Green Transformation of Solid-Phase Peptide Synthesis

Abstract

Peptides play key roles in medicinal chemistry, being found in therapeutics and diagnostic agents, among others. Furthermore, their synthetic protocols have also been optimized for other fields such as the solid-phase organic synthesis of other organic compounds. However, the classical protocols for peptide synthesis fall short of Green Chemistry parameters. The excess of reagents and solvents used in classical protocols is costly. Moreover, the widely used hazardous chemicals pose a threat to the environment and to human health. In this review, we examine peptide synthesis in the context of green chemistry and address its pros and cons. Furthermore, we discuss several attempts to make peptide synthesis greener. These attempts have followed two major pathways, namely reducing the amount of material used or replacing hazardous materials for friendlier ones. Although this work focuses mostly on the solid-phase peptide synthesis approach, a brief description of some reagents, solvents, methods or strategies used in solution is given because these compounds could be easily adapted to the solid-phase mode.

Assessing the correlation of microscopy‐based and volumetry‐based measurements for resin swelling in a range of potential greener solvents for SPPS

“…Ethyl acetate and ethanol are recommended in the CHEM21 guide, as is anisole in the ether solvent category and methyl ethyl ketone (MEK, 2‐butanone) in the ketone category. Previous researchers have reported the use of acetonitrile (MeCN), 2‐methyltetrahydrofuran (2‐MeTHF) and gamma‐valerolactone (GVL) as greener replacements for DMF and NMP in SPPS and demonstrated that ‘difficult’ peptides can be successfully synthesised when using the aforementioned greener solvents 15,25,46–48 . We have also reported the use of GVL and another green solvent Cyrene (dihydrolevoglucosenone) 49 as part of our previous studies involving the critical initial loading stage of SPPS 50 .…”

“…DCM, a solvent that is also generally regarded as problematic, is mainly used in SPPS during the washing and swelling steps 5,14 . Advances in green SPPS (GSPPS) have been recently reviewed by Jad et al 15 and by Varnava and Sarojini 16 …”

Flow‐based SPPS for protein synthesis: A perspective

“…As environmental factors are becoming increasingly important, there is a growing interest to develop more sustainable alternatives to traditional SPPS reagents, solvents and peptide purification. [ 90–93 ] The E‐factor for amide‐bond formation is very low and improvements are urgently needed, especially considering that this reaction is among the most commonly utilized transformations in the pharmaceutical industry. [ 94–96 ] Current strategies rely on the use of hazardous solvents (DMF and N ‐methyl‐2‐pyrrolidone, NMP) and stoichiometric activating or coupling reagents resulting in poor atom economy and accumulation of toxic waste.…”

An environmentally sustainable biomimetic production of cyclic disulfide-rich peptides

“…19 These low concentrations require handling of large volumes of aqueous folding buffers that add to the complexity of synthesizing cyclic disulfide-rich peptides. Overall, SPPS of cyclic disulfiderich peptides has poor atom economy, high environmental (E)-factor and process mass intensity following the Green Chemistry metrics regardless of the type of solvent used 21 and is not only costly but generates substantial amounts of hazardous waste.…”