Efficient Solid‐Phase Synthesis of Peptide‐Based Phosphine Ligands: Towards Combinatorial Libraries of Selective Transition Metal Catalysts

Abstract

A new methodology for the solid-phase synthesis of peptide-based phosphine ligands has been developed. Solid supported peptide scaffolds possessing either primary or secondary amines were synthesised using commercially available Fmoc-protected amino acids and readily available Fmoc-protected amino aldehydes for reductive alkylation, in standard solid-phase peptide synthesis (SPPS). Phosphine moieties were introduced by phosphinomethylation of the free amines as the final solid-phase synthetic step, immediately prior to complexation with palladium(II), thus avoiding tedious protection/deprotection of the phosphine moieties during the synthesis of the ligands. The extensive use of commercial building blocks and standard SPPS makes this methodology well suited for the generation of solid-phase combinatorial libraries of novel ligands. Furthermore, it is possible to generate several different phosphine ligand libraries for every peptide scaffold library synthesised, by functionalising the scaffold libraries with different phosphine moieties. The synthesised ligands were characterised on solid support by conventional (31)P NMR spectroscopy and, cleaved from the support, as their phosphine oxides by HPLC, (1)H NMR, (31)P NMR and high resolution ESMS. Palladium(II) allyl complexes were generated from the resin bound ligands and to demonstrate their catalytic properties, palladium catalysed asymmetric allylic substitution reactions were performed. Good yields and moderate enantioselectivity was obtained for the selected combination of catalysts and substrate, but most importantly the concept of this new methodology was proven. Screening of ligand libraries should afford more selective catalysts.

Coordination complexes and biomolecules: A wise wedding for catalysis upgrade

“…In this way, peptidic environment surrounds the coordination complexes. A first attempt with phosphine ligands displayed high yields but mild selectivities [101]. Interestingly, the doubly coordinated complex (Fig.…”

Incorporating ECE-pincer metal complexes as functional building blocks in semisynthetic metalloenzymes, supramolecular polypeptide hybrids, tamoxifen derivatives, biomarkers and sensors

“…Peptides substituted by phosphines have been used successfully as chiral backbones for transition metal catalysts in asymmetric hydrogenation, alkylation and allylic substitution reactions [83][84][85][86][87]. ECE-pincer palladium complexes, which have been broadly applied as homogeneous catalysts, e.g.…”

Solid‐Phase Synthesis of Transition‐Metal Complexes

“…[17,58] To allow incorporation of a transition-metal complex at any position within a peptide the transition-metal building block requires both an amino functionality and a carboxylic acid group. To this end a variety of side-chain modified amino acids has been designed (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)Scheme 15). [39,[59][60][61][62][63][64][65][66] Recently, a stable a-amino acid derivative incorporating a ferrocene unit at the a-position has been reported.…”

“…These peptides serve as chiral ligands for organometallic fragments, for example, {Rh(norbonadiene)} or {PdA C H T U N G T R E N N U N G (allyl)Cl} in asymmetric catalytic reactions. [28,29] Metal-modified biomolecules prepared by SPS with one metal label attached to the terminus of the oligomer (see, for example, references [30][31][32][33][34][35]) as well as side-chain modifications of biooligomers (see, for example, references [36][37][38][39]) will not be considered further in this article. The preparation of metal-complex/peptide conjugates by solid-phase peptide synthesis has been recently summarised in microreviews and will not be covered in this article.…”