Authors: Morales, Fidel E.; Garay, Hilda E.; Munoz, Daniela F.; Augusto, Yarelys E.; Otero-Gonzalez, Anselmo J.; Reyes Acosta, Osvaldo; Rivera, Daniel G.; Organic Letters; (2015); 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.