Herein, we wish to describe for the first time an expedient synthesis of the hexaoxygenated guaianolide thapsigargin (1), a potent inhibitor of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), from the natural product nortrilobolide (2). This innovative protocol involves three key steps: a one-pot substitution-oxidation reaction of an allylic ester into its corresponding α,β-unsaturated ketone, a stereoselective α´-acyloxylation in the presence of Mn(OAc)3 and a highly stereoselective reduction of a ketone into its corresponding alcohol highlighting the vital importance of the solvent used during the reaction.