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.

Automated summary

Many natural products are derived from enzymatic dearomative oxygenation of 2-alkylphenolic precursors into 6-alkyl-6-hydroxycyclohexa-2,4-dienones, which cyclodimerize via a bispericyclic Diels-Alder reaction. The involvement of catalytic or dirigent proteins in this process is still a question, but the cyclodimerization of ortho-quinols can be chemically reproduced in the laboratory with the same level of regioselectivity and stereoselectivity.