Biomimetic Total Synthesis of (+)-Ranuncoside, a Unique Tricyclic Spiroacetal Glycoside of Christmas Rose (Helleborus niger L.)

Abstract

Christmas Rose (Helleborus niger L.) is an alpine plant belonging to the Ranunculaceae family. Typical for this popular ornamental plant are white flowers that appear during winter. Root extracts contain numerous medicinally active ingredients and potent cardiac glycosides. Recent findings indicate that Helleborus root extracts possess the potential for cancer treatment and inhibit the proliferation of tumor cells. In 2022, we published a practical extraction method of (+)-ranucoside 1 from the dried leaves of H niger L. Here, we describe for the first time the total synthesis of 1. Starting from 5-hydroxylevulinic acid methyl ester 8 and acetobromo-α-D-glucose 13, the β-glycoside 14 is formed stereoselectively on the application of Koenigs-Knorr conditions. Subsequent cleavage of the acetyl-protecting groups and saponification of the ester function yields the pyrano dioxane derivative 17. Its lactonization gives (+)-ranuncoside 1. The presented synthesis is practical and very efficient, consisting of 6 steps from D-glucose and giving 22% overall yield. Furthermore, it is biomimetic due to its concordance with the biosynthesis of (+)-ranuncoside 1 in H foetidus.