Speeding up sustainable solution-phase peptide synthesis using T3P® as a green coupling reagent: methods and challenges

Abstract

In peptide synthesis, the issues related to poor sustainability, long reaction times and high process mass intensity (PMI) make necessary to promote actions aimed at redefining procedural aspects projected towards...

Dipropyleneglycol Dimethylether, New Green Solvent for Solid-Phase Peptide Synthesis: Further Challenges to Improve Sustainability in the Development of Therapeutic Peptides

“…PMI is a parameter that measures the sustainability of a process. It considers all the materials used in a process and can be easily calculated using the ratio between the total mass of materials and the mass of the isolated product [ 31 , 32 ]. DMM can be easily recovered by distillation, considering that its boiling point is quite different from that of the other volatile components (DMM: 175 °C, DIC: 145 °C, and piperidine: 106 °C).…”

“…DMM can be easily recovered by distillation, considering that its boiling point is quite different from that of the other volatile components (DMM: 175 °C, DIC: 145 °C, and piperidine: 106 °C). The green solvent recycled was directly analysed by 1H NMR spectroscopy ( Figure S41 ) [ 32 ]. The recovered DMM can be used for further synthesis.…”

Fast Solution-Phase and Liquid-Phase Peptide Syntheses (SolPSS and LPPS) Mediated by Biomimetic Cyclic Propylphosphonic Anhydride (T3P®)

“…Anyway, this behavior unfortunately represents a great limitation when this reagent is applied to iterative processes requiring intermediate treatments with water solutions. Indeed, although in the past T3P ® was claimed several times as a peptide coupling reagent, its use was only reported for the formation of a single amide bond; the first example of an iterative synthesis in SolPPS, without the isolation of intermediate oligomers, has been recently reported by our group [26]. The use of T3P ® in peptide syntheses, therefore, considers two main issues: the steric hinderance of the reagent itself and the extreme sensitivity to water traces.…”

Solid-State Strategy for the S-Conjugation of Peptides Catalyzed by Zeolites and Promoted by Microwave Radiation: A Green Approach

“…However, it is worth emphasizing that the SPPS approach still requires large excess of reactants and large amounts of organic solvents, ultimately resulting in large amounts of chemical waste . To date, several approaches have been considered to develop green chemistry protocols for peptide synthesis, including (i) performing the coupling step in the absence of solvents with stoichiometric amounts of amino acids and with a slight excess of an inorganic base (e.g., NaHCO 3 ), (ii) pursuing increased yields with microwave (MW) irradiation, (iii) replacing organic solvents with water, − (iv) employing greener activating agents, and (v) choosing protecting groups that can be removed under greener conditions. , In particular, the new technology named LPPS technology (liquid phase peptide synthesis) combines the advantage of the solid approach, concerning the ease of the workup, with the greener reaction conditions of the solution approach that requires a reduced amount of reagents and more environmentally friendly (and less toxic) solvents. , …”

“…3 To date, several approaches have been considered to develop green chemistry protocols for peptide synthesis, including (i) performing the coupling step in the absence of solvents with stoichiometric amounts of amino acids and with a slight excess of an inorganic base (e.g., NaHCO 3 ), 4 (ii) pursuing increased yields with microwave (MW) irradiation, (iii) replacing organic solvents with water, 5−8 (iv) employing greener activating agents, and (v) choosing protecting groups that can be removed under greener conditions. 9,10 In particular, the new technology named LPPS technology (liquid phase peptide synthesis) combines the advantage of the solid approach, concerning the ease of the workup, with the greener reaction conditions of the solution approach that requires a reduced amount of reagents and more environmentally friendly (and less toxic) solvents. 11,12 Following this streamlined path to green peptide chemistry, we reasoned about improving the protocol we have been developing over the last years to introduce chemical diversities into preformed peptide sequences.…”