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Overweight and obesity, which are major risk factors for a number of chronic diseases, including diabetes, cardiovascular diseases and cancer, have become a major health concern nowadays. Thus, the discovery of appetite suppressant property of Hoodia plants growing in the desert of South Africa attracts a great attention and has led to many commercial preparations. A series of pregnane glycosides have been isolated from Hoodia species, among them only P57 (or P57AS3) is reported to have the activity. Animal studies show that P57 increases the content of ATP in hypothalamic neurons and this might be relevant to the appetitive responses. However, the detailed structure-activity relationship and mechanism of action of P57 has yet to be known. Synthesis of P57 has only been mentioned in a patent, in which the aglycone was synthesized from progesterone employing micro-organism transformation to introduce the 12,15-OH for further elaboration and the trisaccharide assembled onto the aglycone via sequential glycosylation with fluoride donors in low yields (<15% for each step). Recently, Miesch et al. reported a synthesis of the aglycone employing a Norrish type I–Prins reaction as the key step for introduction of the 14-OH, albeit in low yield. Herein, we describe an expeditious synthesis of P57 in a linear 20 steps and 2.4% overall yield from digoxin. The present synthesis provides a consulting strategy to other Hoodia saponins and analogues; the availability of these pregnane glycosides (including stereoisomers) shall facilitate the studies on the SAR and mechanisms of the appetite suppressant activity of P57. For a practical synthesis of P57, however, the stereoselectivity of glycoyslation in the present synthesis remains as a challenge to address.