Influence of 2′-Fluoro versus 2′‑O‑Methyl Substituent on the Sugar Puckering of 4′‑C‑Aminomethyluridine

Herein, we report the synthesis of 4′-C-aminomethyl-2′-deoxy-2′-fluorouridine, a therapeutically appealing RNA modification. Conformational analysis by DFT calculations and molecular dynamics simulations using trinucleotide model systems revealed that modified sugar adopts C3′-endo conformation. In this conformer, a weak intramolecular C–H···F H-bond between the hydrogen atom of the 4′-C-CH2 group and the F atom at the 2′ position is observed. Comparative studies with unmodified, 2′-fluoro-, 2′-O-methyl-, and 4′-C-aminomethyl-2′-O-methyluridine showed the chemical nature of 2′-substituent dictates the sugar puckering of 2′,4′-modified nucleotides.