Resin-free peptide synthesis mediated by tri(4-benzoylphenyl) phosphate (TBP) derivatives as small-molecule supports

In this paper, a series of novel tri(4-benzoylphenyl) phosphate derivatives with unique precipitation-inducing properties were synthesized and used as C-terminal supports for peptide synthesis. Mediated and assisted by tri(4-benzoylphenyl) phosphate derivatives, intermediate and target peptides could be separated conveniently via precipitation, which was likely to occur and was conducive to the rapid purification of the intermediates of peptide synthesis without the time-consuming and high-cost process of chromatographic separation and/or recrystallization. Based on these small-molecule supports, both Fmoc and Boc strategies for efficient peptide synthesis via the processes of liquid reaction and solid precipitation were proposed and demonstrated. Due to the peptide synthesis supports developed herein combined with the higher loading performance (loading value 3 mol/1 mol support) and the easily recyclable nature, and the processes of liquid reaction and solid precipitation combining the merits of both liquid-phase peptide synthesis and solid-phase peptide synthesis, a high-yielding, scalable, atom-economical and environment-friendly method of peptide synthesis was developed. The innovative method holds great promise in the fields of organic chemistry and chemical biology research, especially in peptide-based biomedical material and drug synthesis.