Siphonaria zelandica, a pulmonate mollusk, has been the subject of many natural product isolation studies by several, independent research groups. These studies have yielded several polypropionate structures (e.g. 4, 6, 8, and 10), which, upon careful inspection, were proposed to be related. There has been speculation that none of these isolated structures (4, 6, 8, and 10) are biosynthetic products, but are artifacts of isolation. Instead, it has been proposed that an unstable, acyclic precursor, such as 14/15 is the biosynthetic product produced by this mollusk; the putative acyclic precursor has not been isolated or synthesized. None of the synthetic studies on this series of compounds have attempted to address the potential relationships between these structures or speak to their status as natural products.<p> This work describes the enantioselective synthesis of the putative acyclic precursor 14/15 and its isomerization to siphonarin B (4). This was the first enantioselective synthesis of siphonarin B (4). Siphonarin B (4) was shown to readily undergo a retro-Claisen rearrangement to afford baconipyrone C (6) and concurrently undergo a retro-Claisen rearrangement/aldol cascade to provide baconipyrone A (6). This was the first total synthesis of baconipyrone A (6) through an unprecedented retro-Claisen rearrangement/aldol cascade and the first total synthesis of baconipyone C (8) by a biomimetic route versus the classical esterification route. The fourth compound in this series of potentially related compounds, caloundrin B (10), was never observed despite a careful search of each reaction crude where it may have been present.<p> The relationships between these compounds were probed and it was found, that under the conditions examined, the putative acyclic precursor 14/15 is not a biosynthetic product. Instead, siphonarin B (4) or perhaps caloundrin B (10), are the most likely biosynthetic products of the mollusk. Baconipyrone C (8) is not a precursor of baconipyrone A (6). The processes responsible for baconipyrones A (6) and C (8) are irreversible. As had been previously hypothesized, baconipyrones A (6) and C (8) are most likely artifacts of isolation (i.e., not natural products). The missing link in this series of compounds is caloundrin B (10) and its isomerization and rearrangement behavior.

Siphonaria zelandica, a pulmonate mollusk, has been the subject of many natural product isolation studies by several, independent research groups. These studies have yielded several polypropionate structures (e.g. 4, 6, 8, and 10), which, upon careful inspection, were proposed to be related. There has been speculation that none of these isolated structures (4, 6, 8, and 10) are biosynthetic products, but are artifacts of isolation. Instead, it has been proposed that an unstable, acyclic precursor, such as 14/15 is the biosynthetic product produced by this mollusk; the putative acyclic precursor has not been isolated or synthesized. None of the synthetic studies on this series of compounds have attempted to address the potential relationships between these structures or speak to their status as natural products.<p> This work describes the enantioselective synthesis of the putative acyclic precursor 14/15 and its isomerization to siphonarin B (4). This was the first enantioselective synthesis of siphonarin B (4). Siphonarin B (4) was shown to readily undergo a retro-Claisen rearrangement to afford baconipyrone C (6) and concurrently undergo a retro-Claisen rearrangement/aldol cascade to provide baconipyrone A (6). This was the first total synthesis of baconipyrone A (6) through an unprecedented retro-Claisen rearrangement/aldol cascade and the first total synthesis of baconipyone C (8) by a biomimetic route versus the classical esterification route. The fourth compound in this series of potentially related compounds, caloundrin B (10), was never observed despite a careful search of each reaction crude where it may have been present.<p> The relationships between these compounds were probed and it was found, that under the conditions examined, the putative acyclic precursor 14/15 is not a biosynthetic product. Instead, siphonarin B (4) or perhaps caloundrin B (10), are the most likely biosynthetic products of the mollusk. Baconipyrone C (8) is not a precursor of baconipyrone A (6). The processes responsible for baconipyrones A (6) and C (8) are irreversible. As had been previously hypothesized, baconipyrones A (6) and C (8) are most likely artifacts of isolation (i.e., not natural products). The missing link in this series of compounds is caloundrin B (10) and its isomerization and rearrangement behavior.