https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

Aflatoxins, a group of polyketide-derived furanocoumarins (Fig. [1][1]), are the most toxic and carcinogenic compounds among the known mycotoxins. Among the at least 16 structurally related aflatoxins characterized, however, there are only four major aflatoxins, B1, B2, G1, and G2 (AFB1, AFG1, AFB2

Clustered pathway genes in aflatoxin biosynthesis.

Within 14 years of the seminal experiments of J. D. Roberts
leading to the first proposal of the structure of benzyne (1), synthetic organic chemists recognized the potential to exploit this highly reactive intermediate (and its substituted variants) in the total synthesis of natural products. More specifically, it was recognized that arynes offered the strategic advantage of rapidly functionalizing an aromatic ring by forming multiple carbon− carbon or carbon−heteroatom bonds in a single operation, often in a regioselective manner. Initially, the scope of synthetic
applications was somewhat limited by the harsh conditions
required to produce the aryne species. Many of these methods required strong bases, such as n-BuLi, or high temperatures (Scheme 1). However, with the development of milder methods for the generation of arynes came increased interest in employing them in the synthesis of more complex polycyclic systems. Most recently, the use of o-silyl aryl triflates as aryne precursors has allowed generation of the reactive intermediate under almost neutral conditions.
To date, over 75 individual natural products have been
prepared using arynes to generate key synthetic intermediates. Herein are recounted the reports of total syntheses that utilize arynes in ways that build complexity or introduce motifs essential to the completion of their targets. The methods by which the authors featured in this review accomplish this task reflect the versatility of arynes as reactive intermediates for synthesis (Scheme 2). For the purposes of organization, the syntheses are divided into subgroups on the basis of the type of aryne transformation: (i) nucleophilic additions or multicomponent reactions, (ii) σ-bond insertion reactions, (iii) [4 + 2]- and [2 + 2]-cycloaddition strategies, and (iv) metal-catalyzed aryne reactions.

A Comprehensive History of Arynes in Natural Product Total Synthesis

The aflatoxin producing fungi, Aspergillus spp., are widely spread in nature and have severely contaminated food supplies of humans and animals, resulting in health hazards and even death. Therefore, there is great demand for aflatoxins research to develop suitable methods for their quantification, precise detection and control to ensure the safety of consumers’ health. Here, the chemistry and biosynthesis of the mycotoxins is discussed their occurrence and the health hazards to humans and livestock. This review focuses on resources, production, detection and control measures of aflatoxins to ensure food and feed safety. The results presented herein will facilitate health-conscious consumers and for experts, while providing knowledge on new and innovative approaches to ensure food safety and meet the future demands of the increasing population by decreasing the incidence of outbreaks by aflatoxins.

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Aflatoxins: A Global Concern for Food Safety, Human Health and Their Management

Chemistry and Biology of Mycotoxins and Related Fungal Metabolites

Methoxymethyl-directed aryl metalation. Total synthesis of (.+-.)-averufin

Hexanoate as a starter unit in polyketide biosynthesis

Described are two total syntheses of (±)-averufin (4) proceeding through a common intermediate and predicated on the efficient introduction of isotopic label(s) at side-chain and nuclear sites for the purpose of biosynthetic investigations of aflatoxin B1(8). Using these methods, (±)-[4′-13C]- and -[1′-13C,2H]-averufin, (65) and (68) respectively, and a 1:1 mixture of (±)-[5,6-13C2]- and -[8,11-13C2]-averufin (71) were prepared and incorporated into aflatoxin B1 using mycelial suspensions of Aspergillus parasiticus(SU-1). In each instance efficient and specific utilization of label was observed in the product by 13C-{1H} n.m.r. spectroscopy, demonstrating the intact incorporation of averufin. When compared with earlier observations of [1,2-13C2]acetate incorporation, a complete correlation of the carbon skeleton from the intermediate anthraquinone stage of the pathway to the substituted coumarin of compound (8) was made possible, and the four carbons lost in this overall process were unambiguously identified. In the formation of the dihydrobisfuran, the anthraquinone nucleus migrates to C-2′ to branch the linear side-chain of averufin. Deuterium bound at C-1′ in averufin is carried to C-13 of aflatoxin. Preparation from (±)-[1′-13C,2H]averufin (68) of (±)-[1′-13C,1′,4′,4′,6′,6′,6′-2H6]-averufin (73) and incorporation of the latter into versiconal acetate (5) demonstrated loss of the terminal two carbons of the averufin side-chain, presumably as acetate, by way of a Baeyer–Villiger-like oxidation.

Siegfried B. Christensen

Papers

Methoxymethyl-directed aryl metalation. Total synthesis of (.+-.)-averufin

Hexanoate as a starter unit in polyketide biosynthesis

Synthesis of averufin and its role in aflatoxin B1 biosynthesis

Stable isotope studies of anthraquinone intermediates in the aflatoxin pathway

Bisfuran formation in aflatoxin biosynthesis: the role of versiconal acetate