Highly Efficient Total Synthesis of the Marine Natural Products (+)‐Avarone, (+)‐Avarol, (−)‐Neoavarone, (−)‐Neoavarol and (+)‐Aureol

Biologically important and structurally unique marine natural products avarone ( 1 ), avarol ( 2 ), neoavarone ( 3 ), neoavarol ( 4 ) and aureol ( 5 ), were efficiently synthesized in a unified manner starting from (+)‐5‐methyl‐Wieland–Miescher ketone 10 . The synthesis involved the following crucial steps: i) Sequential BF 3 ⋅Et 2 O‐induced rearrangement/cyclization reaction of 2 and 4 to produce 5 with complete stereoselectivity in high yield ( 2 → 5 and 4 → 5 ); ii) strategic salcomine oxidation of the phenolic compounds 6 and 8 to derive the corresponding quinones 1 and 3 ( 6 → 1 and 8 → 3 ); and iii) Birch reductive alkylation of 10 with bromide 11 to construct the requisite carbon framework 12 ( 10 + 11 → 12 ). An in vitro cytotoxicity assay of compounds 1 – 5 against human histiocytic lymphoma cells U937 determined the order of cytotoxic potency ( 3 > 1 > 5 > 2 > 4 ) and some novel aspects of structure‐activity relationships.