Total Synthesis of Guajavadimer A via Lewis Acid-Catalyzed Cascade Double Hetero-Diels–Alder Reactions

The first total synthesis of guajavadimer A, a dimeric caryophyllene-derived meroterpenoid featuring an unprecedented 4-9-6-6-6-9-4-fused ring system, is reported. Key to the approach is the construction of the pyrano[4,3,2-de]chromene core via a cascade of double hetero-Diels-Alder reactions. Practically, a 4-substituted-2,6-dihydroxybenzaldehyde dimethyl acetal serves as an effective surrogate for ortho-quinone methide, which is generated from the corresponding aldehyde and trimethyl orthoformate, with β-caryophyllene undergoing cycloaddition to generate pyrano[4,3,2-de]chromene derivatives with excellent regioselectivity and stereoselectivity in one pot under mild conditions.