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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.

To achieve the synthesis of head-to-tail cyclic peptides via the liquid-phase on-support cyclization and synergistic self-cleavage strategy, 4,4’-bis(diphenylphosphinyloxyl) diphenyl ketoxime (BDKO) and 4-diphenyl phospholoxy benzyl alcohol (DPBA) were designed and prepared as small-molecular supports for greener peptide synthesis. During liquid-phase peptide synthesis on BDKO (or DPBA) support for peptide chain extension by Boc protocol, the last amino acid at the N-terminus of the peptide chain ends with a Fmoc protected amino acid. With the removal of the Fmoc group, head-to-tail cyclization and self-cleavage of the peptide chain synchronously occurred on BDKO (or DPBA) support to release the target cyclic peptide and the original support itself. They can be easily separated and purified, and the support can be recycled for reusing directly. The total synthesis of naturally occurring cyclic peptides such as Mortiamide A-E, Gramicidin S and cyclo(Phe-Pro) on BDKO (or DPBA) support in a resin-free manner was successfully demonstrated.

The tri(4'-diphenylphosphonyloxylbenzoyl phenyl) phosphate (TDPBP) derivatives were designed and developed as C-terminal supports to aid the greener and highefficient liquid-phase peptide synthesis (LPPS) without the need of unrecyclable resin and chromatographic separation, whereby the anti-SARS octapeptide (2) (AVLQSGFR) was synthesized with TDPBP-OH support via Fmoc chemistry and support-aided precipitation (SAP) technology. Furthermore, the ACE inhibition and the inhibitory structure-activity relationship (SAR) between the synthetic C-terminal amidated derivate (1), anti-SARS octapeptide (2) and its alanine-scanning sequence analogues (3) to (9) were systematically studied by HPLC analysis and 3D-QSAR via molecular docking.

To seek the novel application of organophosphorus compounds, the designed tri(4-formylphenyl) phosphonate (TFP) derivatives were successfully synthesized herein, which were used as C-terminal protecting groups of amino acid or greener triple-equivalent supports in liquid-phase peptide synthesis (LPPS). Through the support-aided precipitation effect of TFP derivatives, the peptide intermediates during peptide synthesis were separated and collected via rapid precipitation and facile filtration without chromatographic purification. Furthermore, the TFP derivative support can be directly recycled for reuse without further regeneration after being sheared from the target peptide.