Three pairs of Securinega alkaloid epimers with a piperidin-2-yl moiety (1-6) were isolated from Flueggea suffruticosa, and their structures including absolute configurations were definitely characterized. An interconvertible C-2′ epimerization process within each pair of epimers was observed. The following comprehensive experimental and theoretical investigations demonstrated an unusual stereochemical inversion mechanism of an N-substituted carbon stereogenic center, which was evidenced to be a protic solvent mediated process involving a tandem 1,4-elimination/1,4-addition as the key step. Copyright © 2020 American Chemical Society.