Synthetic Approach to Cyclobutastellettolide B with an Improved Lindgren Oxidation Featuring an Enol Ether Additive

Abstract Cyclobutastellettolide B is a structurally unique C19 norterpenoid bearing a highly strained 6/5/4-fused tricyclic core with three contiguous quaternary stereocenters. We describe synthetic studies toward this target based on a thermal ene–ketene [2+2] cycloaddition strategy to forge the central cyclobutanone. Starting from (+)-sclareolide, we developed a concise, chromatography-free, three-step isomerization that delivers a key carboxylic acid on a multigram scale in 78% overall yield. Central to this sequence is an improved Lindgren oxidation in which ethyl vinyl ether serves as a more effective and less expensive hypochlorous acid scavenger than the commonly used 2-methyl-2-butene, thereby suppressing competitive halohydrin formation at the electron-rich tetrasubstituted alkene. Despite an extensive survey of ketene and keteneiminium cycloadditions, the tetrasubstituted olefin could not be engaged, which we attribute to steric encumbrance. These results indicate that polar cycloadditions are poorly suited to constructing this cyclobutanone and reinforce that a Norrish–Yang cyclization is likely part of the biosynthetic pathway.