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

Abstract

The degree of resin swelling in a particular solvent system is one of the critical parameters for solid-phase peptide synthesis (SPPS) and for solid-phase synthesis in general. Methods used for measuring the degree of resin swelling include microscopy-based and volumetry-based methods. This study describes and compares the use of both methods for a number of commercially available resins commonly used in SPPS, with a range of solvents, which have been identified in the literature as 'greener' than DCM, DMF and NMP. The results were analysed by statistical methods, and a significant correlation between the two distinct methods has been demonstrated for the first time. The results will likely be used, in conjunction with other literature methods, to help in choosing both the resin and solvent system for greener SPPS, as well as for continuous flow SPPS, which is of growing importance. K E Y W O R D S continuous flow SPPS, green chemistry, green solid-phase peptide synthesis (GSPPS), resin swelling, solid-phase peptide synthesis (SPPS)

Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges

“…79 The paramount importance of resin swelling is highlighted by the number of publications focused on investigating this step in green solvents, 82 despite traditional solvents (DMF, NMP and DCM) maintaining the highest swelling values overall. 83 The concept of binary mixtures was then expanded to other SPPS steps. The Pawlas and Rasmussen group proposed a twodimensional, green approach, where the first dimension involves a full SPPS and the second describes examples of onresin derivatization in neat, green solvents or in a 1 : 1 EtOAc/ MeCN mixture (i.e., selective removal of acid-labile protecting groups and on-resin cyclization).…”

“…79 The paramount importance of resin swelling is highlighted by the number of publications focused on investigating this step in green solvents, 82 despite traditional solvents (DMF, NMP and DCM) maintaining the highest swelling values overall. 83…”

Green and Sustainable Solvents for Solid-Phase Peptoid Synthesis

“…The optimal solvation of the resin in SPS is essential for efficient and high-yielding reactions. , Poor swelling causes decreased access to the reaction sites within the resin for the deprotection, acylation, and displacement steps, resulting in reduced yields. We evaluated the swelling performance of the selected greener solvents and their mixtures (GVL, DMSO, and EtOAc) alongside traditional solvents (DMF and NMP) to assess their suitability for SPS.…”

General Installation of (4H)-Imidazolone cis-Amide Bioisosteres Along the Peptide Backbone

“…THF was chosen as a co-solvent instead of MeCN because it swells polystyrene-based SPPS resins similarly to DMF and DCM, but provided the highest yields in our solution-phase solvent screening (Entries 4 & 9-11, Table 1). 54 Since the amine nucleophile is immobilized on resin, we utilize an excess of thioimidate, Fmoc-Gly SMe -Aib-OMe (13, Scheme 2) for the reaction. We found that the typical concentration employed for amide coupling on resin (0.1 M) was sufficient to effect complete installation of the imidazolones when treated with 0.1 M 13 and 0.1 M AcOH under gentle heating conditions at 55 • C (Scheme 2).…”