Synthetic Cardenolides and Related Products. III. Isocardenolides

Abstract

The synthesis of novel cardenolides, closely related to naturally-occurring cardiotonic agents, is described. They were obtained from 17p- [3-furyl]androstanes derived from digitoxigenin, gitoxigenin, digoxigenin, and strophanthidin by hypohalous acid or organic peracid oxidation. The preparation of !3-D-and a-L-glycosidic derivatives is also reported.On a synthttise de nouveaux agents cardiotoniques, isomeres des cardenolides naturels. 11s ont tte obtenus par I'oxidation a l'aide de l'acide hypohaleux ou des peracides organiques de [3-furylI-17!3 androstanes, derives de la digitoxigenine, la digoxigenine, la gitoxigenine et la strophanthidine. Des dtrives B-D-et a-L-glycosidiques sont aussi decrits.Can. J. Chem.,52. 1652(1974) As part of a program aimed to improve the therapeutic ratio of cardiotonic agents, we prepared novel i~ocardenolides,~ which possessed all the characteristics of the natural cardenolides except for the location of the 0x0 group of the 5-membered lactone (3). In addition, 21-hydroxydigitoxigenin was also synthesized.When 17P-[3-furyl]-5p-androstane-3P, 14P-diol 3-acetate (26) was treated with a hypohalo~~s acid in aqueous dioxane, lactones 3a and 4 were isolated. The ma-ior product was 3a when 1 equiv. of the oxidant was used, while a larger excess of the reagent (2 equiv.) afforded mainly lactone 4. The structures were ascertained by spectral analyses (see Experimental). Furthermore, the aldehyde 4 was converted to the acid 5 and to the corresponding saturated lactone-aldehyde 6 by reducing the ene-dione system with zinc and acetic acid. Finally, 30 and 4 were both oxidized with potassium permanganate to the well-known ( 5 ) a-ketolactone 7. This constit~~tes an unanibig~~ous proof of the 17P-stereocheniistry of lactone 3u (Scheme 1).Scheme 2 illustrates a likely mechanism for the formation of 3a and 4. Initially an electrophilic attack of X + of the hypohalous acid on the lesshindered side of the furan ring, concerted with a n~~cleophilic addition of OH-, affords 9. Eliniination of HX, followed by rearrangement of the re-'For Parts I and I1 see refs. l a and b. 'This work was presented in part at the 6th International Symposi~~m on the Chemistry of N a t~~r a l Products, Mexico, April 22, 1969 (20).30ther types of isocardenolides and modified butenolides have been reported in the literature (4). suiting hydroxyfuran 10, yields 3a. In a competitive pathway further oxidation of 9 gives the bromolactone4 11, which is converted into 4 by an internal attack of the 14-hydroxyl on the carboxyl group with concomitant elimination of HX.The fury1 derivatives (2) were in general obtained by diisobutylaluminum hydride reduction of the natural cardenolides (1) (6). A n alternative process for the preparation of 2a was also used. Reduction of digitoxigenin l a with an excess diisobutylalumin~~m hydride afforded the diol 8, which was oxidized to 2a with 1 equiv. triethylamine -sulfur trioxide complex (7) (Scheme I). In this last process the key step involves the formation of an unstable lactol 13, w...

Seeds of Thevetia species as an alternative source of digitoxigenin

“…Digitoxigenin is of importance in that it can serve as a useful point of embarcation for the synthesis of modified cardenolides. 12 This paper describes a method whereby neriifolin and neriifolin monoacetate can be chemically degraded, under mild conditions and in practical yield, to digitoxigenin.…”