Aminocatalysis-Mediated on-Resin Ugi Reactions: Application in the Solid-Phase Synthesis of N‑Substituted and Tetrazolo Lipopeptides and Peptidosteroids

• Published in: Organic letters Vol. 17; no. 11; pp. 2728 - 2731
• Main Authors: Morales, Fidel E., Garay, Hilda E., Muñoz, Daniela F., Augusto, Yarelys E., Otero-González, Anselmo J., Reyes Acosta, Osvaldo, Rivera, Daniel G.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 05.06.2015; Amer Chemical Soc
• Subjects: Alkylation; Chemistry; Chemistry, Organic; Lipopeptides - chemical synthesis; Lipopeptides - chemistry; Molecular Structure; Physical Sciences; Science & Technology; Solid-Phase Synthesis Techniques; Steroids - chemistry; Tetrazoles - chemical synthesis; Tetrazoles - chemistry; METHYLATION; PEPTIDES; ANALOGS; STRATEGY; PEPTOIDS; GENERATION; MULTIPLE MULTICOMPONENT APPROACH; CATALYSTS; MACROCYCLIZATIONS
• ISSN: 1523-7060; 1523-7052
• DOI: 10.1021/acs.orglett.5b01147

A new solid-phase protocol for the synthesis of N-substituted and tetrazolo peptides is described. The strategy relies on the combination of aminocatalysis-mediated on-resin Ugi reactions and peptide couplings for the N-alkylation of peptides at selected sites, including the N-terminal double lipidation, the simultaneous lipidation/biotinylation, and the steroid/lipid conjugation via tetrazole ring formation. The solid-phase Ugi four-component reactions were enabled by on-resin transimination steps prior to addition of the acid and isocyanide components. The strategy proved to be suitable for the feasible incorporation of complex N-substituents at both termini and at internal positions, which is not easily achievable by other solid-phase methods.