The total synthesis of ouabain was achieved in 2008 by Deslongchamps laboratory in Canada. It was synthesized under the hypothesis that a polyanionic cyclization (double Michael addition followed by aldol condensation) would allow access to a tetracyclic intermediate with the desired functionality. The figure below shows the key steps in the synthesis of ouabain.
In their synthesis, Zhang et al. from the Deslongchamps laboratory condensed cyclohexenone A with Nazarov substitute B in a double Michael addition to produce tricycle C. At the indicated position, C was reduced to the aldehyde and the alcohol group was protected with p-methoxybenzyl ether (PMB) to form the aldol precursor needed to produce D. After several steps, intermediate E was produced. E contained all the required functionalities and stereochemistry needed to produce ouabain. The structure of E was confirmed by comparison against the degradation product of ouabain. Methylation of E, catalyzed by rhodium, produced F. The dehydroxylation and selective oxidation of the secondary hydroxy group of F produced G. G reacted with triphenyl phosphoranylidene ketene and the ester bonds in G were hydrolyzed to produce ouabagenin, a precursor to ouabain. The glycosylation of ouabagenin with rhamnose produced ouabain.