Synthesis of a Non-Heme Template for Attaching Four Peptides:  An Approach to Artificial Iron(II)-Containing Peroxidases

• Published in: Journal of organic chemistry 2004-01, Vol.69 (2), p.250-262
• Main Authors: van den Heuvel, Marco, van den Berg, Tieme A, Kellogg, Richard M, Choma, Christin T, Feringa, Ben L
• Format: Article
• Language: English
• Subjects: Chemistry; Exact sciences and technology; Heme - chemistry; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Iron - chemistry; Ligands; Magnetic Resonance Spectroscopy; Mass Spectrometry; Organic chemistry; Peptides - chemistry; Peroxidases - chemistry; Preparations and properties
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo035157z

We are developing all-synthetic model cofactor−protein complexes in order to define the parameters controlling non-natural cofactor activity. The long-term objective is to establish the theoretical and practical basis for designing novel enzymes. A non-heme pentadentate ligand (N4Py) is being developed as a template for the site-specific attachment of a designed four-helix bundle. Previously, we attached two unprotected peptides via CH2Cl handles to N4Py. In the presence of hydrogen peroxide, the iron(II) complex of this ligand (2a) generates an FeIIIOOH intermediate (3a) that can oxidize a wide variety of organic compounds. Here, we describe the synthesis of 27, a N4Py derivative in which four three-carbon spacers have been introduced, and show that four copies of an unprotected, single-cysteine peptide can be coupled via a thioether linkage to the ligand. In addition, a divergent synthesis route to tetrabromide ligand 1b has also been developed, providing the opportunity to prepare alternative pentadentate ligands efficiently by four cross-coupling reactions on a single molecule. Also, two of the four bromides of 1b can be selectively addressed by magnesium−bromide exchange.