Synthesis of Saponins with Cholestanol, Cholesterol, and Friedelanol as Aglycones

Abstract

Procedures for the synthesis of branched Xylβ(1→3)[Galβ(1→2)]‐Glc and Xylβ(1→3)[Galβ(1→2)]‐GlcUA trisaccharides β‐linked to the 3‐O of cholesterol, cholestanol, and friedelanol, respectively, were developed. To this end, β‐selective glucosylation of cholesterol with glucosyl donors giving selective access to 2‐O, 3‐O, and 6‐O was studied. This way intermediates 10 and 21 having 2‐O‐acyl, 3‐O‐benzyl and 4,6‐O‐benzylidene or also benzyl protection were obtained. Removal of the 2‐O‐acyl group and then galactosylation afforded β(1→2)‐linked disaccharide intermediates 14 and 23. Standard manipulations with the O‐benzylidene and/or O‐benzyl protecting groups gave selective access to the 3‐O of the glucosyl residue, thus affording with a xylosyl donor the trisaccharide β‐linked to the cholesteryl residue (compound 18) as decisive intermediate. Also an alternative procedure to this compound via attachement of a Xylβ(1→3)Glc residue to cholesterol and then galactosylation could be developed. Total deprotection of 18 or regioselective introduction of a sulfate group and of a dodecylcarbamoyl residue at 6a‐O furnished saponins 34, 36, and 38, respectively. Hydrogenation of cholesteryl disaccharide 23 led directly to a 3a‐O‐unprotected cholestanyl disaccharide 39. β‐Selective xylosylation and transformation of the liberated glucose hydroxymethyl group into a carboxylic group afforded target molecule 1b having the desired Xyl(1→3)[Gal(1→2)]‐GlcUA β‐linked to cholestanol. Similarly, a saponin analog was obtained having an α‐linked L‐rhamnosyl residue instead of the β‐linked D‐xylosyl residue. Application of the glycosylation sequence, as worked out for cholesterol, to friedelanol led to attachment of the Xylβ(1→3)[Galβ(1→2)]‐Glc residue to the 3‐O (compound 54). Complete O‐deacylation led to saponin 55; oxidation of the hydroxymethyl group of the glucose residue to the carboxylic group and then deprotection afforded target molecule 2 containing the same trisaccharide residue as 1b. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Synthesis of Saponins with Allobetulin and Glycyrrhetic Acid as Aglycones

“…The 2a-O-galactosylation could therefore be carried out immediately, and the desired trisaccharide 8 was obtained in practically quantitative yield with galactosyl donor 7 [33] under IP conditions, even though access to the 2a-OH group would be anticipated to be sterically hindered. The 1 H NMR spectroscopic data for 8 and also for the next compound indicate the presence of a 1 C 4 h 4 C 1 conformational equilibration of the xylopyranosyl residue, as was also observed previously; [25] however, the 13 C NMR spectroscopic data clearly indicate the generation of the β-anomer. For the transformation of the glucosyl residue into a glucuronic acid residue, the 4a,6a-Obenzylidene group was removed with ethyl mercaptan as nucleophile in the presence of p-toluenesulfonic acid (TsOH) as catalyst; [34] subsequent oxidation of the 4a,6a-O-unprotected intermediate with tetramethylpiperidine Noxide (TEMPO)/sodium hypochlorite (NaOCl) [35,36] resulted in clean oxidation of the primary hydroxy group to furnish the uronic acid derivative 9, which could be structurally fully assigned.…”

“…For the 3-O-glycosylation of the aglycones, a linear strategy (i.e., construction of the trisaccharide moiety at the aglycon) was chosen because a convergent strategy (i.e., glycosylation of the aglycon with a preprepared trisaccharide donor [23,26] ) lacking anchimeric assistance in the glycosylation step did not provide satisfactory anomeric selectivities. [23,27] Through this approach, with the help of anchimeric assistance, [25] good glycosylation results were expected. Success in this endeavour should also greatly facilitate the total synthesis of QS 21 and analogues.…”

“…[24] Therefore, for the glucosylation of methyl glycyrrhetinate, glucosyl donor 10 [23,25] In conclusion, the construction of branched trisaccharides of allobetulin and glycyrrhetic acid, containing β-linked glucopyranosyl or glucuronopyranosyl, galactopyranosyl, and xylopyranosyl residues, could be successfully accomplished in a stepwise fashion. The glucuronate derivatives were readily obtained by chemoselective oxidation of the glucose hydroxymethyl group.…”

“…[22] Hence, QS L1 should use a different mechanism from QS 21 for immune stimulation, and so the synthesis of QS L1 analogues containing the Xylβ (1)(2)(3)[Galβ(1-2)]-GlcUA trisaccharide moiety attached to structurally closely related aglycones -thus avoiding the use of the not readily accessible quillaic acid -became of interest. [23][24][25] In this paper, allobetulin and glycyrrhetic acid have been selected as structurally related triterpene aglycones, thus giving compounds 1 and 2a as target compounds (Figure 2); for comparison studies compound 2b was also prepared. For the 3-O-glycosylation of the aglycones, a linear strategy (i.e., construction of the trisaccharide moiety at the aglycon) was chosen because a convergent strategy (i.e., glycosylation of the aglycon with a preprepared trisaccharide donor [23,26] ) lacking anchimeric assistance in the glycosylation step did not provide satisfactory anomeric selectivities.…”

Synthesis of a carborane-containing cholesterol derivative and evaluation as a potential dual agent for MRI/BNCT applications

“…As reported in Scheme 2, the benzylic protecting group was selectively removed by Pd/C catalyzed hydrogenation. 24 Different catalyst concentrations and solvents were tested in order to avoid the concomitant hydrogenation of the cholesterol double bond. It was found that 5% of Pd/C in EtOH/CH 2 Cl 2 2/1 provide the best conditions, affording after 24 h the desired product 5 in 92% overall yield.…”