We have developed a convergent synthetic route to the potent cAMP signaling agonist (-)-alotaketal A that employs two stages of SmI2-mediated reductive allylation reactions for assembling the polycycle and fragment coupling. Also notable are a Hg(OAc)(2)-mediated selective alkene oxidation and the subtlety of the formation of the unprecedented spiroketal ring system. The probes AKAR4 and ICUE3 were used to evaluate the cAMP singaling agonistic activity of (-)-alotaketal A and elucidate its structure-activity relationship.