Eine Aldolkondensation ist der Schlüsselschritt bei der linearen Synthese von 23‐Oxa‐Analoga des Antitumorwirkstoffs OSW‐1. Ausgehend von dem industriell hergestellten Steroid 1 wird 2 in acht Stufen mit über 20 % Gesamtausbeute erhalten. Die Verbindung 2 inhibiert das Wachstum von Tumorzellen bis zu 2000‐mal wirksamer als Cisplatin.

5,6-Dihydro-OSW-l (1) was synthesized following our previous procedure for the total synthesis of OSW-1. This compound demonstrated slightly stronger potency than that of OSW-1 against the growth of cancer cells. Keywords5.6-dihydro-OSW-1, analog, synthesis, anti-tumor lntroduct ionA group of cholestane saponins featuring a novel 3,!3,16~,17a-trihydroxycholest-5-en-22-one aglycone with a sugar residue at the 16-OH has been disclosed by Sashida, Mimaki and coworkers, from the bulbs of Ornithogalum saudersiae and taxonomically related plants.'-' Those saponins have attracted great attention due to their potent anti-tumor a~tivities.~" OSW-1, the major and representative member, was tested against the NCI (the US. National Cancer Institute) 60 cell lines, showing 10-100 times more intense potency than those of the clinically applied anticancer agents, e.g., cisplatin, as positive controls.2 Requirement of the 16-0-disccharide moiety of OSW-1 for its significant cytotoxic activity was clearly concluded, and those with mdfication on the sugar residue showed much weaker a~tivities.~.~.' Inversion of the C-16 configuration, where the disaccharide is attached, was also not allowed to retain the significant cytotoxic activity of OSW-l.'j However, substitution with a glucose on the 3-OH, a site remote to the 16-O-disaccharide, did not affect apparently the cytotoxic activity.2 Thus, we anticipated that saturation of the 5,6-double bond, a position distant from the disaccharide residue, would not alter significantly the cytotoxicity of OSW-1, and the resulting 5,6-dihydro-OSW-l (1) would be a more convenient target than OSW-1 for chemical synthesis. Here we report the synthesis of 1 and the test of its anti-tumor activity.Although 5,6-dihydro-OSW-1 (1) could be prepared by direct hydrogenolysis of OSW-1, the synthesis was carried out employing a similar route as that we developed previously for the synthesis of OSW-1 to examine whether the yields of some steps could be improvedwith substrates in the absence of the 5,6-double bond' (Scheme 1). Thus, hydrogenolysis of 3p-hydroxyandrost-5-en-17-one 2 under forced conditions i(2.0 X lo6 Pa of H2, 10% PdC, 50 "2, 24 h) afforded 3 in good yield (80%).* Wittig olefination of ketone 3 gave diene 4 stereo~electively,~ which was subjected to TBDPS (tert-butyldiphenylsilyl) protection to provide the 3-0-TBDPS ether 5.'' Ene reaction of 5 with paraformaldehyde in the presence of catalytic BF3-OEt2 generated the desired homoallylic alcohol 6 stereoselectively. Oxidation of alcohol 6 with Dess-Martin periodinane provided aldehyde 7. Grignard addition of aldehyde 7 with 3-methylbutylmagnesium bromide led to the 22a-01 8, which was oxidized with PDC (pyridium dichromate) to afford C-22-keto 9. Then, the C-22 car--bony1 of 9 was masked as an ethylene glycol ketal under mild conditions (catalytic TsOH, HC(OEt)i3, r.t.), providing 10 slowly (6 d). After transformation of the 3-0-TBDPS ether into the 3-0-TBS ether (two steps), the resulting 16(17)-ene 11 was subjected to Os04 (1.2 equiv.) to f...

Six T-O-, 3'-O-glycosylated diosgenyl p-D-glucopyranosides (4-9), which have a typical structural pattern of diosgenyl saponins, were synthesized; their synthetic routes are discussed.