Recent advances in the synthesis of naturally occurring tetronic acids

During the last decades the interest towards natural products containing the tetronic acid moiety augmented significantly, due to their challenging structures and to the wide range of biological activities they display. This increasing enthusiasm has led to noteworthy advances in the development of innovative methodologies for the construction of the butenolide nucleus. This review provides an overview of the progress in the synthesis of tetronic acid as a structural key motif of natural compounds, covering the last 15 years. Herein, the most representative synthetic pathways towards structurally diverse natural tetronic acids are grouped according to the strategy followed. The first part describes the functionalization of a preformed tetronic acid core by intermolecular reactions (cross-coupling reactions, nucleophilic substitution, multicomponent reactions) whereas the second part deals with intramolecular approaches (Dieckmann, cycloaddition or ring expansion reactions) to construct the heterocyclic core. This rational subcategorization allowed us to make some considerations about the best approaches for the synthesis of specific substrates, including modern intriguing methodologies such as microwave irradiation, solid phase anchoring, bio-transformations and continuous flow processes.