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Peptide synthesis is an area with a wide field of application, from biomedicine to nanotechnology, that offers the option of simultaneously synthesizing a large number of sequences for the purpose of preliminary screening, which is a powerful tool. Nevertheless, standard protocols generate large volumes of solvent waste. Here, we present a protocol for the multiple Fmoc solid-phase peptide synthesis in tea bags, where reagent recycling steps are included. Fifty-two peptides with wide amino acid composition and seven to twenty amino acid residues in length were synthesized in less than three weeks. A clustering analysis was performed, grouping the peptides by physicochemical features. Although a relationship between the overall yield and the physicochemical features of the sequences was not established, the process showed good performance despite sequence diversity. The recycling system allowed to reduce N, N-dimethylformamide usage by 25–30% and reduce the deprotection reagent usage by 50%. This protocol has been optimized for the simultaneous synthesis of a large number of peptide sequences. Additionally, a reagent recycling system was included in the procedure, which turns the process into a framework of circular economy, without affecting the quality of the products obtained., This research was funded by grants to F.G. (REDES 180203 and Fondecyt 1210056) from the National Agency for Research and Development (ANID), Chile. This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska Curie grant agreement No. 861190 (PAVE). The work of Omar Luna in Spain is funded by PAVE.

It has been reported that DIC can react with OxymaPure to render an oxadiazole compound with the concomitant formation of HCN. Here we demonstrate that this reaction is not a feature of all carbodiimides but rather depends on the alkyl structure that flanks the two N atoms of the carbodiimide. Furthermore, we have identified two carbodiimides, TBEC and EDC·HCl, whose reaction with OxymaPure is exempt from HCN formation., We thank Yoav Luxembourg (Luxembourg Bio Technologies) for encouraging this work. This project received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Marie Skłodowska-Curie Grant Agreement 861190 (PAVE). O.L.’s work was funded by PAVE. The authors acknowledge an American Chemical Society (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable Ignition Grant awarded to S.R.M. The work carried out in South Africa was partially funded by the National Research Foundation (NRF) (Blue Sky’s Research Programme 120386). Peptide preparation was performed at the NANBIOSIS–CIBER BBN Peptide Synthesis Unit (U3).