No abstract

A general method for constraining peptide conformations via linkage of aromatic sidechains has been developed. Macrocyclization of suitably functionalized tri-, tetra- and pentapeptides via Suzuki-Miyaura cross-coupling has been used to generate side chain to side chain, biaryl-bridged 14- to 21-membered macrocyclic peptides. Biaryl bridges possessing three different configurations, meta-meta, meta-ortho, and ortho-meta, were systematically explored through regiochemical variation of the aryl halide and aryl boronate coupling partners, allowing fine-tuning of the resultant macrocycle conformation. Suzuki-Miyaura macrocyclizations were successfully achieved both in solution and on solid phase for all three sizes of peptide. This approach constitutes a means of constraining peptide conformation via direct carbogenic fusion of side chains of naturally occurring amino acids such as phenylalanine and tyrosine, and so is complementary to strategies involving non-natural, for example, hydrocarbon, bridges.

Functionalized alpha-amino acid building blocks have been prepared in good yield with high regiocontrol and preservation of stereochemistry via iridium-catalyzed borylation of suitably protected aromatic alpha-amino acid derivatives. The utility of these systems in peptide couplings and Suzuki reactions has been demonstrated.

Kurz und bündig: Mit einer kupferkatalysierten Umsetzung vom Friedel‐Crafts‐Typ ließ sich die Titelreaktion verwirklichen. Eine iterative C‐H‐Arylierungsstrategie konnte auch zur Arylierung von Anilinen durch sequenzielles Anbinden unterschiedlicher aromatischer Gruppen an die para‐, ortho‐ und meta‐Positionen genutzt werden (siehe Schema, Bn=Benzyl, Piv=Pivaloyl).