Tbso

Scheme 10 Assembly of Maidong saponin C (16). (a) TMSOTf (0.2 equiv). (b) TMSOTf (2.0 equiv); NaOMe, 85% (for two steps).

It is obvious that the present synthetic approach to Maidong saponin C (16) is of no practical use because the final glycosylation is so inefficient. From this example, we sensed the disadvantage in applying strategy 1 to the saponin synthesis, especially when the final glycosylation would involve either an oligosaccharide in the absence of a neighboring group (containing 1^2 linkage) or a steroid with a stereohindered hydroxyl group.

C. Strategy 2: Synthesis of Two Series of Diosgenyl Saponins

Diosgenyl saponins are the most abundant existing steroidal saponins [1,16]. A typical structural pattern of the "glycoforms'' in this family is one with a ¡-d-gluco-pyranoside as the first sugar attched to diosgenin, which in turn has an a-l-rham-nopyranose substituted at 2-OH and another sugar or sugar chain at either the third (series 1) or the fourth (series 2) hydroxyl of the glucopyranose moiety (Scheme 11). Many members of these two series of diosgenyl saponins have been found in a number of traditional Chinese herbs, such as those in species of Paris, Ophiopagon, Dioscorea, and Allium. Some members, which have been isolated in sufficient amounts to permit investigators to conduct bioactivity evaluations, have demonstrated various interesting antitumor, cardiovascular, and antifungal activities.

According to strategy 2, the glucopyranose residue is coupled to diosgenin first. At this stage, a large array of glucopyranosyl donors and the glycosylation conditions are readily screened. Some results are listed in Scheme 12. The glycosylation of a steroid was known to be a rather special glycosylation reaction [17]. Two side reactions—namely, acetyl group transfer and orthoester formation—took place easily and under some conditions dominated. It was found that acyl group transfer could be avoided completely by substituting a benzoyl group for the acetyl group as neighboring group; orthoester formation depended on the promoter used. Finally, we disclosed that the combined use of benzoyl-protected trichloroacetimidate as donor and TMSOTf as promoter produced the normal glycoside quantitatively (entry 6 of Scheme 12). Moreover, this reaction was conveniently conducted at a 40 g scale without any loss in yield [18].

Diosgenyl disaccharides 44 and 45 with only 3'-OH and 4'-OH free, respectively, were two key intermediates in the synthesis of the two series of diosgenyl saponins. Their preparations are shown in Scheme 13. Coupling of the benzoyl-protected glucopyranosyl imidate 34 with diosgenin, followed by removal of the benzoyl protection, afforded the diosgenyl ¡-d-glucopyranoside (trillin, 37) quantitatively and on a large scale. Attempts to regioselectively glycosylate diol (38) with rhamnopyranosyl imidate 41 were not successful. Therefore, a bulky protecting group o

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