Developing greener synthesis processes is an inescapable necessity to transform the industrial landscape, mainly in the pharmaceutical sector, into a long-term, sustainable reality.

The investigation of new green biogenic pyrrolidinones as alternative solvents to N,N-dimethylformamide (DMF) for solid phase peptide synthesis (SPPS) led to the identification of N-octyl pyrrolidone (NOP) as the best candidate. NOP showed good performances in terms of swelling, coupling efficiency and low isomerization generating peptides with very high purity. A mixture of NOP with 20% dimethyl carbonate (DMC) allowed a decrease in solvent viscosity, making the mixture suitable for the automated solid-phase protocol. Aib-enkephalin and linear octreotide were successfully used to test the methodologies. It is worth noting that NOP, DMC and the piperidine used in the deprotection step could be easily recovered by direct distillation from the process waste mixture. The process mass intensity (PMI), being reduced by 63–66%, achieved an outstanding value representing a clear step forward in achieving green SPPS.

Can the green innovations introduced in peptide synthesis be transferred to oligonucleotide manufacturing? A critical analysis to disclose the green potential of TIDES.

The selection of Pd salt, ligand, solvent, base, and temperature enables controlled Pd(ii) reduction, achieving quantitative metal conversion while preventing substrate loss, nanoparticle formation, an ensuring efficient cross-coupling reactions.

The replacement of toxic solvents with greener alternatives in Heck–Cassar–Sonogashira (HCS) cross-couplings was investigated. The fine-tuning of the HCS protocol allowed to achieve complete conversions and high speed under mild conditions. N-Hydroxyethylpyrrolidone (HEP) gave the best results. Moreover, the methodology was successfully applied to the synthesis of an intermediate of the anticancer drug Erlotinib, demonstrating the versatility of the new green protocol.