine derivative, is formed as a result of double nucleophilic addition of the ketene acetal. When the isoxazole is not substituted, the main product is the corresponding carboxylic acid, i.e., the isoxazoline derivative.

show abstract

Synthetic fermentation of β-peptide macrocycles by thiadiazole-forming ring-closing reactions

Abstract: A new thiadiazole-forming macrocyclization reaction enables the one-pot synthesis of cyclic β-peptide libraries from readily accessible building blocks without additional reagents.

Cited by 10 publications

References 58 publications

Predicting Three-Component Reaction Outcomes from 40k Miniaturized Reactant Combinations

Predicting Three-Component Reaction Outcomes from 40k Miniaturized Reactant Combinations

Heteroaryl Rings in Peptide Macrocycles

Synthesis of novel isoxazoline and isoxazolidine derivatives: carboxylic acids and delta bicyclic lactones via the nucleophilic addition of bis(trimethylsilyl)ketene acetals to isoxazoles

Contact Info

Product

Resources

About