Efficient Isolation and Structure Analysis of (+)-Ranuncoside, a Unique Tricyclic Spiroacetal Glycoside, from Christmas Rose (Helleborus niger L.)

Abstract

The use of medicinal herbs as remedies reaches back to the Stone Age, and their importance as a source of drugs has continuously increased since then. Herbal ingredients can serve as active pharmaceuticals themselves or as lead substances for the development of synthetic pharmaceuticals with less toxicity, higher effectiveness or with new properties. To date, only 6% of the ∼600,000 plants on earth have been tested pharmacologically. Among these, the medicinal plant Helleborus niger L. (Christmas rose) is especially promising because its leaves contain ( + )-ranuncoside 1, characterized by a spiroacetal ring system, a motif which is responsible for the biological activity of a multitude of natural products. Structure-activity relationship studies of ( + )-ranuncoside 1 are lacking and no synthesis of 1 has been described yet. Therefore, we developed a protocol for the rapid and efficient isolation of 1 from the leaves of cultivated Christmas rose. Crystals of high purity were obtained that enabled us to study the stereochemistry of 1 by NMR spectroscopy in solution for the first time. The spiro configuration, the absolute stereochemistry, and the geometry of all three rings was then confirmed by x-ray structure analysis. Our data will enable future structure-activity relationship studies to assess the potential of 1 as a lead substance for the development of novel antibiotics and anticancer agents.

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

“…In all respects, the synthesized product was identical with a sample isolated from H niger L. by Cuny and Klingler. 20 The elaborated synthesis is highly efficient, due to shortness (6 steps starting from D-glucose) and a high overall yield of 22%.…”

“…All physical and spectroscopic data of synthesized 1 were identical with a sample isolated from H niger L. by Cuny and Klingler. 20…”

“…[12][13][14] Recently, we published a practical extraction method of ( + )-ranucoside 1 from the leaves of cultivated H niger L. plants and confirmed the structure by 500 MHz NMR spectroscopy and X-ray structure analysis. 20 Based on the fact that the spiroacetal ring system is responsible for the biological activity of numerous natural products [21][22][23] and stimulated by our developed synthetic routes to motifs of spiroacetal natural products 24 and ranuncoside derivatives, 25 we here describe for the first time the total synthesis of ( + )-ranucoside 1 by biomimetic means.…”

“…The synthesized natural product was identical in all respects to a sample isolated from H niger by Cuny and Klingler. 20…”

“…In 1974, (+)-ranucoside 1 (structure Figure 1) was isolated by Martinek 19 from dried stems, leaves, and flowers of H niger L., which had been collected in the Austrian Alps (South Carinthia). Recently, we 20 published a practical extraction method of (+)-ranucoside 1 from the dried leaves of cultivated H niger L. plants. These are cheap and easily accessible in large quantities from nurseries.…”