A two-step palladium-catalyzed coupling scheme for the synthesis of ferrocene-labeled amino acids

This work describes a Pd-catalyzed coupling of ferrocene alkyne derivatives to iodo amino acids. Ferrocene carboxylic acid propargyl amides were easil y obtained in high yield. The crystal structures of the propargyl amine der ivative 3 and the 1,1-diethylpropargylamine derivative 4 have been determin ed by X-ray diffraction. Pd-catalyzed coupling to p-iodoanilide amino acids gave the corresponding ferrocene-labeled amino acid derivatives, which wer e easily purified by diethyl ether extraction in the case of the 1,1-diethy l derivatives 8. The coupling reaction did not require anhydrous solvents a nd tolerated a variety of functional groups present in peptides such as alc ohols (8a, Ser), thioethers (8b, Met), disulfide bonds (cystine, 12) esters (as in the N-labeled Leu derivative 10) and of course amides. A minor by-p roduct of the coupling reaction, namely the homo-dimer bis(ferrocene carbox ylic acid propargylamide) 9, was identified in the crude reaction mixtures by mass spectrometry and independently synthesized by oxidative coupling (G laser and Eglington) of 3. All new compounds were completely characterized spectroscopically, including N-15- and 2D NMR spectroscopy, Mossbauer spect roscopy and electrochemistry. This work introduces a versatile procedure fo r a selective functionalization of amino acids with organometallics at the C-terminus which is expected to be of general applicability to peptide chem istry.