The solid-phase conjugation of the antimicrobial peptide c(KKLKKFKKLQ) (BPC194) to a linear or cyclic sequence through a 1,2,3-triazole ring is described. Cyclic alkynyl-peptidyl resins derived from BPC194 were treated with azidopeptides derived from the antimicrobial peptide BP100 or from the bacteriocin iturin A. The cyclic alkynyl-peptidyl resins incorporated at the 3-position a propargylglycine, a glutamic acid residue derivatized with propargylamine or a lysine bearing a propioloyl group. The reactions of the cyclic alkynyl resins with the BP100-derived azidopeptides depended on the length and the sequence of the azidopeptides. The reactions were performed by treatment of the alkynyl resin with CuI and ascorbic acid, and required the presence of piperidine/DMF or DIEA in 2,6-lutidine/DMF. The latter conditions also allowed the conjugation of the alkynyl-peptidyl resin bearing a propioloyl lysine to a linear or cyclic azidopeptide derived from the cyclic moiety of iturin A.

The solid-phase synthesis of cyclic lipopeptidotriazoles derived from the cyclic decapeptide c(Lys-Lys²-Leu-Lys-Lys⁵-Phe-Lys-Lys-Leu-Gln) (BPC194), incorporating a triazolyl ring at Lys² and a hexanoyl group at Lys⁵, was studied. Four different strategies that required the use of five orthogonal protecting groups (Fmoc, tBu, All, pNZ, ivDde) were explored. The influence of the side-chain protection of Lys² and Lys⁵ with the ivDde and pNZ groups was evaluated by incorporating Lys²(ivDde)/Lys⁵(pNZ) or Lys²(pNZ)/Lys⁵(ivDde). The order of removal of these protecting groups and of the introduction of the hexanoyl and triazolyl moieties was also studied. The best strategy included: (i) synthesis of a cyclic peptidyl resin bearing Lys²(ivDde) and Lys⁵(pNZ); (ii) pNZ group removal; (iii) acylation with hexanoic acid; (iv) ivDde group removal; and (v) acylation with propiolic acid followed by an azide–alkyne 1,3-dipolar cycloaddition. By using this protocol, a set of cyclic lipopeptidotriazoles was prepared in high purities.

Cyclic peptidotriazoles derived from the antimicrobial cyclic peptide c(Lys-Lys-Leu-Lys-Lys-Phe-Lys-Lys-Leu-Gln) (BPC194) were prepared by incorporating a triazolyl amino acid at the 3-position. The synthesis was accomplished on solid-phase and involved as the key step a copper-catalyzed cycloaddition reaction between a resin-bound alkyne or a resin-bound azide and a range of azides or alkynes in solution, respectively. This methodology was also applied to the synthesis of a conjugated peptide containing a cyclic and a linear peptidyl sequence linked through a triazolyl ring. Cyclic peptidotriazoles were obtained in excellent purities starting either from an alkynyl or an azido peptidyl resin. These compounds were screened in vitro for their growth inhibition of bacterial phytopathogens and for their cytotoxic effects on eukaryotic cells. Peptide sequences with high antibacterial activity and low hemolysis were identified, constituting good candidates for the design of new antimicrobial agents.

A concise and efficient solid-phase synthesis of biaryl cyclic peptides containing a Phe–Tyr or a Tyr–Tyr linkage has been accomplished. The key steps include a Miyaura borylation of a resin-bound 3-iodotyrosine and a microwave-assisted Suzuki–Miyaura reaction for the formation of the macrocycle. First, the feasibility of the solid-phase Miyaura borylation of a 3-iodotyrosyltripeptide was established. Then, the Suzuki–Miyaura reaction was applied to the cross-coupling of linear 3-boronotyrosine-containing peptidyl resins with iodobenzene and with halogenated aromatic amino acids. Finally, this methodology was extended to the synthesis of biaryl cyclic peptides through the preparation of a linear peptidyl resin containing both the required boronate and halogenated derivatives, followed by a microwave-assisted Suzuki–Miyaura macrocyclization.

A microwave-assisted solid-phase Suzuki–Miyaura reaction has been employed for the synthesis of 5-arylhistidine-containing peptides. In particular, sequences containing a 5-arylhistidine at the 1- or 4-positions have been designed based on lead antimicrobial peptides. The cross-coupling involved the arylation of a resin-bound 5-bromohistidine with an arylboronic acid in solution under microwave irradiation. This protocol is compatible with common protecting groups used in peptide chemistry. The resulting biaryl linear undecapeptides were screened for their antibacterial, antifungal and hemolytic activities. The results showed that the presence of an imidazole ring significantly decreases the cytotoxicity.

Resin-bound phenylalanine boronates were prepared by solid-phase Miyaura borylation of 4-iodophenylalanine peptides. Subsequent arylation through a Suzuki–Miyaura cross-coupling was carried out using a variety of aryl halides under conventional heating and under microwave irradiation. Microwaves greatly enhanced the arylation, shortening thereaction time and providing the biaryl peptides in higherpurities.

The cover picture shows the skyline of the old part of Girona in northeast Catalonia, Spain. In the foreground is one of the many bridges that span the river Onyar from the new part of the town to the Jewish quarter. This bridge, named the Pont de Sant Feliu, is the usual starting point for visiting this quarter. It offers a nice view of the narrow colourful houses that back onto the river and allows an impressive view of the Cathedral and the Sant Feliu church. Built in different styles (11th–17th century AD), the Cathedral preserves a Gothic nave with the widest arched span in the world. In this picture, the Pont de Sant Feliu serves as a means to depict the synthesis of a 4-arylphenylalanine tripeptide from a resin-bound phenylalanine boronate. Details can be found in the article by L. Feliu et al. on p. 1461 ff, and results on the formation of the boronate through a solid-phase Miyaura borylation are also discussed.