Synthesis of alkynyl amino acids and peptides and their palladium-catalyzed coupling to ferrocene

A method for attaching organometallics to the C-terminus of amino acids via a Pd-catalyzed two-step procedure is presented. Boc-protected enantiomeric ally pure amino acids 1 (a Phe, b Leu, c Met, d Ser) are reacted with 1,1-d iethylpropargylamine to yield alkynyl amino acids 2. After reaction with (p -iodoanilido)ferrocene carboxylic acid 3 in the presence of 5 mol % PdCl2(P Ph3)(2)/CuI ferrocene amino acids 4 are obtained in ca. 80% yield. The reac tion does not require anhydrous conditions and tolerates functional groups such as amides, alcohols (Ser, 4d) or thioethers (Met, 4c). A complete char acterization by multinuclear NMR (including N-15) is carried out. Cyclic vo ltammetry shows a reversible wave at about +190 mV (vs Fc/Fc(+)) independen t of the nature of the attached amino acid. In the solid state, 2a forms a left-handed helix along the crystallographic c axis which is stabilized by hydrogen bonds as revealed by a single-crystal X-ray structure determinatio n. A comparison of IR data in solution and the solid slate suggests that hy drogen bonding is also important for the solid-state structures of ferrocen e amino acids 4 but does not play a role in solution. The use of this metho dology for peptide chemistry is demonstrated by labeling the dipeptide Boc- Met-Phe-OH at the C-terminus and the tripeptide Boc-Phe-Glu-Leu-OMe with fe rrocene. The alkyne anchoring group in the tripeptide is introduced at the Cy(Glu) atom at an early stage of the peptide synthesis and is not affected by subsequent deprotection and coupling reactions.