The synthesis of Lipoxin B4 analogs (LXB4) to gain access to stabilized inflammation resolving compounds is an actual field of research. Focusing on variation and stabilization of the conjugated E,Z,E,E C6–C13 tetraene moiety of natural LXB4, a methylene bridge introduced between C6 and C11 suppresses any Z/E isomerization of the C8–C9 olefin. Intending to enable prospective structure variations in connection with the C1–C5 and C14–C20 fragments, a convergent total synthesis has been developed. Optically active C1–C12 building blocks were build‐up from cycloheptatriene 1‐carbonester (C6–C11, C21) and glutaryl chloride (C1–C5) using Friedel‐Crafts‐type acylation and chiral HPLC. The C13–C20 segment had been generated via a five‐step sequence starting from heptanoyl chloride. Horner key olefination enabled the assembly of the carbon backbone. A final five‐step sequence including a chelate Cram reduction of the unsaturated ketone moiety afforded the target 6,11‐methylene LXB4 methyl ester.

The synthesis of Lipoxin B4 analogs (LXB4) to gain access to stabilized inflammation resolving compounds is an active field of research. Focusing on variation and stabilization of the conjugated E,Z,E,E C6–C13 tetraene moiety of natural LXB4, a methylene bridge introduced between C6 and C11 suppresses any Z/E isomerization of the C8–C9 olefin. Furthermore, rapid ω-oxidation (C20) should be avoided by replacing the C18-C20 segment by an aromatic moiety. Optically active C1–C12 building blocks were accessed from cycloheptatriene 1-carbonester (C6–C11, C21) and glutaryl chloride (C1–C5) as described earlier. The ω-segment had been generated via a five-step sequence starting from 4-arylbutanoic acid. Horner key olefination enabled assembly of the carbon backbone. A final five step sequence including a chelate Cram reduction of the unsaturated ketone moiety afforded the target ω-aryl 6,11-methylene-LXB4 methyl ester.

Starting from methyl cycloheptatrienyl-1-carboxylate, 6-acylation was successfully achieved employing glutaryl chloride in the presence of AlCl3 under controlled reaction conditions to furnish keto carboxylic acid product. After protection of this keto carboxylic acid as tert-butyl ester, reagent-controlled enantioselective reductions delivered configuration-defined methyl-6-hydroxylalkyl cycloheptatriene-1-carboxylates with up to 80% ee. Whereas simple NaBH4 reduction of the keto carboxylic acid and subsequent lactonization afforded a methyl-6-tetrahydropyranonyl cycloheptatriene-1-carboxylate. Resolution using chiral HPLC delivered the product enantiomers with up to >99% ee Finally, ECD analyses enabled structure elucidation. The products are used as key intermediates in enantioselective 6,11-methylene-lipoxin B4 syntheses.