TY - JOUR

T1 - Efficient solid-phase synthesis of peptide-based phosphine ligands

T2 - Towards combinatorial libraries of selective transition metal catalysts

AU - Christensen, Christian A.

AU - Meldal, Morten

PY - 2005/7/4

Y1 - 2005/7/4

N2 - 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 31P NMR spectroscopy and, cleaved from the support, as their phosphine oxides by HPLC, 1HNMR, 31PNMR 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.

AB - 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 31P NMR spectroscopy and, cleaved from the support, as their phosphine oxides by HPLC, 1HNMR, 31PNMR 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.

KW - Allylic compounds

KW - Asymmetric catalysis

KW - Peptides

KW - Phosphine ligands

KW - Solid-phase synthesis

U2 - 10.1002/chem.200500105

DO - 10.1002/chem.200500105

M3 - Journal article

C2 - 15861474

AN - SCOPUS:22044452183

VL - 11

SP - 4121

EP - 4131

JO - Chemistry: A European Journal

JF - Chemistry: A European Journal

SN - 0947-6539

IS - 14

ER -