The first synthetic approach to the core structure of cardiac glycoside oleandrin exhibiting a potent cytotoxic activity, starting from a common androstane derivative, has been accomplished. The synthesis is focused on stereoselective transformations in the densely substituted and sterically shielded five-membered ring (steroid ring D). The developed synthesis paves a route to the synthesis of related bufadienolides, i.e., constituents of traditional drug Ch'an Su, bufotalin, and cinobufagin.