Metallocene based peptidomimetics and chiral catalysts

Abstract: Several optically active organometallic Phe-AAn-Phe peptidomimetics and macrocyclic Phe-(Phe)n peptides have been synthesized by either intra- or intermolecular peptide bond formation of the corresponding bis(amino acid) derivatives. The key bis(amino acid) derivatives were available from an improved multi-step synthetic route, utilising Horner-Wadswort-Emmons olefination of organometallic aldehydes with phosphonylglycine reagents, enantioselective hydrogenation of didehydro amino acids and classical solution and/or solid phase peptide synthesis methodology. The stereochemically well characterised Phe-AAn-Phe peptidomimetics were incorporated in small neurotransmitter peptides, substance P and Leu(5)-enkephalin, with the goal to test whether the effect of the incorporation mimic the bioactive conformations. Conformational analysis of the peptide analogues was undertaken with computational energy minimisation, CD and various NMR-experiments. It revealed that the modification of substance P and Leu(5)-enkephalin induced random coil and b-turn like conformations, respectively. NMR titration and UV-Vis spectroscopic studies of ferrocene or ruthenocene based derivatives of phenylalanine, indicated that in contrast to ruthenocenylamino acids the ferrocenylamino acids were easily air oxidised in aqueous solution at pH?{5-7}. A series of chiral ferrocene based mono- and bis(amino alcohol) derivatives were also synthesized from the mono- and bis(amino acids), respectively. These were further evaluated as catalysts in asymmetric addition of diethylzinc to benzaldehyde. The results revealed that indeed all ferrocene based amino alcohol derivatives worked as catalysts and that the catalytic effect was not positively influenced by the introduction of one extra amino alcohol arm.