Synthesis of Optically Active 15-epi-9,14-Methylene Lipoxin A₄

Dedicated to Prof. Dr. Werner Skuballa on the occasion of his 75^th birthday

Abstract

The synthesis of lipoxin A₄ and B₄ analogues (LXA₄, LXB₄) to gain access to stabilized inflammation resolving compounds is an important field of research. Starting from known structural requirements of the natural compounds displaying biological activity and a broad investigation of their rapid metabolism, various LXA₄ derivatives have been developed and tested. Focusing on variation and stabilization of the conjugated E,E,Z,E C7–C14 tetraene moiety of natural LXA₄, a methylene bridge introduced between C9 and C14 might suppress any Z/E isomerization of the C11–C12 olefin. Intending to enable at least known structure variations in connection with the C1–C7 and the C15–C20 fragments, a convergent total synthesis starting from a known cycloheptatriene is developed. The C1–C8 building blocks are generated via six-step ex-chiral pool sequences starting from 2-deoxy-d-ribose delivering two 5,6-dihydroxy carboxylic acid derivatives with C7 aldehyde functions. The synthesis of the C8–C21 building block starts from a known cycloheptatriene 1-carbonester (C8–C14, C21) and hexanoyl chloride (C15–C20). After Friedel–Crafts-type coupling, the defined configuration of the C15 OH group is introduced via enantioselective reduction of the ketone precursor. Following an additional four steps, an aryl sulfone C9–C21 building block is completed ready for a key Julia–Kocienski olefination with the C1–C7 compounds. Finally, removal of the protecting groups completes the synthesis of the target optically active 9,14-methylene LXA₄ methyl ester.

Key words

lipoxin analogue - eicosanoid - fatty acid - cycloheptatriene - enantioselective reduction - Julia–Kocienski olefination - convergent synthesis - Mosher analysis

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