Replacing DMF in solid-phase peptide synthesis: varying the composition of green binary solvent mixtures as a tool to mitigate common side-reactions. Issue 9 (23rd April 2021)

• Record Type: Journal Article
• Authors: Jadhav, Sandip; Martin, Vincent; Egelund, Peter H. G.; Johansson Castro, Henrik; Krüger, Tobias; Richner, Franziska; Thordal Le Quement, Sebastian; Albericio, Fernando; Dettner, Frank; Lechner, Carolin; Schönleber, Ralph; Pedersen, Daniel Sejer
• Is Part Of: Green chemistry. Volume 23:Issue 9(2021)
• Page Start: 3312
• Page End: 3321
• Publication Date: 2021-04-23
• Subjects: Environmental chemistry -- Industrial applications -- Periodicals; Environmental management -- Periodicals; 660
• DOI: 10.1039/d1gc00604e
• Languages: English
• ISSNs: 1463-9262

Abstract

Abstract : The composition of green binary solvent mixtures is used as a tool to mitigate side-reactions in SPPS. Abstract : Significant efforts have been made in recent years to identify more environmentally benign and less hazardous alternatives to N, N -dimethylformamide (DMF) in solid-phase peptide synthesis (SPPS). Several greener solvents have been endorsed as suitable candidates yet finding a neat solvent that fully matches the qualities of DMF in SPPS has proven challenging. To this end, we recently demonstrated that green binary solvent mixtures are viable alternatives to DMF and showed that the polarity and viscosity profile of a binary solvent mixture can be used to predict its utility in SPPS. In this report, we systematically investigate how the composition of green binary solvent mixtures influences Fmoc-removal, peptide coupling and common side-reactions in SPPS and show that the purity profile is not impacted adversely in binary solvent mixtures when compared to DMF. Furthermore, we demonstrate that the sole variation of the composition of the binary solvent mixture during synthesis represents a novel and simple tool to mitigate certain side-reactions in SPPS, exemplified by suppression of Arg-lactamisation and aspartimide formation. When applied to the synthesis of the peptide therapeutic Bivalirudin on a 7.5 mmol scale, we showed that simply adjusting the solvent ratio in a single step of the synthesis significantly suppressed a problematic Arg-lactamisation side-reaction. These results underline that green binary solvent mixtures not only can replace DMF in SPPS but also provide novel solutions for mitigating common side-reactions in SPPS.