A continuous flow protocol to generate, regenerate, load, and recycle chlorotrityl functionalised resins

From a screen of chlorinating agent concentration, flow rates, and reagent addition methodologies, a continuous flow protocol to activate, reactivate, and recycle both 2-chlorotrityl chloride functionalised polystyrene and trityl-hydroxy ChemMatrix functionalised resins was established. This protocol significantly reduced resin loading periods. Under batch conditions, previously reported trityl resin chlorination protocols are effected over 1-24 hours whereas the continuous flow chlorination procedure was completed within 10 min. Further amino acid residue tethering to the resin was effected within 5 min as opposed to the 2-hour loading period typically applied under batch conditions. Moreover, an injection-based continuous-flow methodology proved effective in maintaining the chiral integrity of Fmoc-His(Trt)-OH, Fmoc-Cys(Trt)-OH, and Fmoc-Ser(t-Bu)-OH, which are susceptible to direct base-induced epimerisation. Further, through incorporating the optimised AcCl resin chlorination protocol into a continuous flow solid-phase peptide construction procedure, a facile and resin recyclable approach to conduct SPPS was established.