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 enantiomerically pure amino acids 1 (a Phe, b Leu, c Met, d Ser) are reacted with
1,1-diethylpropargylamine to yield alkynyl amino acids 2. After reaction with (p-iodoanilido)ferrocene carboxylic
acid 3 in the presence of 5 mol % PdCl2(PPh3)2/CuI ferrocene amino acids 4 are obtained in ca. 80% yield. The
reaction does not require anhydrous conditions and tolerates functional groups such as amides, alcohols (Ser, 4d)
or thioethers (Met, 4c). A complete characterization by multinuclear NMR (including 15N) is carried out. Cyclic
voltammetry shows a reversible wave at about +190 mV (vs Fc/Fc+) independent 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 determination. A comparison of IR data in
solution and the solid state suggests that hydrogen bonding is also important for the solid-state structures of
ferrocene amino acids 4 but does not play a role in solution. The use of this methodology 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 ferrocene. The alkyne anchoring group in the tripeptide is introduced at the Cγ(Glu) atom at an
early stage of the peptide synthesis and is not affected by subsequent deprotection and coupling reactions.