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

Abstract

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.