The macrocyclic core (35) of the marine natural product leiodermatolide (1) was synthesized from two key fragments, vinyl iodide 23 (C1-C11 part) and vinyl stannane 31 (C12-C18 part). A Stille coupling led to conjugated Z,Z-diene 32. The derived seco acid 34 was cyclized using a Yamaguchi macrolactonization. Key steps in the assembly of vinyl iodide 23 were a Paterson aldol reaction, and a Kumada coupling on a triflate derivative to create the C4-C5 trisubstituted double bond. The two stereocenters in fragment 31 were established by a Marshall-Tamaru reaction. The longest linear sequence comprises 20 steps.

We explored the possibility of attaching a side chain to a leiodermatolide fragment by forming the C18/C19 double bond via Julia/Kocienski olefination. This worked with a δ‐lactone surrogate, the meta‐anisole derivative 17 in reasonable yield to give the acyclic pentaene 32. However, due to problems during cleavage of the silyl ether at the 15‐OH, the corresponding macrolactone could not be obtained. Instead, it was possible to convert enal 31 by Tebbe olefination to pentaene 37. This compound could be converted to macrolactone 41 from where the side chain truncated leiodermatolide analogues 42 (9‐O‐carbamoyl) and 43 (7‐O‐carbamoyl) were obtained. Both isomers were moderately cytotoxic highlighting the importance of the side chain with the δ‐lactone.

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