Total Synthesis of Hibispeptin A via Pd-Catalyzed C(sp³)–H Arylation with Sterically Hindered Aryl Iodides

Abstract

To access the key Ile-Hpa pseudodipeptide motif in hibispeptins, a series of bidentate carboxamide-based auxiliary groups have been explored to facilitate the palladium-catalyzed arylation of unactivated γ-C(sp(3))-H bonds of Ile precursor with aryl iodides. A new pyridylmethylamine-based auxiliary group PR is introduced, which permits the use of more sterically hindered ortho-substituted aryl iodide substrates and can be removed under mild conditions. Pd-catalyzed PR-directed γ-C(sp(3))-H arylation enabled the first total synthesis of hibispeptin A.

A visible-light-promoted radical reaction system for azidation and halogenation of tertiary aliphatic C–H bonds

“…Our research in radical C–H functionalization chemistry stems from our interest in the synthetic and biological studies of peptides 15. Compared with α-amino acid (αAA) residues bearing polar or aromatic side chains, the structural and functional roles of hydrophobic aliphatic αAA residues such as leucine and valine in peptides and proteins are much more difficult to probe due to the lack of suitable chemical handles in these residues.…”

A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

“…Note that PE-directed arylation of isoleucine derivatives at the γ-position was previously reported by the authors. 554 In comparison, when PM was used as DG ( Scheme 92B ), the reaction was really sensitive to steric hindrance leading to poor yields (15–26%) with 2-substituted aryl iodides but the transformation was still efficient with para -substituted aryl iodides (62–86% yields). 553 …”

2-Oxiranyl-pyridines: Synthesis and Regioselective Epoxide Ring Openings with Chiral Amines as a Route to Chiral Ligands

“…us, in the next step, 4, 5, and 6 were reacted with NBS in dioxane/water acidified with acetic acid giving the respective bromohydrins 8, 9, and 10 that were smoothly converted into the epoxides 11 [52,53,54], 12, and 13 (Scheme 1). Also, rac-2-(oxiranyl)pyridine (14) [55] was prepared analogously from 2-vinylpyridine.…”