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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: The [4+2] cyclodimerization of cyclohexa-2,4-dienone derivatives of the orthoquinone monoketal and orthoquinol types has been the topic of numerous investigations over the last 50 years in the aim of rationalizing the extraordinary level of regio-, site-, and stereoselectivities observed in these processes. In particular, the double diastereo-π-facial differentiation expressed in cyclodimerizations of chiral orthoquinols (i.e., 6-alkyl-6-hydroxycyclohexa-2,4-dienones) is an important aspect of these transformations, for they relate to the construction of several natural products. The experimental and theoretical results that are described in this article offer a comprehensive understanding of the factors controlling these site-specific regio- and diastereoselectivities. Our interpretation of these results relies on a combination of Woodward–Hoffmann and Salem–Houk secondary orbital interactions and Cieplak-type hyperconjugative effects in bispericyclic C2-symmetric transition states. [Copyright &y& Elsevier]

Under high pressure, this transition state leads to the product, the natural (+)-maytenone, which was first isolated from the plant I Maytenus dispermus i , here appearing in the background image. Asymmetric synthesis, cycloaddition, hypervalent compounds, total synthesis, transition states Keywords: asymmetric synthesis; cycloaddition; hypervalent compounds; total synthesis; transition states EN asymmetric synthesis cycloaddition hypervalent compounds total synthesis transition states 15111 15111 1 06/23/21 20210625 NES 210625 B From the teaching class b with the bispericyclic Diels-Alder reaction of I ortho i -quinols drawn on the chalk board to the laboratory with the (+)-ferruginol substrate and a chiral bisiodyl reagent in the flask: The single I ortho i -quinol diastereomer thus produced combines in pairs to reach a I C i SB 2 sb -symmetric transition state in which [4+2] and [2+4] processes are equivalent, as described by Laurent Pouységu, Stéphane Quideau, and co-workers in their Research Article on page 14967. [Extracted from the article]

Keywords: asymmetric synthesis; cycloaddition; hypervalent compounds; total synthesis; transition states EN asymmetric synthesis cycloaddition hypervalent compounds total synthesis transition states 15239 15239 1 06/23/21 20210625 NES 210625 B Von der Kreidetafel b mit der bispericyclischen Diels-Alder-Reaktion von I ortho i -Chinolen zum Labor mit dem (+)-Ferruginol-Substrat und einem chiralen Bisiodyl-Reagenz im Kolben: Die so erzeugten I ortho- i Chinol-Diastereomere verbinden sich paarweise zu einem C SB 2 sb -symmetrischen Übergangszustand, in dem [4+2]- und [2+4]-Prozesse äquivalent sind, wie Laurent Pouységu, Stéphane Quideau et al. im Forschungsartikel auf S. 15094 berichten. Innenrücktitelbild: Bispericyclic Diels-Alder Dimerization of ortho-Quinols in Natural Product (Bio)Synthesis: Bioinspired Chemical 6-Step Synthesis of (+)-Maytenone (Angew. Asymmetric synthesis, cycloaddition, hypervalent compounds, total synthesis, transition states. [Extracted from the article]