A Two-Step Palladium-Catalyzed Coupling Scheme for the Synthesis of Ferrocene-Labeled Amino Acids

Abstract

This work describes a Pd-catalyzed coupling of ferrocene alkyne derivatives to iodo amino acids. Ferrocene carboxylic acid propargyl amides were easily obtained in high yield. The crystal structures of the propargyl amine derivative 3 and the 1,1-diethylpropargylamine derivative 4 have been determined by X-ray diffraction. Pd-catalyzed coupling to p-iodoanilide amino acids gave the corresponding ferrocene-labeled amino acid derivatives, which were easily purified by diethyl ether extraction in the case of the 1,1-diethyl derivatives 8. The coupling reaction did not require anhydrous solvents and tolerated a variety of functional groups present in peptides such as alcohols (8a, Ser), thioethers (8d, Met), disulfide bonds (cystine, 12) esters (as in the N-labeled Leu derivative 10) and of course amides. A minor by-product of the coupling reaction, namely the homo-dimer bis(ferrocene carboxylic acid propargylamide) 9, was identified in the crude reaction mixtures by mass spectrometry and independently synthesized by oxidative coupling (Glaser and Eglington) of 3. All new compounds were completely characterized spectroscopically, including 15N- and 2D NMR spectroscopy, Mössbauer spectroscopy and electrochemistry. This work introduces a versatile procedure for a selective functionalization of amino acids with organometallics at the C-terminus which is expected to be of general applicability to peptide chemistry.