Hibispeptins are complex cyclic peptide natural products, whose structure features an unusual C-C cross linkage between the g methyl of an isoleucine residue and the arene motif of a 4-hydroxy phenacylamine (Hpa) residue. To access the key Ile-Hpa pseudodipeptide motif, we have explored a series of bidentate carboxamide-based auxiliary groups to facilitate the palladium-catalyzed arylation of unactivated g C(sp3)-H bonds of Ile with aryl iodides. We successfully introduced a new pyridylmethylamine-based auxiliary group, which allows us to not only utilize more hindered ortho-substituted aryl iodide substrates and but also carry out its removal under very mild reaction condition. Application of this more removable auxiliary group-mediated g C(sp3)-H arylation reaction enabled us to finish the first total synthesis of hibispeptin A and B.

Total synthesis of hebispeptin A and B via palladium-catalyzed C-H arylation

247th National Meeting (2014)

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