Total Synthesis of Dammarane-Type Saponins Ginsenoside Re and Notoginsenoside R1

Ginsenoside Re (1) and Notoginsenoside R-1 (2) are two representative dammarane type protopanaxatriol-6,20-O-bisglycosides occurring widely founded in Panaxginseng. Ginsenoside Re (1) showed potent antioxidative, anti-inflammatory and antihy perlipemia activities, and Notoginsenoside R-1 (2) showed potent antioxidative and antiinflammatory activities, so it would be helpful to synthesize these homogeneous natural products in appreciable amounts by accelerating their structure-activity relationship study. As a persistent effort on the chemical syntheses of the diverse ginsenosides in our group, we report herein the efficient syntheses of these two complex natural products. Thus, based on the reactivity sequence of the four hydroxyl groups (i.e., 12-OH> 3-OH>6-OH >> 20-OH) of the protopanaxatriol aglycon, an orthogonal and efficient protecting group strategy was applied to distinguish these hydroxyl groups. The subsequent installation of the 6,20-O-bisglycosides are challenging, given the poor reactivity of the secondary 6-OH and tertiary 20-OH, moreover, with the latter being labile toward acidic conditions. Taking advantage of the neutral conditions of the Au(I)-catalyzed glycosylation reaction (0.3 equiv. Ph3PAuNTf2, 4 angstrom MS, CH2Cl2, r.t.), the glycosylation of the acid-labile 20-hydroxyl group was achieved effectively in a high 84% yield firstly. To be convergent for the syntheses of these two ginsenosides, the 6-O-disorcharide residues were installed in a stepwise manner. For the glycosylation of the 6-OH of protopanaxatriol, a higher loading of the catalyst Ph3PAuNTf2 (0.5 equiv.) was employed in order to increase the glycosylation yield while reduce the orthoester formation, thus, the desired 6 beta-O-glucosides were prepared in satisfactory yields (77%similar to 83%). Both terminal alpha-L-Rha/beta-D-Xyl moieties at the 2' position of 6-O-glc were installed efficiently under 0.2 equiv. Ph-3 PAuNTf2 catalyzing condition (ClCH2CH2Cl, 5 angstrom MS, 40 degrees C) with 86% and 81% yields, respectively. After global deprotection, Ginsenoside Re (1) and Notoginsenoside R-1 (2) were synthesized with the longest 13 linear steps in 5.1% and 4.5% overall yields, respectively.