Presentation Summary
Prof. Fernando Albericio, Research Professor in the School of Chemistry of the University of Kwazulu-Natal (South Africa), talked about how the classical protocols for peptide synthesis fall short of Green Chemistry parameters, which is defined as the “design of chemical products and processes to reduce or eliminate the use and generation of harmful substances”.
Solid-Phase Peptide Synthesis (SPPS) allows easy manipulations, good excellent yields, high purity, easy work-ups, possibility of recycling and reusing the resin, usage of solvents of high boiling point, and automatization.
However, the excess of reagents and solvents used in classical protocols is costly and it has a very poor atom economy, due to the presence of protecting groups. Moreover, the widely used hazardous chemicals pose a threat to the environment and to human health.
According to Prof. Albericio, several attempts have been made 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.
Relevant examples of reagents appearing to be more sustainable are Ethyl cyano(hydroxyimino)acetate “oxyma pure”, which is used in combination with a carbodiimide, and its derived uronium salt COMU36, generally show equal or better coupling efficiencies and lower amino acid racemization than their benzotriazole counterparts.
Prof. Albericio talked about a recent study that has shown that COMU is relatively stable in γ-valerolactone, which makes it potentially more attractive for greener automated solid-phase peptide synthesis.
Other, less used, but relatively green coupling agents are TFFH and its derivatives, which can generate amino acyl fluorides in situ and be applied in a number of solid-phase peptide syntheses, and propylphosphonic anhydride (T3P), which is stable in solution and can potentially be used in SPPS.
Currently, the solvent of choice for the SPPS is N,N‐dimethylformamide (DMF), which is considered as reprotoxic. Thus, Prof. Albericio reminded the audience of the urgent necessity to replace it with safer solvents.
Of course, the DMF substitution by a green solvent is not a trivial task, because it needs to solubilize all the reagents and byproducts involved in the process; and, in addition facilitate the coupling of the different amino acids, and not favour the formation of side‐reactions compared with DMF.
Prof. Albericio advised the use of the green solvent N‐butylpyrrolidinone (NBP) as a replacement of DMF. This has been recognised has beneficial in two well‐documented side reactions in peptide synthesis: racemization and aspartimide formation.
Recent findings demonstrate that the use of a green solvent does not hamper the synthetic process and could even improve it, making it environmentally friendlier and synthetically better.
For the Fmoc removal step, Prof. Albericio’s group showed that 4-methyl piperidine is an excellent alternative to the usually used piperidine in terms of purity and compliance with green chemistry principles.
In summary, according to Prof. Albericio, in many cases greener solutions do not impair the peptide synthetic process; and, their adoption in current synthetic schemes will be translated into a smaller impact on the environment and on human health.
