Oxacyclododecindione (1), a fungal secondary metabolite, and some of its natural and synthetic derivatives show remarkably high anti-inflammatory activities in cell culture and were successfully used in an in vivo mouse model of systemic lupus erythematodes. The 12-membered macrolactones therefore might serve as lead structures for the discovery of novel therapeutics against autoimmune and inflammatory diseases. To identify the biological targets and to gain a better understanding of structure-activity relationships, we strive for total syntheses of the natural product 1 and synthetic derivatives. Since the 12-membered ring bears a significant strain, a ring closing method, which allowed the installation of the correct double bond geometry and substitution pattern, was difficult to find. A Wittig Olefination/Steglich esterification/Intramolecular Friedel-Crafts acylation sequence proved to be suitable for the racemic syntheses of 14-deoxyoxacyclododecindione (2), the C-14 gem-dimethyl derivative 3 and the C-10 ethyl derivative 4. However, the synthesis of oxacyclododecindione 1 is still subject of ongoing research.

Synthesis of anti-inflammatory oxacyclododecindione-type macrolactones

256th National Meeting (2018)

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