Ferrocenoyl conjugates of hydroxyl group containing side chain amino acids: Synthesis, electrochemical study and reactivity toward electrophiles

Mono- and disubstituted ferrocenoyl amino acid conjugates having free hydroxyl (OH) group at the amino acid side chain is synthesized, namely Fc-CO-aa-OCH3 (1a, 2a, 3a), and Fc-[CO-aa-OCH3](2) (1b, 2b, 3b), Fc = ferrocene, aa = L-serine (L-Ser, 1), L-tyrosine (L-Tyr, 2), L-threonine (L-Thr, 3). The reactivity of the OH group in 1a toward substitution reaction by acetyl chloride, p-toluene sulfonyl chloride and phosphoric acid is investigated. The resulting compounds are Fc-CO-L-Ser(C(O)-CH3)-OCH3 (1c), Fc-CO-L-Ser(S(O)(2)-C6H4-CH3)-OCH3 (1d) and Fc-CO-L-Ser(P(O)-(OH)(2))-OCH3 (1e). The prepared Fc-amino acid conjugates are fully characterized by standard spectroscopic methods. The cyclic voltammetry of the Fc-compounds show a quasi-reversibility for conjugates 1a-3a (E-1/2 = 0.64 V) and for 1b, 3b (E-1/2 = 0.85 V), while an irreversible behavior for 2b is observed. The compounds 1c and 1d exhibit quasireversibility with E-1/2 = 0.71 V, which is shifted anodically by 100 mV compared to the parent conjugate 1a. Fc-conjugate 1e shows complete irreversibility. The study suggests that profound changes in Fc-redox potential is accessible through varying the substituent at the OH group in the amino acid side chain, either by anodic shift of the Fc signal (acylation and tosylation) or turn the signal off by phosphorylation. (C) 2019 Elsevier B.V. All rights reserved.