The first total synthesis of the highly N-methylated acetylene-containing lipopeptide jahanyne, an apoptosis-inducing natural product from marine cyanobacteria, is reported. A late-stage solution-phase coupling enabled introduction of the C-terminal ketone pyrrolidine moiety. A modified Fmoc solid-phase synthesis strategy was adopted to effectively couple multiple sterically hindered N-methylated amino acids while suppressing epimerization. The total synthesis has enabled confirmation of the proposed absolute configuration of natural jahanyne.
The chiral cyclic α,α‐disubstituted α‐amino acids, Hms[(–)‐Men] and Hms[(+)‐Men] with (–)‐ and (+)‐menthones in their side‐chains, respectively, were designed and synthesized. Hms[(–)‐Men] homopeptides and Hms[(–)/(+)‐Men]‐containing l‐Leu‐based peptides were prepared in order to investigate the conformational properties of Hms[(–)/(+)‐Men]. The preferred conformations of the Hms[(–)/(+)‐Men]‐containing peptides were determined by FTIR, 1H NMR, and CD spectroscopy in solution, and by X‐ray crystallographic analysis in the crystal state. Conformational analysis in solution revealed similar right‐handed (P) 310‐helical structures for the Hms[(–)/(+)‐Men]‐containing octapeptides. In the solid state of the hexapeptides, the peptide main‐chain structures were mostly similar; however, some differences were observed in the side‐chains. The Hms[(–)/(+)‐Men] may function as helical inducers, but their side‐chain chiralities had only a negligible effect on their helical‐screw control of l‐Leu‐based peptides.
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