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The first total synthesis of cordyheptapeptide A is described. The synthesis is accomplished by a convergent approach featuring a combination of peptide coupling and the Ugi reaction for the preparation of the main building blocks and the acyclic precursor. The assembly of an N-methylated fragment by the Ugi reaction comprised the utilization of a convertible isonitrile followed by activation of the C-terminal amide. Two different macrocyclization sites were evaluated, proving greater efficacy the macrolactamization at the site Ile-Tyr, likely due of a more suitable conformational bias of the acyclic precursor having an internal β-turn centered at the N-Me-d-Phe-Pro moiety.
Publications
A multicomponent approach enabling the installation of turn-inducing moieties that facilitate the macrocyclization of short and medium-size oligopeptides is described. The strategy comprises the Ugi ligation of peptide carboxylic acids and isocyanopeptides in the presence of aldehydes and acid or photolabile amines followed by cyclization and cleavage of the backbone N-substituents to render canonical cyclopeptides. Implementing the approach on solid phase with the use of Rink amide resins led to a new class of backbone amide linker strategy.
Publications
A multicomponent macrocyclization strategy towards cyclic lipopeptides is described. The approach relies on the utilization of the Ugi and Passerini multicomponent reactions for the cyclization of peptides and oxo-peptides, and here it is employed for the construction of a small library of analogues of the natural products mycosubtilin and surfactin A. A key feature of this method is the simultaneous incorporation of either one or two exocyclic lipid tails along with the macrocyclic ring closure, which is only possible due to the multicomponent nature of the macrocyclization step. The evaluation of the anticancer activity of the lipopeptide library showed that the installation of a second lipid moiety in the surfactin scaffold leads to a more potent cytotoxicity in cancer cells. This is a new example of the multicomponent reaction potential in rapidly producing natural product analogues for biological screening.
Books and chapters
Macrocyclizations may be performed through two main processes: single‐component reactions and multicomponent reactions (MCRs). This chapter discusses MCRs and details approaches where isonitrile‐based MCRs (IMCRs) were applied to accomplish the macrocyclization of long linear molecules. It also introduces some insights about general aspects, concepts, and classifications of IMCR‐based macrocyclizations. The chapter then focuses on the early development of this method and case studies, where it was applied to the synthesis of rationally designed macrocyclic molecules. It further covers a special topic on the use of multiple IMCR‐based macrocyclizations for synthesizing three‐dimensional structures. In the past, most studies were directed toward understanding the principles of using MCRs in macrocyclizations and to explore the scope of these reactions, especially of the valuable IMCRs. In the future, this will be extended to even more and different MCRs, which in themselves are only at the advent of being explored.