Hydrophobic Tag‐Assisted Scalable Synthesis of Trofinetide and Its GPE Analogues

Trofinetide (H-Gly-α-MePro-Glu-OH), an FDA-approved drug for Rett syndrome, is a modified derivative of the neuroprotective tripeptide glypromate (H-Gly-Pro-Glu-OH; GPE). We report a scalable, high-yielding liquid-phase peptide synthesis (LPPS) route employing (2,4-bis(octadecyloxy)phenyl)methanol (Tag-OH) as a hydrophobic auxiliary. The method is compatible with both linear and convergent paradigms, with process mass intensity (PMI) analysis confirming the superior efficiency of the convergent approach. In addition to establishing a robust process for trofinetide, the strategy enabled synthesis of two novel non-natural GPE analogues, H-Gly-Aib-Glu-OH and H-Gly-Aib-Asp-OH. This tag-assisted LPPS provides a greener alternative to existing routes and offers a versatile platform for industrial production of short-chain oligopeptides.