Furosemide Synthesis And Antitumor Activity Of Steroidal Saponins Derivatives

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 little report about their synthesis until very recently because of their complexity, instability and non-clear functional mechanism.We designed and synthesized four derivative compounds of furostan saponins. Retrosynthetically, the four derivatives we designed can be logically disconnected into three distinct fragments: aglycone, C26-monosaccharide and C₃-monosaccharide moiety. Based on the analysis of its structural character, the aglycone moiety was obtained in an overall yield of 49% via three steps by using diosgenin as the starting material: that is, protecting the Ca-OH of diosgenin with TBDPSC1 first, then selectively oxidizing with DMDO at both the double bond and spiroketal, and 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.Afterwards, glucopyranose and rhamnopyranose were introduced to the C26-OH of the aglycone under the action of TMSOTf and the protective group of C₃-OH was cleaved by TBAF. The two intermediates that we obtained were connected with two monosaccharide donors in the same conditions, thus we synthesized four compounds. Selective reduction of the 16-ketone of the resulting cholestan-16, 22-dioxo with NaBH4 in i-PrOH was achieved, then the newlygenerated secondary alcohol concurrently cyclized to give the hemiketal compound. The four derivative compounds of furostan saponins were eventually obtained by deprotection of benzoyl groups, and in situ methoxylation at C22 position using NaOMe in MeOH solution.At the same time, we designed and synthesized two 1?6 linked disaccharide thioglycoside donors. 6-OH of phenylthioglucopyranoside was linked with glucopyranose and rhamnopyranose. We designed three routes to synthesize them. All these three routes were studied and the target molecules were obtained by methods in route 3. Both of the two disaccharide donors can react with the aglycone and it is not necessary to change them to other reactive donors. 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.All the important 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.