Bisphosphine-Functionalized Cyclic Decapeptides Based on the Natural Product Gramicidin S: A Potential Scaffold for Transition-Metal Coordination

• Published in: Chemistry : a European journal Vol. 15; no. 33; pp. 8134 - 8145
• Main Authors: Burck, Sebastian, van Assema, Sander G. A., Lastdrager, Bas, Slootweg, J. Chris, Ehlers, Andreas W., Otero, José M., Dacunha-Marinho, Bruno, Llamas-Saiz, Antonio L., Overhand, Mark, van Raaij, Mark J., Lammertsma, Koop
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 17.08.2009; WILEY‐VCH Verlag; Wiley
• Subjects: Amino Acid Sequence; amino acids; Biological Products - chemistry; Chemistry; Chemistry, Multidisciplinary; Gramicidin - chemistry; Ligands; Molecular Structure; peptides; Peptides, Cyclic - chemistry; phosphanes; Phosphines - chemistry; Physical Sciences; Science & Technology; solid-phase synthesis; Transition Elements - chemistry; X-Ray Diffraction; SCHIFFS BASES; SOLID-PHASE-SYNTHESIS; ENANTIOSELECTIVE SYNTHESIS; amino acids; COMBINATORIAL LIBRARIES; X-ray diffraction; peptides; ALPHA-AMINO-ACIDS; EFFICIENT ASYMMETRIC-SYNTHESIS; phosphanes; solid-phase synthesis; ABSOLUTE-CONFIGURATION; PHOSPHINE-LIGANDS; PEPTIDE-SYNTHESIS; CATALYZED CONJUGATE ADDITIONS
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200901127

The natural product Gramicidin S is a promising scaffold for novel oligopeptide‐based bisphosphine ligands, combining the advantageous rigid chiral backbone with the close proximity of phosphine substituents. The required unnatural, phosphine‐containing, amino acid building blocks were synthesized by means of a novel protocol that involves the enantioselective alkylation of a chiral nickel Schiff base template. Three Ni complexes were prepared with different alkyl chains between the phosphine group and the α‐carbon atom of the incorporated glycine; the absolute stereochemistry of two of them was determined by single‐crystal X‐ray structure analysis. By detaching the template, enantiopure L‐phosphine amino acids resulted enabling the solid‐phase, stepwise construction of a linear sequence of the phosphine‐modified oligopeptides. On cyclization three bisphosphine‐substituted Gramicidin S analogues resulted, differing only in the size and shape of the linkage between the phosphine groups and the oligopeptides backbone. Their crystal structures suggest these species to have potential as chelating ligands. Come together! The natural compound gramicidin S serves as a platform for the design of novel bisphosphine ligands. The conformational rigidity of this C2‐symmetrical cyclic decapeptide induces close proximity of the two incorporated phosphine substituents making these compounds promising ligands for transition‐metal coordination (an example is shown here).