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.
Subject(s)
Amino Acids/chemistry , Peptides, Cyclic/chemistry , Peptides/chemistry , Phenylalanine/chemistry , Tyrosine/chemistry , Molecular Structure , Solutions , StereoisomerismSubject(s)
Aniline Compounds/chemistry , Copper/chemistry , Phenol/chemistry , Catalysis , Iodine/chemistryABSTRACT
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.
