An improved method for the synthesis of cardiac glycosides was used to prepare 3.beta.-glucosides [(E)-21-cyano-14.beta.-hydroxy-5.beta.-pregn-20-en-3.beta.-yl .beta.-D-glucoside, (E)-21-(methoxycarbonyl)-14.beta.-hydroxy-5.beta.-pregn-20-en-3.beta.-yl .beta.-D-glucoside, (E)-21-(ethoxycarbonyl)-14.beta.-hydroxy-5.beta.-pregn-20-en-3.beta.-yl .beta.-D-glucoside, (E)-21-(n-propoxycarbonyl)-14.beta.-hydroxy-5.beta.-pregn-20-en-3.beta.-yl .beta.-D-glucoside, (E)-21-(isopropoxycarbonyl)-14.beta.-hydroxy-5.beta.-pregn-20-en-3.beta.-yl .beta.-D-glucoside, (E)-21-(n-butoxycarbonyl)-14.beta.-hydroxy-5.beta.-pregn-20-en-3.beta.-yl .beta.-D-glucoside, (E)-21-(isobutoxycarbonyl)-14.beta.-hydroxy-5.beta.-pregn-20-en-3.beta.-yl .beta.-D-glucoside and (E)-21-(methylcarbonyl)-14.beta.-hydroxy-5.beta.-pregn-20-en-3.beta.-yl .beta.-D-glucoside] of digitoxigenin derivatives in which the 17.beta. side chain was CH.dbd.CHX (X = COOH, CONH2, COCH3, CN or COOR). The inotropic activity of the compounds was compared with that of digitoxigenin glucoside using guinea pig left atria. All compounds were active except for the acid and the amide. The inactivity of the amide, in spite of its favorable shape and high capacity for forming intermolecular H bonds, is incompatible with some previous structure.sbd.activity relationship theories. Of the active genins, glucosidation enhanced activity by a factor of about 2. All glucosides, including those with high potency, showed rapid onset and offset of action. The stepwise fall in potency that occurred when the ester group (CH.dbd.CHCOOR) was increased in bulk supported previous suggestions that the portion of the digitalis receptor that interacts with the C17 side chain lies within a cleft.