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

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• 作者：Micjel C. Morejón ; Annegret Laub ; Bernhard Westermann ; Daniel G. Rivera ; Ludger A. Wessjohann
• 刊名：Organic Letters
• 出版年：2016
• 出版时间：August 19, 2016
• 年：2016
• 卷：18
• 期：16
• 页码：4096-4099
• 全文大小：390K
• 年卷期：0
• ISSN：1523-7052

文摘

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 N-aryl-bridged cyclic lipopeptides occurring as single atropisomers.