| Furostan saponins, usually regarded as the synthetic precursors of the corresponding spirostan saponins in plants, have recently been paid emphasis attention due to the increased understanding of their broad range of biological and pharmacological activities. However, there is few report about their synthesis until very recently because of their complexity, instability and non-clear functional mechanism.Methyl protodioscin 1, is a member of furostan saponin family with the chemical name: 3-(9-[a-Z-rhamnopyranosyl-(1→2)-{a-Z,-rhamnopyranosyl -(1→4)}-β-Z)-glucopyranosyl] -26-O-[β-Z)-glucopyranosyl]-22-methoxy-25(R)-furost-5-ene-3→,26-diol. This molecule was first isolated and identified by Kawasaki and co-worker in 1974 from fresh rhizomes of Dioscorea gracillima MiQ. In continuing efforts to identify active components from traditional Chinese herbal medicine, professor Yao and co-worker also obtained this compound from the rhizome of Dioscoreaceae by repeated bioactivity-guided isolation and tested its anticancer activities in vitro with a panel of 60 human cancer cell lines performed in NCI. Among the fourteen steroidal saponins tested, 6 compounds gave good activities in vitro and methyl protodioscin showed the most potent activity. In order to get a sufficient amount of the compound for further biological investigations, we therefore initiated a program to synthesize this target molecule.Retro synthetically, methyl protodioscin can be logically disconnected into three distinct fragments: aglycone, C26-glucopyranose and Cs-trisaccharide moiety. Based on the analysis of its structural character, two routes were designed and systemically studied to synthesize the aglycone moiety. Finally, we chose route 2 for our purpose and the title compound was readily obtained in an overall yield of 49% via three steps by using diosgenin as the starting material: that is, protecting the Ca- hydroxyl group in diosgenin with TBDPSC1, then selectively oxidizing with DMDO at both the double bond and spiroketal, and then without further purification, directly undergoing reductive cleavage and acetolysis in one step in very mild condition. Therefore, this short and simple route was an ideal method to synthesize aglycone.Structurally, the constitution of the trisaccharide is quite unique, the sequential linkage of a-L-rhamnopyranosyl-(1→)-a-i-rhamnopyranosyl-(1→4)-bata-D-glucopyranoside led us to design three routes to synthesize it. All these three routes were studied and the title compound was obtained by methods in route 3. Compared to route 1 and 2, route 3 possessed advantages of reasonable design, short steps and simply operation because it skillfully utilized the different activity of the hydroxyl groups in glucose and the characteristic of the relatively large stereo barrier of pivaloyl chloride.Afterwards, we successfully connected glucopyranosyl trichloroacetimidate to the C26-hydroxyl of the aglycone in the present of TMSOTf and coupled trisaccharide moiety to the C3-hydroxyl with TV-iodosuccinimide (NIS) and a catalytic amount of trifluoromethanesulfonic acid (TfOH). Selective reduction the 16-ketone of the resulting cholestan-16, 22-dioxo with NaBHU in i-PrOH was achieved, and the newly generated secondary alcohol concurrently cyclized to give the hemiketal compound. The final target furostan saponin 1 was eventually obtained by deprotection of benzoyl and pivaloyl groups, and in situ methoxylation at C22 position using NaOMe in MeOH solution.Thus, a simple method to methyl protodioscin was established after two years effort, which starting from commercially available diosgenin through mainly 9 steps in an overall yield of 7.8%. All the intermediates were identified correctly by 'H-NMR, 13C-NMR and ESI-MS and the solid-state materials were also measured melting point and optical rotation. The analytical data for the synthesized methyl protodioscin were identical in all respects to those reported for the natural material such as IR, 'H-NMR, 13C-NMR, DEPT, ESI-MS, mp and optical rotation.In conclu...
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