Asymmetric Total Synthesisof Venezuelaene A via TEMPO+BF4–-Mediated OxidativeNazarov Cyclization and Cascade Metathesis

The first and asymmetric total synthesis of venezuelaene A, a rare [5–5–6–7] tetracyclic diterpenoid featuring a highly strained trans-fused [5–5] bicyclic motif alongside a densely functionalized cyclopentane ring and six contiguous stereogenic centers, is reported. Our approach highlights (1) a TEMPO+BF4–-mediated oxidative Nazarov cyclization that rapidly assembles the hydrindane core bearing the key C15-quaternary center; (2) a Stoltz decarboxylative allylic alkylation to highly diastereoselectively install the adjacent C3-quaternary center; (3) a strategic intramolecular carbon atom transfer that overcomes formidable challenges of both homologation and stereochemical control encountered with conventional approaches; and (4) an ene-yne-ene cascade metathesis that efficiently forges the [5–7] bicyclic system and ultimately the entire tetracyclic skeleton, representing the first example of constructing a highly strained trans-fused [5–5] bicyclic ring system via a metathesis reaction.