The one-pot, three-step, four-component Ugi-IMDAF reaction with 5-hydroxymethylfurfural provides simple access to hydroxymethyl-substituted epoxyisoindolones in a diastereoselective and stereospecific manner. The protocol avoids the transfer or isolation of isocyanides, and the broad scope was illustrated by the synthesis of 22 different compounds bearing various substituents on the heterocyclic core.