Stereo‐Defined Ferrocenyl Glycol Nucleic Acid (Fc‐GNA) Constituents: Synthesis, Electrochemistry, Mechanism of Formation, and Anticancer Activity Studies.

In this paper, we report the Yb(OTf)3‐mediated etherification reaction that allowed obtaining R,R and S,R isomers of ferrocenyl glycol nucleic acid (Fc‐GNA) nucleosides from their corresponding stereo‐defined (S,R) precursor. The R,R absolute configuration of the chiral carbon atoms in one of the Fc‐nucleoside isomers was assigned by single‐crystal X‐ray diffraction. Density functional theory calculations showed that the stereochemical outcome of the reaction can be explained by an exo attack of ethylene glycol on the pro‐R‐ or pro‐S‐configured α‐ferrocenyl carbenium ion intermediate. The R,R isomer was transformed into the corresponding nucleotide diethyl ester which is, to the best of our knowledge, the first Fc‐GNA nucleotide ever reported. The obtained compounds feature reversible one‐electron oxidation of the ferrocenyl portion of their molecular structures. Anticancer activity studies showed that the (S,R) nucleoside was the most active against HeLa and Ishikawa cancer cells, while it did not show any activity against nontumorigenic L929 cells. The compound induced apoptosis in HeLa cells at IC50=66.0 μM concentration upon 72 h of treatment. [ABSTRACT FROM AUTHOR]