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

Abstract

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.

ortho‐Quinols in (Bio)Synthesis of Natural Products

“… [2] Moreover, treatment of 27 b with the ( S )‐atropoisomer of the bis(iodyl) ( 127 b ) furnished the other ortho ‐quinol diastereomer (6S) ‐ 27 a , which, upon high pressure‐promoted cyclodimerization, delivered the maytenone diastereomer 26 ’ in 29 % yield through the same bispericyclic process (Scheme 26). This diastereomer is identical to a natural compound that was isolated from the roots of Harpagophytum procubens (Devil's claw) [2,53] …”

“…This remarkable cycloaddition that led to a single enantiomer of the maytenone target goes through a C 2 ‐symmetric endo ‐transition state from which the [4+2] and the [2+4] processes are fully equivalent (i.e., a case of bispericyclism) (Scheme 26). [2] Moreover, treatment of 27 b with the ( S )‐atropoisomer of the bis(iodyl) ( 127 b ) furnished the other ortho ‐quinol diastereomer (6S) ‐ 27 a , which, upon high pressure‐promoted cyclodimerization, delivered the maytenone diastereomer 26 ’ in 29 % yield through the same bispericyclic process (Scheme 26). This diastereomer is identical to a natural compound that was isolated from the roots of Harpagophytum procubens (Devil's claw) [2,53] …”

“…The explanation of this extraordinary level of control resides in the inherent and unique chemical reactivity of ortho ‐quinols that cyclodimerize in a bispericyclic manner through C 2 ‐symmetric transition states. For more details, we would like to refer the reader to our previous articles and references cited therein on this topic [2,5,17,47] …”

“…ortho ‐Quinols (i.e., 6‐alkyl‐6‐hydroxycyclohexa‐2,4‐dienone derivatives, Figure 1) belong to this category of intermediate compounds. The biosynthesis of numerous microbial or plant specialized metabolites goes through the formation of such ortho ‐quinols, which would be derived from the controlled dearomative oxygenation of 2‐alkylphenolic precursors [2] . This transformation thus converts electron‐rich aromatic compounds into electrophilic entities and creates one stereogenic center.…”

Synthesis and Evaluation of Antimicrobial Activity of the Rearranged Abietane Prattinin A and Its Synthetic Derivatives

“…The first step involved the transformation of alcohol 19 into 8,11,13-abietatriene 38 through previously described reaction [18]. Subsequently, ferruginol (2) was formed in two steps from 38 using the Friedel-Crafts reaction, followed by a Baeyer-Villiger transformation, and concluded with deprotection in a basic medium [19], as described in Scheme 4. The oxidation of ferruginol (2) was then examined using the (PhSeO) 2 O promoted reaction, as described in our previous work [8], resulting in quinone 39.…”