Solution- and Solid-Phase Macrocyclization of Peptides by the Ugi–Smiles Multicomponent Reaction: Synthesis of <i>N</i>‑Aryl-Bridged Cyclic Lipopeptides

A new multicomponent methodology for the solution- and solid-phase macrocyclization of peptides is described. The approach comprises the utilization of the Ugi–Smiles reaction for the cyclization of 3-nitrotyrosine-containing peptides either by the N-terminus or the lysine side-chain amino groups. Both the on-resin and solution cyclizations took place with good to excellent efficiency in the presence of an aldehyde and a lipidic isocyanide, while the use of paraformaldehyde required an aminocatalysis-mediated imine formation prior to the on-resin Ugi–Smiles ring closure. The introduction of a turn motif in the peptide sequence facilitated the cyclization step, shortened the reaction time, and delivered crude products with >90% purity. This powerful method provided a variety of structurally novel <i>N</i>-aryl-bridged cyclic lipopeptides occurring as single atropisomers

Chilenopeptins A and B, Peptaibols from the Chilean <i>Sepedonium</i> aff. <i>chalcipori</i> KSH 883

The Chilean <i>Sepedonium</i> aff. <i>chalcipori</i> strain KSH 883, isolated from the endemic <i>Boletus loyo</i> Philippi, was studied in a polythetic approach based on chemical, molecular, and biological data. A taxonomic study of the strain using molecular data of the ITS, EF1-α, and RPB2 barcoding genes confirmed the position of the isolated strain within the <i>S. chalcipori</i> clade, but also suggested the separation of this clade into three different species. Two new linear 15-residue peptaibols, named chilenopeptins A (<b>1</b>) and B (<b>2</b>), together with the known peptaibols tylopeptins A (<b>3</b>) and B (<b>4</b>) were isolated from the semisolid culture of strain KSH 883. The structures of <b>1</b> and <b>2</b> were elucidated on the basis of HRESIMS^<i>n</i> experiments in conjunction with comprehensive 1D and 2D NMR analysis. Thus, the sequence of chilenopeptin A (<b>1</b>) was identified as Ac-Aib¹-Ser²-<b><u>Trp</u></b>^<b>3</b>-Aib⁴-Pro⁵-Leu⁶-Aib⁷-Aib⁸-Gln⁹-Aib¹⁰-Aib¹¹-Gln¹²-Aib¹³-Leu¹⁴-Pheol¹⁵, while chilenopeptin B (<b>2</b>) differs from <b>1</b> by the replacement of Trp³ by Phe³. Additionally, the total synthesis of <b>1</b> and <b>2</b> was accomplished by a solid-phase approach, confirming the absolute configuration of all chiral amino acids as l. Both the chilenopeptins (<b>1</b> and <b>2</b>) and tylopeptins (<b>3</b> and <b>4</b>) were evaluated for their potential to inhibit the growth of phytopathogenic organisms