Total Synthesis, Structure 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 configuration 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 C-13 stereocenter 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 configuration 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.