Harnessing polarity and viscosity to identify green binary solvent mixtures as viable alternatives to DMF in solid-phase peptide synthesis

Martin, Vincent; Jadhav, Sandip V.; Egelund, Peter H. G.; Liffert, Raphael; Castro, Henrik Johansson; Krüger, Tobias; Haselmann, Kim F.; Quement, Sebastian Thordal Le; Alberício, Fernando; Dettner, Frank; Lechner, Carolin C.; Schönleber, Ralph; Pedersen, Daniel Sejer

doi:10.1039/d1gc00603g

Cited by 48 publications

(75 citation statements)

References 58 publications

(93 reference statements)

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“…Fine-tuning the chemical/physical features of solvents by using a binary mixture is a valuable instrument for obtaining the appropriate polarity and/or viscosity for successful resin swelling and reagent solubilization, 81 as highlighted in the guidelines for a perfect SPPS solvent. 46 The influence of different solvent mixtures on swelling was first described by the North group, who developed a computational model outlining, for the first time, that resin swelling did not correlate linearly with solvent composition. More importantly, they showed that a binary mixture could be better at achieving swelling than neat solvents; mimicking the properties of traditional, polar, aprotic solvents; and replacing them.…”

Section: Technologies and Synthesis Modifications Toward “Greening” Peptide Synthesismentioning

confidence: 99%

See 1 more Smart Citation

Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges

Ferrazzano

Catani²,

Cavazzini³

et al. 2022

Green Chem.

116

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Section: Technologies and Synthesis Modifications Toward “Greening” Peptide Synthesismentioning

confidence: 99%

“…Considering all aspects, 3 : 7 DMSO/DOL (Table 3, entries 38–42) and 3 : 7 DMSO/2-MeTHF (Table 3, entries 33–37) provided the best results when compared to DMF, while 4 : 6 NBP/DOL gave slightly worse results (Table 3, entry 43). 46…”

Section: Technologies and Synthesis Modifications Toward “Greening” Peptide Synthesismentioning

confidence: 99%

Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges

Ferrazzano

Catani²,

Cavazzini³

et al. 2022

Green Chem.

116

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“…Alternatively, natural deep eutectic solvents (NADES) have also been applied [12,[20][21][22][23][24][25][26] for this purpose. In general, many multicomponent liquid mixtures, such as NADES [27][28][29][30][31][32], ionic liquids [30,[33][34][35], and organic solvent mixtures [36][37][38] are considered as promising green solvents. Another reason for binary solvents research is the optimization of reactants concentrations and crystallization efficiency [39][40][41][42][43][44].…”

Section: Introductionmentioning

confidence: 99%

Experimental and Theoretical Screening for Green Solvents Improving Sulfamethizole Solubility

2021

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Solubility enhancement of poorly soluble active pharmaceutical ingredients is of crucial importance for drug development and processing. Extensive experimental screening is limited due to the vast number of potential solvent combinations. Hence, theoretical models can offer valuable hints for guiding experiments aimed at providing solubility data. In this paper, we explore the possibility of applying quantum-chemistry-derived molecular descriptors, adequate for development of an ensemble of neural networks model (ENNM), for solubility computations of sulfamethizole (SMT) in neat and aqueous binary solvent mixtures. The machine learning procedure utilized information encoded in σ-potential profiles computed using the COSMO-RS approach. The resulting nonlinear model is accurate in backcomputing SMT solubility and allowed for extensive screening of green solvents. Since the experimental characteristics of SMT solubility are limited, the data pool was extended by new solubility measurements in water, five neat organic solvents (acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, and methanol), and their aqueous binary mixtures at 298.15, 303.15, 308.15, and 313.15 K. Experimentally determined order of decreasing SMT solubility in neat solvents is the following: N,N-dimethylformamide > dimethyl sulfoxide > methanol > acetonitrile > 1,4dioxane >> water, in all studied temperatures. Similar trends are observed for aqueous binary mixtures. Since N,N-dimethylformamide is not considered as a green solvent, the more acceptable replacers were searched for using the developed model. This step led to the conclusion that 4-formylmorpholine is a real alternative to N,N-dimethylformamide, fulfilling all requirements of both high dissolution potential and environmental friendliness.

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“…The typical aqueous SPPS resins PEGA [39] and ChemMatrix [40] are not well suited for large‐scale peptide synthesis due to their high cost and excessive swelling in trifluoroacetic acid (TFA), [28b] and we thus examined the more common polystyrene (PS)‐based resins [41] instead. Although several studies on resin swelling in different solvents were reported, [27c,28c,d,42] to our knowledge swelling in mixtures of water with green DA solvents was not evaluated.…”

Section: Methodsmentioning

confidence: 99%

Circular Aqueous Fmoc/t‐Bu Solid‐Phase Peptide Synthesis

Pawlas

Rasmussen

2021

ChemSusChem

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Circular economy and aqueous synthesis are attractive concepts for sustainable chemistry. Here it is reported that the two can be combined in the universal method for peptide chemistry, fluorenylmethoxycarbonyl(Fmoc)/t‐Bu solid‐phase peptide synthesis (SPPS). It was demonstrated that Fmoc/t‐Bu SPPS could be performed under aqueous conditions using standard Fmoc amino acids (AAs) employing TentaGel S as resin and 4 : 1 mixture of water with inexpensive green solvent PolarClean. This resin/solvent combination played a crucial dual role by virtue of improving resin swelling and solubility of starting materials. In a model coupling, TCFH and 2,4,6‐collidine afforded a full conversion at only 1.3 equiv. AA, and these conditions were used in SPPS of Leu enkephaline amide affording the model peptide in 85 % yield and 86 % purity. A method to recycle the waste by filtration through a mixed ion exchange resin was developed, allowing reusing the waste without affecting quality of the peptide. The method herein obviates the use of unconventional or processed AAs in aqueous SPPS while using lower amounts of starting materials. By recycling/reusing SPPS waste the hazardous dipolar aprotic solvents used in SPPS were not only replaced with an aqueous medium, solvent use was also significantly reduced. This opens up a new direction in aqueous peptide chemistry in which efficient use of inexpensive starting materials and waste minimization is coupled with the universal Fmoc/t‐Bu SPPS.

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Harnessing polarity and viscosity to identify green binary solvent mixtures as viable alternatives to DMF in solid-phase peptide synthesis

Abstract: Solid-phase peptide synthesis (SPPS) enables routine synthesis of virtually any type of peptide sequence and is the preferred method for peptide synthesis in academia and the pharmaceutical industry alike. Still,...

Cited by 48 publications

References 58 publications

Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges

Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges

Experimental and Theoretical Screening for Green Solvents Improving Sulfamethizole Solubility

Circular Aqueous Fmoc/t‐Bu Solid‐Phase Peptide Synthesis

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