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We report a scalable, high\u2010yielding liquid\u2010phase peptide synthesis (LPPS) route employing (2,4\u2010bis(octadecyloxy)phenyl)methanol (Tag\u2010OH) 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\u2010natural GPE analogues, H\u2010Gly\u2010Aib\u2010Glu\u2010OH and H\u2010Gly\u2010Aib\u2010Asp\u2010OH. This tag\u2010assisted LPPS provides a greener alternative to existing routes and offers a versatile platform for industrial production of short\u2010chain oligopeptides.<\/jats:p>","DOI":"10.1002\/psc.70096","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T09:30:58Z","timestamp":1777973458000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hydrophobic Tag\u2010Assisted Scalable Synthesis of Trofinetide and Its GPE Analogues"],"prefix":"10.1002","volume":"32","author":[{"given":"Veeranjaneyulu","family":"Avula","sequence":"first","affiliation":[{"name":"Teadus Pharma  Hyderabad India"},{"name":"Department of Chemistry REVA University  Bangalore Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai\u00a0Krishna","family":"Vangapelly","sequence":"additional","affiliation":[{"name":"Teadus Pharma  Hyderabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamanappa","family":"Mang","sequence":"additional","affiliation":[{"name":"Teadus Pharma  Hyderabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Umamaheshwar","sequence":"additional","affiliation":[{"name":"Teadus Pharma  Hyderabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5099-3384","authenticated-orcid":false,"given":"Nagendra","family":"Govindappa","sequence":"additional","affiliation":[{"name":"Department of Chemistry REVA University  Bangalore Karnataka India"},{"name":"Centre for Bio\u2010Organic Chemistry, REVA Research Centre REVA University  Bangalore Karnataka India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0816-0116","authenticated-orcid":false,"given":"H.","family":"Surya\u00a0Prakash\u00a0Rao","sequence":"additional","affiliation":[{"name":"Teadus Pharma  Hyderabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.37349\/eds.2023.00011"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-020-00135-8"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.2c00675"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(00)01988-0"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/ACSABM.3C00254"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/JPET.123.001690"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/BIOMEDICINES10020343"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.4324\/9780429470851"},{"key":"e_1_2_9_10_1","unstructured":"P. D.Gluckman G. B.Thomas J.Guan et\u00a0al. \u201cEffects of Glycyl\u20102 Methyl Prolyl Glutamate on Neurodegeneration \u201d U.S. Patent 7 605 177 Neuren Pharmaceuticals Ltd (2009)."},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.4c00007"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.10.001"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1086\/303078"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/13696998.2023.2286778"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2023.06.008"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.medj.2024.06.007"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1341746"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2015.06.003"},{"key":"e_1_2_9_19_1","unstructured":"L. I.Glass M. J.Bickerdike M. F.Snape andP. P.deCogram \u201cTreatment of Autism Spectrum Disorders Using Glycyl\u2010l\u20102\u2010Methylprolyl\u2010l\u2010Glumatic Acid \u201d U.S. Patent Application 14 602 600 (2015)."},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm12155114"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/FPHAR.2023.1284035\/FULL"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2008.12.003"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.2015.1010514"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2005.08.026"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1039\/b605293b"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0GC00143K"},{"key":"e_1_2_9_27_1","unstructured":"N. A.AboodandM. 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