With protoescigenin as starting material and through orchestrated application of Yu and Schmidt glyco-sylation protocols, the synthesis of acyl group-free escin derivatives were achieved for the first time. As the undesired non-specific toxicity, originated from the existence of acyl groups on aglycone, prohibits the wide application of escins, the established strategies toward non-acylated protoescigenin-type sap-onins would dramatically ease the access to escin derivatives dispense of acyl groups, thereby speeding up the pace of pharmaceutical use of these valuable compounds.