Calotropin and related cardiac glycosides isolated from plants such as calotropis gigantea represent an interesting target for biological investigations and are based on a cardiac steroid that is doubly connected to a sugar moiety. This naturally occurring family of cardiac glycosides was not only reported to have similar cardiac properties as the drugs digitoxin and digoxin, but also show cytotoxic activity against several cancer cell lines. Herein, the first synthetic access to these molecules is reported highlighting the required transformations of the A-ring of the steroid when starting from commercially available and inexpensive 3-epiandrosterone. Our strategy is based on a regioselective C–H oxidation of the methyl group at C-17 delivering the 2α,3β-trans-diol moiety at the same time and ensuring its connection to the sugar unit.