Choosing the Right Coupling Reagent for Peptides: A Twenty-Five-Year Journey

Alberício, Fernando; El‐Faham, Ayman

doi:10.1021/acs.oprd.8b00159

Cited by 128 publications

(123 citation statements)

References 125 publications

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“…The synthesis of amides is among the most important reactions in organic chemistry and biochemistry because of the widespread occurrence of amides in pharmaceuticals, peptides, biologically active compounds, industrial polymers, detergents, and lubricants [ 1 , 2 , 3 , 4 , 5 , 6 ]. Consequently, many different physical [ 7 ] and chemical protocols have been developed for the synthesis of amides by dehydro-condensation of a carboxylic acid and an amine [ 8 , 9 , 10 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Sustainable Triazine-Based Dehydro-Condensation Agents for Amide Synthesis

et al. 2021

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Conventional methods employed today for the synthesis of amides often lack of economic and environmental sustainability. Triazine-derived quaternary ammonium salts, e.g., 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM(Cl)), emerged as promising dehydro-condensation agents for amide synthesis, although suffering of limited stability and high costs. In the present work, a simple protocol for the synthesis of amides mediated by 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and a tert-amine has been described and data are compared to DMTMM(Cl) and other CDMT-derived quaternary ammonium salts (DMT-Ams(X), X: Cl− or ClO4−). Different tert-amines (Ams) were tested for the synthesis of various DMT-Ams(Cl), but only DMTMM(Cl) could be isolated and employed for dehydro-condensation reactions, while all CDMT/tert-amine systems tested were efficient as dehydro-condensation agents. Interestingly, in best reaction conditions, CDMT and 1,4-dimethylpiperazine gave N-phenethyl benzamide in 93% yield in 15 min, with up to half the amount of tert-amine consumption. The efficiency of CDMT/tert-amine was further compared to more stable triazine quaternary ammonium salts having a perchlorate counter anion (DMT-Ams(ClO4)). Overall CDMT/tert-amine systems appear to be a viable and more economical alternative to most dehydro-condensation agents employed today.

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Section: Introductionmentioning

confidence: 99%

Sustainable Triazine-Based Dehydro-Condensation Agents for Amide Synthesis

et al. 2021

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“…As an example, we can consider peptide bond formation between an amine and a carboxylic acid. This transformation is a very important reaction in organic synthesis and therefore, many coupling reagents are available on the market [25][26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Efficient synthesis of dipeptide analogues of α-fluorinated β-aminophosphonates

Kaźmierczak

Koroniak

2020

Beilstein J. Org. Chem.

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“…The first challenge was coupling the sterically hindered N -alkylated amino acids to the preceding amino acid because standard conditions suffered from low conversion yields. This was overcome by using a more reactive coupling reagent 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (abbreviated HATU), and optimized conditions (steps b, Figure 5 ) (Albericio and El-Faham, 2018 ). The second challenge was to improve the low yield of the in-situ reductive alkylation step on the solid support (step c, Figure 5 ).…”

Section: Resultsmentioning

confidence: 99%

Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs

Talhami

Swed

Hess³

et al. 2020

Front. Chem.

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Painkillers are commonly used medications. Native peptide painkillers suffer from various pharmacological disadvantages, while small molecule painkillers like morphine are highly addictive. We present a general approach aimed to use backbone-cyclization to develop a peptidomimetic painkiller. Backbone-cyclization was applied to transform the linear peptide Tyr-Arg-Phe-Sar (TAPS) into an active backbone-cyclic peptide with improved drug properties. We designed and synthesized a focused backbone-cyclic TAPS library with conformational diversity, in which the members of the library have the generic name TAPS c(n-m) where n and m represent the lengths of the alkyl chains on the nitrogens of Gly and Arg, respectively. We used a combined screening approach to evaluate the pharmacological properties and the potency of the TAPS c(n-m) library. We focused on an in vivo active compound, TAPS c(2-6) , which is metabolically stable and has the potential to become a peripheral painkiller being a full μ opioid receptor functional agonist. To prepare a large quantity of TAPS c(2-6) , we optimized the conditions of the on-resin reductive alkylation step to increase the efficiency of its SPPS. NMR was used to determine the solution conformation of the peptide lead TAPS c(2-6) .

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Choosing the Right Coupling Reagent for Peptides: A Twenty-Five-Year Journey

Cited by 128 publications

References 125 publications

Sustainable Triazine-Based Dehydro-Condensation Agents for Amide Synthesis

Sustainable Triazine-Based Dehydro-Condensation Agents for Amide Synthesis

Efficient synthesis of dipeptide analogues of α-fluorinated β-aminophosphonates

Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs

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