Total Synthesis and Biological Evaluation of 19-Hydroxysarmentogenin-3-O-α-l-rhamnoside, Trewianin, and Their Aglycons

Abstract

Cardenolides comprise an important family of natural steroids with a wide spectrum of biological activities. Although 19-hydroxysarmentogenin-3-O-α-L-rhamnoside (1a) and trewianin (1b) were structurally determined to have cardenolide structures, their biological activities have not been evaluated. The 6/6/ 6/5-membered ABCD-ring systems of both 1a and 1b are decorated by a β-oriented C17-butenolide, three C11,14,19-hydroxy groups, and a C3−O-L-rhamnoside moiety. On the other hand, 1a and 1b are epimeric at the C5-position. The structures of 1a and 1b were assembled from four simple fragments by applying a convergent and unified strategy. The AB-ring 10a/b and the D-ring 8/9 were tentatively tethered at the acetal moiety, and a subsequent stereoselective 6-exo radical reaction linked the two fragments. Next, an aldol reaction enabled simultaneous introduction of three new stereocenters of the C-rings of 5aa and 54. Attachment of the C17-butenolide led to aglycons 2a and 2b. L-Rhamnose was then installed into 2a and 2b to yield the targets 1a and 1b, respectively. Finally, the growth inhibitory activity of 1a, 1b, 2a, and 2b was assessed against MCF-7 human breast carcinoma cells. The significantly higher activities of 1a and 1b in comparison to 2a and 2b demonstrated the biological importance of the monosaccharide substructure.

Biological and Pharmacological Effects of Synthetic Saponins

“…The roles of carbohydrate in the bioactivity of saponin has been discussed extensively in cytotoxicity assays and can significantly influence the activity. In assays against cancer cells, the existence of carbohydrates showed both positive [58,71,107,108] and negative [37,55,[98][99][100][101] effects. Changing the composition of sugar chains could enhance the cytotoxic effect [14,29,67,70] but also showed no differences in some studies [13,34].…”

“…Total syntheses of sarmentogenin, trewianin, ouabagenin and other cardenolides have also been reported. Inoue and co-workers synthesized the sapogenin moiety of sarmentogenin and trewianin, as well as their glycosylated derivatives, revealing the important role of 3-O-glycosylation for cytotoxicity against MCF-7 cells [71]. Nagorny used a Cu (II)-catalyzed diastereoselective Michael/aldol cascade approach to synthesize cardiac glycosides incorporating carbon atoms in various states of oxidation.…”

Recent Progress in Steroid Synthesis Triggered by the Emergence of New Catalytic Methods

“…Despite these numerous studies, the synthesis of highly oxygenated cardenolides, such as ouabagenin, represents a significant challenge, and only recent advances in catalysis and synthetic methodology allowed to overcome some of these challenges. Such landmark efforts include the recently disclosed syntheses of ouabagenin and 19‐hydroxysarmentogenin by the Deslongchamps, Baran, and Inoue groups as well as the studies by the Nagorny group that will be the focus of this mini‐review…”

“…142 , R 1 =H), led to the formation of nor‐steroid skeleton 130H in good yield and selectivity (85 %, 8:1 dr, 93 % ee, gram scale). [51c] The tentative mechanism of this transformation is depicted in Scheme C. Unlike the majority of other Cu(II)Box‐catalyzed reactions, 129 is proposed to bind and activate nucleophile 131 rather than enone electrophile.…”

“…More advanced intermediate 147 contains oxygenations at the C3, C11, C14, C17, and C19 positions as well as the unsaturation at the C‐5 position, which is critical for its rapid elaboration to various highly oxygenated cardenolide ouabagenin (Scheme ). [51a] The presence of the additional C1/C5 oxygenation in ouabagenin makes this important natural product to be one of the most complex targets among the cardiotonic steroids. The synthetic studies towards ouabagenin commenced with the reduction of the Δ 7 ‐olefin of 147 with LiDBB, followed by a basic work‐up with NaHCO 3 to provide 148 .…”