Total Synthesis of Biselyngbyolide B and Its C21–C22 <i>Z</i>‑Isomer

Investigations toward the synthesis of the 18-membered macrolactone biselyngbyolide B (<b>2</b>) from a C1–C13 and a C14–C23 fragment are described. As a key reaction in the synthesis of the C1–C13 fragment, we used an asymmetric propargylation of chiral vinylketene silyl <i>N</i>,<i>O</i>-acetal <b>12</b>. Access to a C14–C23 fragment featuring a skipped diene and a sensitive allyl alcohol function was initially attempted via reductive fragmentation of a pyran template. However, this ring opening on iodide <b>32</b> with <i>t</i>-BuLi led to dienynol <b>33</b> with a 21<i>Z</i> double bond. With a silyl protecting group at 3-OH and by implementing an intramolecular Stille coupling for macrolactonization, the 21<i>Z</i>-isomer of biselyngbyolide B (<b>47</b>) was obtained. For preparation of a C14–C23 fragment with the 21<i>E</i>-configuration, a cross-coupling of vinylstannane <b>48</b> with 4-bromocrotonate (<b>49</b>) set the configuration of the two double bonds. Biselyngbyolide B (<b>2</b>) was then accessed by an intramolecular Heck coupling. In preliminary biological cytotoxicity assays, <b>2</b> turned out to be active, whereas the 21<i>Z</i>-isomer <b>47</b> was much less active. The 3-OMEM analogue <b>40</b> was devoid of activity. These results support the notion that the side chain with the correct configuration is relevant for binding to the Ca²⁺-ATPase and the biological activity