Bispericyclic Diels–Alder Dimerization of ortho‐Quinols in Natural Product (Bio)Synthesis: Bioinspired Chemical 6‐Step Synthesis of (+)‐Maytenone

Many natural products of plant or microbial origins are derived from enzymatic dearomative oxygenation of 2‐alkylphenolic precursors into 6‐alkyl‐6‐hydroxycyclohexa‐2,4‐dienones. These so‐called ortho‐quinols cyclodimerize via a remarkably selective bispericyclic Diels–Alder reaction. Whether or not the intervention of catalytic or dirigent proteins is involved during this final step of the biosynthesis of these natural products, this cyclodimerization of ortho‐quinols can be chemically reproduced in the laboratory with the same strict level of site‐specific regioselectivity and stereoselectivity. This unique yet unified process, which finds its rationale in the inherent chemical reactivity of those ortho‐quinols, is illustrated herein by an efficient and bioinspired first chemical synthesis of one of the most structurally complex and synthetically challenging examples of such natural cyclodimers, the bisditerpenoid (+)‐maytenone. Biosynthesis of many natural bicyclo[2.2.2]octenone products involves the Diels–Alder cyclodimerization of ortho‐quinols according to the same selectivity rules. This is illustrated by the enzyme‐free synthesis of the bisditerpenoid (+)‐maytenone, first achieved by a chiral iodane‐mediated dearomative hydroxylation of (+)‐ferruginol and a high pressure‐promoted Diels–Alder reaction.