Acyl azide generation and amide bond formation in continuous-flow for the synthesis of peptides

Mata, Alejandro; Weigl, Ulrich; Flögel, Oliver; Baur, Pius; Hone, Christopher A.; Kappe, C. Oliver

doi:10.1039/d0re00034e

Cited by 15 publications

(14 citation statements)

References 47 publications

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“…This study began with our desire to prepare 1,7-heptamethylene diisocyanate (HpMDI, 1 ) from azelaic acid (AA, 2 ), a nine-carbon diacid that we derived from algae-sourced palmitoleic acid via ozonolysis . We saw an opportunity to achieve this transformation using the Curtius rearrangement, but the preparation of the requisite diacyl azide intermediate presented stability concerns. ,, For this reason, continuous flow chemistry offered an ideal methodology, where the risks of unstable reactions or intermediates can be mitigated. − ,, As a result, a new strategy for acyl azide preparation was needed, and we turned to well-known hydrazide chemistry, where flow methods could offer a practical solution by allowing both safety and scalability. We reasoned that we could prepare azelaoyl azide ( 4 ) by azidination of the more stable nonanedihydrazide 3 with nitrous acid in flow and couple this to an in-flow Curtius rearrangement.…”

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confidence: 99%

“…We found batch methods to be convenient and reproducible, and experimental conditions for both esterification , and acyl hydrazide synthesis ,, were carried out on the basis of previous reports. , While hydrazine is a toxic and unstable compound, hydrazine hydrate can be safely handled and diluted in methanol to prepare hydrazide derivatives in batch . Transformation of the acyl hydrazide to the isocyanate presents the most critical safety concern because of the instability of the high-energy acyl azide intermediate. , Here flow chemistry is a preferable choice, ,, since a flow reactor can prepare very small quantities of hazardous intermediates with efficient stabilizing conditions such as heat exchange, pressure regulation, and residence time, , thereby avoiding the accumulation of hazardous, explosive materials.…”

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confidence: 99%

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Preparation of Mono- and Diisocyanates in Flow from Renewable Carboxylic Acids

Hai

Backer

Cosford

et al. 2020

Org. Process Res. Dev.

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Diisocyanates used in polyurethanes are commonly prepared by phosgenation of petroleum-sourced diamines. This involves highly toxic phosgene and produces corrosive HCl, limiting synthetic applications. In our search for a renewable source for diisocyanates, we have developed a practical methodology for the production of isocyanates from algae-biomass-derived fatty acids or other renewable sources. This technique utilizes flow chemistry to prepare and convert high-energy intermediates, thus mitigating safety concerns. By the use of continuous flow, acyl azides are prepared from hydrazides and subsequently heated to undergo Curtius rearrangement, affording isocyanates in one scalable process. The method is efficient, safe, and sustainable, offers an opportunity to prepare isocyanates and diisocyanates from renewable feedstocks, and is amenable to distributed manufacturing processes.

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confidence: 99%

mentioning

confidence: 99%

Preparation of Mono- and Diisocyanates in Flow from Renewable Carboxylic Acids

Hai

Backer

Cosford

et al. 2020

Org. Process Res. Dev.

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“…Peptide synthesis via in-situ-generated acyl azides as proposed by Kappe and co-workers. [112] ChemSusChem selective antagonist for the αvβ3 integrin receptor (Table 3, entry 1). [139] The development of micro-flow photochemical macrolactamization can overcome the limit of conventionally cyclization associated with poor solubility, problematic waste originating from excess amount of coupling reagents, and harsh purification.…”

Section: Synthesis Of Cyclic Peptides In Continuous Flowmentioning

confidence: 99%

Amide Bonds Meet Flow Chemistry: A Journey into Methodologies and Sustainable Evolution

2022

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Formation of amide bonds is of immanent importance in organic and synthetic medicinal chemistry. Its presence in "traditional" small-molecule active pharmaceutical ingredients, in linear or cyclic oligo-and polypeptidic actives, including pseudopeptides, has led to the development of dedicated synthetic approaches for the formation of amide bonds starting from, if necessary, suitably protected amino acids. While the use of solid supported reagents is common in traditional peptide synthesis, similar approaches targeting amide bond formation in continuous-flow mode took off more significantly, after a first publication in 2006, only a couple of years ago. Most efforts rely upon the transition of traditional approaches in flow mode, or the combination of solid-phase peptide synthesis principles with flow chemistry, and advantages are mainly seen in improving space-time yields. This Review summarizes and compares the various approaches in terms of basic amide formation, peptide synthesis, and pseudopeptide generation, describing the technological approaches and the advantages that were generated by the specific flow approaches. A final discussion highlights potential future needs and perspectives in terms of greener and more sustainable syntheses.

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“…[24] Another approach to generate a highly reactive amino acid intermediate in situ was shown by Kappe and coworkers. [25] Beginning with acyl hydrazides, acyl azides were generated inline and then reacted with C-terminally protected amino acids to afford dipeptides. Alternatively, Jamison and coworkers used a photochemical nitrone rearrangement for amide bond formation using amino aldehyde and nitrone starting materials.…”

Section: Flow-based Peptide Ligation and Bioconjugationmentioning

confidence: 99%

Flow-based Methods in Chemical Peptide and Protein Synthesis

Schiefelbein

Hartrampf

2021

Chimia

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Flow chemistry has emerged as a powerful method for on-demand chemical synthesis and modification of peptides and proteins. Herein, we discuss the characteristics of flow chemistry and how they are applied to various aspects of peptide chemistry. We highlight recent advances in automated flow-based peptide synthesis, which extend the length of peptides routinely accessible to single-domain proteins and allow for the collection of time-resolved synthesis data. Applications of this data for the prediction of synthesis outcome and the potential for the development of more sustainable synthesis methods are also discussed. Finally, we will review solutionphase approaches, including flow-based ligation strategies and peptide cyclization. Throughout this review, the current challenges and potential future developments are highlighted.

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Acyl azide generation and amide bond formation in continuous-flow for the synthesis of peptides

Abstract: Acyl azides were safely generated by using nitrous acid in water and reacted in situ within a flow system. The acyl azide was efficiently extracted into the organic phase containing an amine nucleophile for a highly enantioselective peptide coupling.

Cited by 15 publications

References 47 publications

Preparation of Mono- and Diisocyanates in Flow from Renewable Carboxylic Acids

Preparation of Mono- and Diisocyanates in Flow from Renewable Carboxylic Acids

Amide Bonds Meet Flow Chemistry: A Journey into Methodologies and Sustainable Evolution

Flow-based Methods in Chemical Peptide and Protein Synthesis

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