# Cyclover-Assisted Liquid-Phase Peptide Synthesis Using T3P® as a Green Coupling Reagent

**Authors:** Priyanka Kushwaha, Marvin Mantel, Peter Talbiersky, Yongfu Li, Anamika Sharma, Beatriz G. de la Torre, Fernando Albericio

PMC · DOI: 10.1021/acs.orglett.6c00353 · 2026-02-24

## TL;DR

This paper introduces Cyclover, a tag that improves green and efficient liquid-phase peptide synthesis using T3P®.

## Contribution

Cyclover enables tunable, sustainable LPPS with T3P® in 2Me-THF, reducing PMI while maintaining yield and purity.

## Key findings

- Cyclover reduces PMI by ∼2.7-fold in LPPS.
- T3P® maintains high purity and isolated yield in peptide synthesis.
- The method offers a greener route for complex peptides.

## Abstract

Liquid-phase peptide
synthesis (LPPS) continues to evolve toward
more sustainable and efficient methodologies. In this study, we introduce
Cyclover as a tag that enables efficient, tunable LPPS in 2Me-THF
using propylphosphonic anhydride (T3P®) as a coupling reagent.
The extraction protocol reduces the PMI ∼2.7-fold while maintaining
high purity and isolated yield, offering a greener and versatile route
to complex peptides

## Linked entities

- **Chemicals:** T3P® (PubChem CID 111923), propylphosphonic anhydride (PubChem CID 111923), 2Me-THF (PubChem CID 7301)

## Full-text entities

- **Genes:** PDYN (prodynorphin) [NCBI Gene 5173] {aka ADCA, PENKB, SCA23}
- **Diseases:** LPPS (MESH:D000210)
- **Chemicals:** butyl acetate (MESH:C006848), DMF (MESH:D004126), tert-butyl methyl ether (MESH:C043243), THF (MESH:C018674), piperidine (MESH:C032727), guanidinium (MESH:D019791), ninhydrin (MESH:D009555), 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (MESH:D005022), n-pentane (MESH:C033353), anisole (MESH:C060998), H-Gly-RinkAmide-Cyclover 5 (-), NaHCO3 (MESH:D017693), Oxytocin (MESH:D010121), ethyl acetate (MESH:C007650), TFA (MESH:D014269), 2Me-THF (MESH:C587233), acetone (MESH:D000096), toluene (MESH:D014050), TIS (MESH:D014025), MgSO4 (MESH:D008278), amino acids (MESH:D000596), Peptide (MESH:D010455), carbodiimides (MESH:D002234), amide (MESH:D000577), H2O (MESH:D014867), ethanol (MESH:D000431), cyclohexane (MESH:C506365), B (MESH:D001895), brine (MESH:C017082), HCl (MESH:D006851), n-hexane (MESH:C026385), phosphorus (MESH:D010758), methanol (MESH:D000432), ACN (MESH:C032159), polymers (MESH:D011108), cyanuric chloride (MESH:C019309), H-C (MESH:D006854), 2-methyltetrahydrofuran (MESH:C550584), DCM (MESH:D008752)

## Figures

8 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12973291/full.md

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Source: https://tomesphere.com/paper/PMC12973291