{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:48:16Z","timestamp":1790272096104,"version":"4.1.0"},"reference-count":20,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,1,2]],"date-time":"2021-01-02T00:00:00Z","timestamp":1609545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Using the classical Ugi four-component reaction to fuse an amine, ketone, carboxylic acid, and isocyanide, here we prepared a short library of N-alkylated \u03b1,\u03b1-dialkylglycine derivatives. Due to the polyfunctionality of the dipeptidic scaffold, this highly steric hindered system shows an interesting acidolytic cleavage of the C-terminal amide. In this regard, we studied the structure-acid lability relationship of the C-terminal amide bond (cyclohexylamide) of N-alkylated \u03b1,\u03b1-dialkylglycine amides 1a\u2013n in acidic media and, afterward, it was established that the most important structural features related to its cleavage. Then, it was demonstrated that electron-donating effects in the aromatic amines, flexible acyl chains (Gly) at the N-terminal and the introduction of cyclic compounds into dipeptide scaffolds, increased the rate of acidolysis. All these effects are related to the ease with which the oxazolonium ion intermediate forms and they promote the proximity of the central carbonyl group to the C-terminal amide, resulting in C-terminal amide cleavage. Consequently, these findings could be applied for the design of new protecting groups, handles for solid-phase synthesis, and linkers for conjugation, due to its easily modulable and the fact that it allows to fine tune its acid-lability.<\/jats:p>","DOI":"10.3390\/molecules26010197","type":"journal-article","created":{"date-parts":[[2021,1,3]],"date-time":"2021-01-03T19:54:46Z","timestamp":1609703686000},"page":"197","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Structure-Acid Lability Relationship of N-alkylated \u03b1,\u03b1-dialkylglycine Obtained via a Ugi Multicomponent Reaction"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1928-4149","authenticated-orcid":false,"given":"Iv\u00e1n","family":"Ramos-Tomillero","sequence":"first","affiliation":[{"name":"Institute for Research in Biomedicine, Barcelona Science Park, 08028 Barcelona, Spain"},{"name":"CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa K.","family":"S\u00e1nchez","sequence":"additional","affiliation":[{"name":"School of Chemical Sciences and Engineering, Yachay Tech University, Yachay City of Knowledge, Urcuqui 100650, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6910-5685","authenticated-orcid":false,"given":"Hortensia","family":"Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine, Barcelona Science Park, 08028 Barcelona, Spain"},{"name":"School of Chemical Sciences and Engineering, Yachay Tech University, Yachay City of Knowledge, Urcuqui 100650, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8946-0462","authenticated-orcid":false,"given":"Fernando","family":"Albericio","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine, Barcelona Science Park, 08028 Barcelona, Spain"},{"name":"CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain"},{"name":"School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3168","DOI":"10.1002\/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO;2-U","article-title":"Multicomponent Reactions with Isocyanides","volume":"39","author":"Ugi","year":"2000","journal-title":"Angew. 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