Solid-Phase Synthesis of Biaryl Cyclic Peptides Containing a Histidine-Phenylalanine Linkage

Abstract

The feasibility of the solid-phase intramolecular 4(5)-arylation of a histidine residue to obtain biaryl cyclic peptides bearing a His-Phe linkage was established. The synthetic strategy involved the preparation of a linear peptidyl resin incorporating a 5-bromohistidine and a 4-boronophenylalanine, and its cyclization through the formation of the biaryl bond between the imidazole of histidine and the phenyl group of phenylalanine via a microwave-assisted Suzuki-Miyaura cross-coupling. This methodology was applied to the preparation of biaryl cyclic peptides consisting of a 3-or 5-residue ring, incorporating the His residue at the N-or the C-terminus and bearing a Leu-Leu spacer or a -NH2 group at the C-terminus.In the case of the 3-residue ring peptides, the position of the His did not influence the macrocyclization.In contrast, to obtain the 5-member ring biaryl cyclic peptides, the His residue should be located at the N-terminus. It was also observed that the Leu-Leu spacer is crucial for the intramolecular arylation. These results suggest that this approach could be useful for the preparation of a diversity of synthetic and natural biaryl cyclic peptides bearing a His-Phe linkage.

Solid-Phase Synthesis of Biaryl Cyclic Lipopeptides Derived from Arylomycins

“…We observed the formation of the expected biaryl cyclic tripeptide 15 in 65% purity together with the protodeborylated H-His(5-Br)-Ala-Tyr(Me)-NH 2 and oxidized H-His(5-Br)-Ala-Tyr(3-OH,Me)-NH 2 byproducts, with the latter also being a common side product from Suzuki–Miyaura cross-couplings. 39 In agreement with previous reports, 34 , 36 this result revealed that the macrocyclization through the formation of a His–Tyr linkage is more difficult than that involving a Phe–Tyr or a Tyr–Tyr bond. The biaryl cyclic tripeptide 15 was purified by column chromatography (75% HPLC purity) and characterized by mass spectrometry and NMR spectroscopy.…”

“…First, the dipeptidyl resin Fmoc-Ala-Tyr­(3-I,Me)-Rink-MBHA ( 10 ) was obtained through sequential Fmoc removal and coupling steps. The Fmoc group was removed by treatment with piperidine/dimethylformamide (DMF) (3:7); coupling of Fmoc-Tyr­(3-I,Me)-OH was mediated by 1-[(1-(cyano-2-ethoxy-2-oxoethylidineaminooxy)­dimethylaminomorpholino)] uronium hexafluorophosphate (COMU), ethyl 2-cyano-2-(hydroxyimino)­acetate (Oxyma), and N,N -diisopropylethylamine (DIEA) in DMF; and Fmoc-Ala-OH was coupled using N , N ′-diisopropylcarbodiimide (DIPCDI) and Oxyma in DMF. An aliquot of resin 10 was treated with trifluoroacetic acid (TFA)/H 2 O/triisoprylsilane (TIS) (95:2.5:2.5) for 2 h at room temperature, providing Fmoc-Ala-Tyr­(3-I,Me)-NH 2 in 98% purity.…”

“…We chose this reaction for the formation of the biaryl bond because of its widely reported advantages. In particular, we have described the synthesis of linear and cyclic peptides containing a biaryl bond between the side chains of a Phe, a Tyr, or a His residue. − Based on the interest arisen from arylomycins, we decided to extend our solid-phase methodology to the preparation of biaryl cyclic lipopeptides related to arylomycins. In particular, we focused our attention on analogues 1 – 3 , which contain a Phe–Tyr, a Tyr–Tyr, or a His–Tyr biaryl linkage, respectively (Figure ).…”

Marine Cyclic Peptides: Antimicrobial Activity and Synthetic Strategies

“…Pitipeptolides A (133) and B (134), as well as one homologue of 133, pitipeptolide F (135), are cyclodepsipeptides isolated from a population of the marine cyanobacterium Lyngbya majuscula sponge symbiosis collected at Piti Bomb Holes, Guam. Pitipeptolide F (135) showed the highest potency in the disc diffusion assay against M. tuberculosis.…”

An overview of recent progress in modern synthetic approach—combinatorial synthesis

“…Ng-Choli et al [42] synthesised biaryl cyclic peptides bearing His-Phe linkage through a feasible method of solid-phase synthesis strategy. The formation of the above product happened by linking a linear peptidyl resin with 5-bromohistidine and 4boronophenylalanine and carried out the cyclisation process between the imidazole of histidine and the phenyl group of phenylalanine through microwaveassisted Suzuki-Miyaura cross-coupling reaction.…”