Biaryl-bridged macrocyclic peptides: conformational constraint via carbogenic fusion of natural amino acid side chains

J Org Chem. 2012 Apr 6;77(7):3099-114. doi: 10.1021/jo202105v. Epub 2012 Mar 13.

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.

MeSH terms

  • Amino Acids / chemistry*
  • Molecular Structure
  • Peptides / chemistry*
  • Peptides, Cyclic / chemistry*
  • Phenylalanine / chemistry*
  • Solutions
  • Stereoisomerism
  • Tyrosine / chemistry*

Substances

  • Amino Acids
  • Peptides
  • Peptides, Cyclic
  • Solutions
  • Tyrosine
  • Phenylalanine