Asymmetric Total Synthesis of Venezuelaene A via TEMPO+BF4--Mediated Oxidative Nazarov 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.