Active ester-based peptide bond formation and its application in peptide synthesis

Yang, Jinhua; Huang, Huanan; Zhao, Junfeng

doi:10.1039/d2qo01686a

Cited by 24 publications

(17 citation statements)

References 238 publications

(344 reference statements)

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“…From the structural standpoint, carbodiimides constitute a class of CRs that has attained a wide usage rate in the peptide synthesis field. , Specifically, DCC, diisopropylcarbodiimide (DIC), and EDCxHCl have all been adopted particularly prominently, although the poor solubility of dicyclohexylurea formed upon using DCC and increased racemization susceptibility associated with EDCxHCl arguably render DIC the most versatile carbodiimide currently in use. While DIC can be used as a standalone CR even in water, it is customary to use it in a combination with the so called coupling additives (CAs), which accelerate the rate of coupling and minimize side reactions such as racemization by converting the initially formed O-acylisourea to an active ester form of a carboxylic acid starting material. To this end, N-hydroxytriazoles HOBt and HOAt served as the preferred CAs for DIC-mediated ABFs for decades.…”

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confidence: 99%

Assessment of Sulfur Impurities in GMP-Grade Diisopropylcarbodiimide and Their Impact on Coupling Reagent-Induced Side Reactions in Peptide Synthesis

Pawlas

Rasmussen

2023

Org. Process Res. Dev.

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Diisopropylcarbodiimide (DIC) constitutes one of the most widely used coupling reagents for amide bond formation in peptide synthesis. We have previously reported that DIC contains a varying amount of sulfur (61–2030 ppm), and that the main S-containing impurity in DIC is the thiourea DITU, which exhibits an excellent ability to suppress side reactions caused by N-oxyl radicals formed from common N-hydroxyl-coupling additives such as HOBt and Oxyma (Green Chem. 2019, 21, 5990). Aiming to understand how the quality of DIC impacts peptide synthesis, here, we report an evaluation of 14 batches of GMP-grade DIC from seven different vendors. With the evaluation by elemental analysis (S), gas chromatography–mass spectrometry, high-performance liquid chromatography, liquid chromatography-mass spectrometry, and nuclear magnetic resonance, we determined that the main S-containing impurity in DIC currently in use is not DITU, but rather the diazetidine-2-thione [1,3-diisopropyl-4-(isopropylimino)-1,3-diazetidine-2-thione, DIDT], formed by a 2 + 2 cycloaddition between DIC and iPr-NCS. The identity of DIDT was confirmed by a synthesis from DIC and iPr-NCS, followed by spiking a batch of DIC with the synthesized DIDT material. In a comparative evaluation of DITU and DIDT aimed at determining their ability to suppress breakdown of Fmoc-Cys(Trt)-OH caused by N-oxyl radicals formed from Oxyma, DITU completely prevented the Cys decomposition, whereas DIDT had no effect on the suppression of the breakdown of the amino acid. Finally, catalytic amounts of DITU as well as thiols DTT and NAC had a positive effect on minimization of the HOBt-induced breakdown of Fmoc-Trp(Boc)-OH, whereas the urea DIU, formed in every DIC-mediated peptide coupling reaction, accelerated the breakdown of the Trp substrate.

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confidence: 99%

Assessment of Sulfur Impurities in GMP-Grade Diisopropylcarbodiimide and Their Impact on Coupling Reagent-Induced Side Reactions in Peptide Synthesis

Pawlas

Rasmussen

2023

Org. Process Res. Dev.

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“…It is worth mentioning that it is not necessary to isolate the α-acyloxyenamide intermediates in the synthesis of peptides and thus terminal ynamides can be regarded as an excellent peptide coupling reagent. By employing this elegant strategy, Zhao's group has accomplished the efficient synthesis of polypeptides, [70][71][72] thionoesters, 73 peptide thioesters, 74 thioamides, 75 macrolactones, 76 and macrocyclic peptides. 77 Meanwhile, by adopting the ynamide hydroacyloxylation strategy, Cui and co-workers realized the rapid assembly of β-amino amides 47 via BF 3 •Et 2 O-catalyzed four-component coupling of terminal ynamides, carboxylic acids, aldehydes, and amines (Scheme 37).…”

Section: C-o Bond Formationmentioning

confidence: 99%

Catalytic intermolecular hydrofunctionalizations of ynamides

Zhao,

Jia,

2024

Org. Chem. Front.

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“…In a broader view, the amidation of esters can be categorized into at least six different scenarios, which will be further explored and subdivided in this section. The use of esters as substrates in peptide synthesis was recently reviewed in the literature [85] …”

Section: Amides From Carbonyl‐containing Compoundsmentioning

confidence: 99%

Contemporary Approaches for Amide Bond Formation

Acosta‐Guzmán,

Ojeda‐Porras,

Gamba‐Sánchez

2023

Adv Synth Catal

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Amide bond construction has garnered significant interest in recent decades due to amides being one of the most prevalent functional groups among bioactive molecules. Out of the thirty‐seven new drugs approved by the FDA in 2022, eleven are small molecules containing at least one amide bond. Additionally, there are nineteen large molecules approved as new drugs, some of which have peptide structures, and therefore, also bear amide bonds. In recent years, multiple teams have embraced the challenge of developing more efficient methods for amide bond formation. This dedication has led to numerous publications appearing monthly in prestigious journals, showcasing significant advancements in this field. The primary goal of this review is to present the most viable strategies for constructing the amide bond. It is crucial to differentiate between amide bond formation and amide synthesis; hence, the focus is on describing specific methods for forming new C(O)−N bonds. In particular, this review concentrates on the methods developed within the last six years. There is a particular emphasis on new approaches that consider the thought process when selecting the starting materials and functional groups. This approach ensures coverage of all the most common chemical transformations that yield new amide bonds.

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Active ester-based peptide bond formation and its application in peptide synthesis

Abstract: Peptide bond, the amide bond formed between α-amino acids, constitutes the backbone of peptides and proteins. Although peptide bonds can be constructed efficiently under mild reaction conditions in nature, their...

Cited by 24 publications

References 238 publications

Assessment of Sulfur Impurities in GMP-Grade Diisopropylcarbodiimide and Their Impact on Coupling Reagent-Induced Side Reactions in Peptide Synthesis

Assessment of Sulfur Impurities in GMP-Grade Diisopropylcarbodiimide and Their Impact on Coupling Reagent-Induced Side Reactions in Peptide Synthesis

Catalytic intermolecular hydrofunctionalizations of ynamides

Contemporary Approaches for Amide Bond Formation

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