Strategy 1 Synthesis of OSW1

Saponin OSW-1 (1) is the major component of a small group of cholestane saponins isolated by Sashida et al. from the bulbs of Ornithogalum saudersia. This molecule, while showing little toxicity to normal cells in vitro, exhibited remarkable activities against a broad spectrum of malignant tumor cells, with IC50 between 0.1 and 0.7 nM, which is about 10-100 times more potent than such clinical anticancer agents as mitomycin C, adriamycin, cisplatin, camptothecin, and taxol [9].

According to strategy 1, OSW-1 (1) was broken down into steroid 2 and di-sasccharide donor 3 (Scheme 3). Glycosyl trichloroacetimidate with a neighboring participation group (3) is believed to be one of the most reliable donors [8b]. Since

Dehydroisoandrosterone Scheme 3 Retrosynthesis of OSW-1 (1).

either acidic or basic conditions might cause migration or cleavage of the acetyl (Ac) and 4-methoxybenzoyl (MBz) groups and the degradation of the whole molecule of OSW-1, protecting groups [ferf-butyldimethylsilyl (TBS) and triethylsilyl (TES) for hydroxyls and ethylene glycol ketal for the keto] were selected to allow complete removal under neutral or near neutral conditions.

Steroid 2 was prepared from dehydroisoandrosterone in a total of 12 steps and 10% yield (Scheme 4) [10]. The stereochemistries involved in the transformations were completely controlled by the steroid substrates themselves (4 ^ 5, 5 ^ 6, 8 ^ 9, 9 ^ 2). The 3-OH was first protected by a ferf-butyldiphenylsilyl (TBDPS) group because the TBS protection was found to be susceptible in the ene reaction (4 ^ 5). Then, because it was found in a model reaction that the conditions for removal of the 3-OTBDPS group resulted in considerable migration and cleavage of the Ac and MBz groups in the sugar moiety of the target molecule (1), the 3-OTBDPS was transferred into TBS protection (7 ^ 8).

The disaccharide donor 3 was prepared as shown in Scheme 5. Coupling of the arabinopyranoside diol 11 with xylopyranosyl imidate donor 10 gave 12, the 3-OH (equatorial hydroxyl) glycosylated product preferentially, in 70% yield. Since

Methyl Imidate

Scheme 4 Preparation of the aglycone of OSW-1 (2). (a) Ph3PEtBr, tert-BuOK, 78%; TBDPSCl, 100%. (b) (CH2O)„, BF3OEt2, 75%. (c) Dess-Martin periodinane, 86%; 3-methyl-butylmagnesium bromide, 96%. (d) PDC, 83%; HOCH2CH2OH, 96%. (e) TBAF, 95%; TBSCl, 96%. (f) OSO4, 41%. (g) ClCOCOCl, DMSO, 78%; NaBH4, CeCl3, 93%.

Benzyl Penicillin

Scheme 5 Preparation of the disaccharide donor 3. (a) BF3OEt2. (b) TESOTf, 70% (two steps). (c) H2, Pd/C, 50%. (d) CCl3CN, DBU, 65%.

anomeric benzyl group was very difficult to remove (13 ^ 14), forcing conditions (50 atm H2, Pd/C, 50°C, 3 days, 50%) were used.

Glycosylation of steroid 2 with disaccharide imidate donor 3 under the promotion of trimethylsilyl trifluoromethanesulfonate (TMSOTf) provided the desired glycoside 15 stereospecifically and in good yield (69%). Finally, all the protecting groups (one TBS, three TES, and one ethylene glycol ketal) were removed cleanly in one step by employing Pd(MeCN)2Cl2 as a catalyst to furnish the target OSW-1 (1) (Scheme 6) [11].

When strategy 1 was used, the first total synthesis of OSW-1 (1) was accomplished from dehydroisoandrosterone, l-arabinose, and d-xylose in a total of 27 steps, with the longest linear sequence being 14 steps, and in 6% yield [11]. The present route, at least after some optimization, would provide a practical entry to various OSW-1 analogs, especially those with the same sugar moiety as OSW-1, which can be readily prepared by coupling disaccharide donor 3 to various steroids.

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