A simple synthesis of the tropone nucleus

Barbier, Michel; Barton, D. H. R.; Devys, Michel; Topgi, Ravindra Satish

doi:10.1039/c39840000743

Cited by 24 publications

(12 citation statements)

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“…This calculation was supported by literature precedent which demonstrated that tropolones could be synthesized from ortho-dearomatized radicals ( Figure 1B). 22,26 We then explored the rebound hydroxylation and semi-pinacol rearrangement (Path 1). As expected, rebound hydroxylation to produce diol 13 was found to be a barrierless process in our active site model.…”

Section: Resultsmentioning

confidence: 99%

“…22 In addition, radical-based approaches have been successful in synthesizing tropolones from ortho-dearomatized catechols (5) through a selective radical ring expansion mechanism ( Figure 1B). [25][26] This approach required pre-functionalization of the arene to ensure that radical initiation occurred at the methyl halide ipso to the site of dearomatization, leading to the desired rearrangement ( Figure 1B). [25][26] While these methods have been successful in enabling ring expansion, they require arduous synthetic efforts to achieve the desired substitution pattern of the tropolone natural product, preventing facile access to the target compound.…”

Section: Introductionmentioning

confidence: 99%

“…[25][26] This approach required pre-functionalization of the arene to ensure that radical initiation occurred at the methyl halide ipso to the site of dearomatization, leading to the desired rearrangement ( Figure 1B). [25][26] While these methods have been successful in enabling ring expansion, they require arduous synthetic efforts to achieve the desired substitution pattern of the tropolone natural product, preventing facile access to the target compound. 22 In contrast, Nature efficiently assembles complex tropolones using available biosynthetic machinery.…”

Section: Introductionmentioning

confidence: 99%

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Radical Tropolone Biosynthesis

Doyon¹,

Skinner²,

Yang³

et al. 2020

Preprint

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<div> <div> <div> <p>Non-heme iron (NHI) enzymes perform a variety of oxidative rearrangements to advance simple building blocks toward complex molecular scaffolds within secondary metabolite pathways. Many of these transformations occur with selectivity that is unprecedented in small molecule catalysis, spurring an interest in the enzymatic processes which lead to a particular rearrangement. In-depth investigations of NHI mechanisms examine the source of this selectivity and can offer inspiration for the development of novel synthetic transformations. However, the mechanistic details of many NHI-catalyzed rearrangements remain underexplored, hindering full characterization of the chemistry accessible to this functionally diverse class of enzymes. For NHI-catalyzed rearrangements which have been investigated, mechanistic proposals often describe one-electron processes, followed by single electron oxidation from the substrate to the iron(III)-hydroxyl active site species. Here, we examine the ring expansion mechanism employed in fungal tropolone biosynthesis. TropC, an α-ketoglutarate- dependent NHI dioxygenase, catalyzes a ring expansion in the biosynthesis of tropolone natural product stipitatic acid through an under-studied mechanism. Investigation of both polar and radical mechanistic proposals suggests tropolones are constructed through a radical ring expansion. This biosynthetic route to tropolones is supported by X-ray crystal structure data combined with molecular dynamics simulations, alanine-scanning of active site residues, assessed reactivity of putative biosynthetic intermediates, and quantum mechanical (QM) calculations. These studies support a radical ring expansion in fungal tropolone biosynthesis. </p> </div> </div> </div>

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Radical Tropolone Biosynthesis

Doyon¹,

Skinner²,

Yang³

et al. 2020

Preprint

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“…The discovery of tropolones paved a new way for scientists at that time to understand aromaticity and bonding [ 65 ]. The method of organic synthesis of tropolones mainly depends on the ring expansion reaction [ 66 ] by double electron rearrangement or the free radical based method [ 67 ] from ortho-dearomatized catechols. The biosynthesis pathway of tropolones was cleverly designed by organisms through FMOs [ 68 , 69 ].…”

Section: Reactions Catalyzed By Fmos In Natural Product Biosynthesismentioning

confidence: 99%

Properties and Mechanisms of Flavin-Dependent Monooxygenases and Their Applications in Natural Product Synthesis

Deng

Zhou

et al. 2022

IJMS

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Natural products are usually highly complicated organic molecules with special scaffolds, and they are an important resource in medicine. Natural products with complicated structures are produced by enzymes, and this is still a challenging research field, its mechanisms requiring detailed methods for elucidation. Flavin adenine dinucleotide (FAD)-dependent monooxygenases (FMOs) catalyze many oxidation reactions with chemo-, regio-, and stereo-selectivity, and they are involved in the synthesis of many natural products. In this review, we introduce the mechanisms for different FMOs, with the classical FAD (C4a)-hydroperoxide as the major oxidant. We also summarize the difference between FMOs and cytochrome P450 (CYP450) monooxygenases emphasizing the advantages of FMOs and their specificity for substrates. Finally, we present examples of FMO-catalyzed synthesis of natural products. Based on these explanations, this review will expand our knowledge of FMOs as powerful enzymes, as well as implementation of the FMOs as effective tools for biosynthesis.

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“…The type of ring expansion depicted in paths 1b and 1c is well precedented for simple β-multiply bonded alkyl radicals 2,10 but has rarely been observed for allyl or dienyl radicals. 11 For aryl isonitriles, at least, some experimental evidence exists to suggest that path 1c is not operable 12 and semiempiral calculations 3a suggest it is likely to be less favourable than a path 2 type process. We therefore believe that path 2 is likely to be the dominant pathway for the conversion of 1 to 6.…”

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confidence: 99%