Total Synthesis, Structural Reassignment, and Biological Evaluation of the Anti-Inflammatory Macrolactone 13-Hydroxy-14-deoxyoxacyclododecindione

Herein, the first total synthesis of natural 13-hydroxy-14-deoxyoxacyclododecindione along with the revision of the proposed stereoconfiguration is reported. This natural product, initially discovered in 2018, belongs to the oxacyclododecindione family, renowned for their remarkable anti-inflammatory and antifibrotic activities. The synthetic route involves an esterification/Friedel-Crafts-acylation approach and uses various triol fragments. It allows the preparation of different stereoisomers, including the (revised) natural product, two threo-derivatives, and two Z-isomers of the endocyclic C=C-double bond. Furthermore, a late-stage inversion of the 13-hydroxy group could transform the originally proposed structure into the revised natural product. With this comprehensive set of compounds and the previously prepared (13R,14S,15R)-isomer, deeper insights into their structural properties and biological activities were obtained. A detailed analysis of the final macrolactones using spectroscopy (NMR, IR, UV-Vis) and X-ray crystallography gave new insights such as the significance of the optical rotation for the elucidation of their stereoconfiguration and the light induced E/Z double bond photoisomerization. The pharmacological potential of the compounds was underlined by remarkably low IC50 values in biological assays addressing the inhibition of cellular inflammatory responses.