Butenolides have good biological activity and serve as the important unit of pharmaceutical intermediates, of which γ-alkylidenebutenolides have gained wide attention over the last past decades particularly. A simple and practical method for the synthesis of butenolide 6 and its 5-substituted analogues 7a-t via vinylogous aldol reaction from 6-aminopenicillanic acid (6-APA) with the ratio of Z/E isomers between 1.1/1.0 and 1.0/0 under mild conditions in 6 steps was first reported. Besides, we also reported the methanolysis behaviors of azetidinone fused oxazoline derivatives. All the synthesized γ-alkylidenebutenolides are new and are currently being evaluated for their biological activities. Due to their large abundance and their biological interest and potential medicinal value, butenolides have been extensively studied. Many natural products, including prominent compounds such as freelingyne, rubrolides, tetrenolin (Figure 1), belong to the pharmacologically important group of γ-alkylidenebutenolides (γ-AIBs), which have gained an increasing amount of attention over the last past decades. Most of them exhibit various interesting biological activities, such as antibacterial, anticancer, antibiotic and so on. For example, freelingyne displays antibiotic activity and rubrolides, which are marine tunicate metabolites, exhibit potent antibiotic activities in vitro. Principally, the efficient synthetic strategies towards the γ-AIBs mainly focus on five major respects, which were reviewed comprehensively by Rao, Negishi, Bruckner, and Langer. Many efforts have been dedicated to seek highly potent γ-AIBs on their pharmacological activities. HETEROCYCLES, Vol. 87, No. 1, 2013 163