Aldimines of Cardenolides and Cardenolide-Glycosides

Abstract

New aldimines were synthesized from the cardenolide strophantidin and cardenolide-glycosides erysimin and cymarin and included morpholine, nitrile, pyridine, furan, hydroxy-and methoxyphenyl, piperidine, and other derivatives. An effective modified method for synthesizing aldimines was proposed. 52 new compounds were synthesized. Their structures were confirmed by IR and PMR spectra and elemental analysis.We previously reported [1, 2] the synthesis of eight aldimines of strophantidin, some of which were slightly toxic cardiotonics, for example, adamantyliminostrophantidin [2].Therefore, it seemed advisable to continue research on the preparation of a broader set of new compounds with subsequent pharmacological screening. For this, we used amines of various structures.The starting natural compounds were the cardenolide strophantidin and the cardenolide-glycosides erysimin and cymarin, which have angular aldehydes [3]. These were synthesized by two methods. Organic compounds containing a free primary amine were reacted directly with the natural aldehydes by boiling in appropriate solvents and removing the water formed during the reaction by azeotropic distillation. It was found that the imines formed most rapidly and completely at the highest possible concentrations of the reactants, when the reaction mixture was like a melt. From the time such a state was reached, the reaction was finished usually within an hour.The second method was necessitated by the fact that primary amines are commonly sold as salts, more often as hydrochlorides. In these instances, the reaction was carried out in boiling solutions with sodium acetate.For both methods the course of the reactions was monitored by TLC or paper chromatography. The yields of the desired products were 60-80% of those calculated. The structures of products 1-52 were confirmed by elemental analysis and IR and PMR spectra. The IR spectra typically lacked absorption bands for aldehyde and contained absorption bands for C=N groups (1650 cm -1 ).During the synthesis of the cardenolide aldoximes we observed the rare case where two types of isomers, conformational (conformers) and geometrical (cis-trans or syn-anti), were formed simultaneously. The conformational isomers formed because free rotation around the C10-C19 single bond is restricted for steric reasons. We have previously reported this during the synthesis of cardenolide oximes [4] and demonstrated that the most stable of the two possible conformers is that in which the H atom of C19-H is oriented toward the angular methyl of the 18-CH 3 . This is completely consistent with the cardenolide aldimines and is confirmed by the following data. Strophantidin aldimines form complexes (green colored) with Cu ions that are soluble in organic solvents. The unshared pair of the N atom and the C3 and C5 OH groups (5) are involved in the complexation. The PMR spectra of the aldimines have signals for the angular 18-CH 3 methyl near 0.66-0.74 ppm, i.e., shifted to strong field. This is due to steric shielding of this group ...

New azomethine cardenolide glycosides

“…These data agree with the literature [3] relative to the stereochemistry of aldimines of cardenolides. Figure 1 shows the PMR spectrum.…”

“…We believe as before [3] that this is the trans-isomer. This is consistent with the PMR spectra and the ability of the obtained azomethines to form complexes with Cu ions.…”

Drug design of medicinal products on the basis of natural cardiosteroids

“…Previous studies of transformed cardiosteroids have shown that aldimines of cardenolides have been shown to be low-toxic cardiotonics (e.g., adamantyliminostrophantidin) [3]. In this regard, it seemed advisable to continue these studies, having received a wider set of new substances with subsequent pharmacological screening and the detection of the most promising in practical terms, physiologically active derivatives.…”

“…In the synthesis of aldimines of cardenolides, we had that comparatively exceptional case when two types of isomerismconformational (conformers) and geomet-ric (cis-trance or syn-anti (Fig. 1)) took place simultaneously [3].…”

“…In addition, it was necessary to study the specific physicochemical properties of bis-ketoimines of C3cardenolides, which consist in their resistance to hydrolysis [3,4].…”