Pumiliotoxins 209F and 251D were synthesized using highly selective nickel-catalyzed epoxide−alkyne reductive cyclizations as the final step. The exocyclic (Z)-alkene found in the majority of the pumiliotoxins was formed stereospecifically and regioselectively, without the use of a directing group on the alkyne, and the epoxide underwent ring opening exclusively at the less hindered carbon to provide the requisite tertiary alcohol. The epoxides were prepared using diastereoselective addition of a sulfoxonium anion to a proline-derived methyl ketone.