Chemical Synthesis of (+)-Brevianamide a Supports a Diels–Alderase-Free Biosynthesis

Godfrey, Robert C.; Green, Nicholas J.; Nichol, Gary S.; Lawrence, Andrew L.

doi:10.26434/chemrxiv.8224148.v1

Cited by 2 publications

(3 citation statements)

References 47 publications

(81 reference statements)

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“…5), NMR analyses (Supplementary Table 1, Supplementary Figs. [13][14][15][16][17][18][19][20][21][22][23][24], and comparison with the corresponding synthesized authentic standards (see Supplementary Information). Their absolute configurations were established by single-crystal X-ray diffraction (CCDC No.…”

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confidence: 99%

“…Recently, the chemical synthesis of BA, the typical structure that contains the dioxopiperazine and 3-spiro-ψ−indoxyl moieties, has been accomplished and suggested a Diels-Alderase-free biosynthesis. 18 However, the biocatalytic details and the sequential timing for the putative indole oxidation, semi-pinacol rearrangement, and IMDA cycloaddition (Supplementary Fig. 1) remain unresolved experimentally due to lack of access to the key enzymes.…”

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Fungal-derived brevianamide assembly by a stereoselective semipinacolase

Zhang

et al. 2020

Nat Catal

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Fungal bicyclo[2.2.2]diazaoctane indole alkaloids represent an important family of natural products with a wide-spectrum of biological activities. Although biomimetic total syntheses have been completed for representative compounds, the details of their biogenesis, especially the mechanisms for assembly of diastereomerically distinct and enantiomerically antipodal metabolites, have remained largely uncharacterized. Brevianamide A represents the most basic form of the sub-family bearing a dioxopiperazine core and a rare 3-spiro-ψ-indoxyl skeleton. Here, we identified the Brevianamide A biosynthetic gene cluster from Penicillium brevicompactum NRRL 864 and fully elucidated the metabolic pathway by gene disruption, heterologous expression, precursor incorporation experiments, and in vitro biochemical analysis. In particular, we determined BvnE as a cofactor-independent isomerase/pinacolase that is essential for selective production of Brevianamide A. Structural elucidation, molecular modeling, and mutational analysis of BvnE, and quantum chemical calculations provided critical mechanistic insights into the diastereoselective formation of the 3-spiro-ψ-indoxyl moiety in Brevianamide A. This occurs through a BvnE-controlled semi-pinacol rearrangement and a subsequent spontaneous intramolecular [4+2] hetero-Diels-Alder cycloaddition. Resolution of this 50-year old mechanistic mystery together with our recent characterization of the Diels-Alderase-mediated biogenesis of monooxopiperazines highlight the diversified biosynthetic strategies deployed by fungi for creating structurally diverse spiro-cyclized indole alkaloids.Fungal indole alkaloids bearing the unusual bicyclo[2.2.2]diazaoctane core have drawn considerable attention from natural product, synthetic and biological chemists for decades. A wealth of studies on the discovery of analogs (including semi-synthetic, synthetic and natural), biological activities and biosynthetic mechanisms have been

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Fungal-derived brevianamide assembly by a stereoselective semipinacolase

Zhang

et al. 2020

Nat Catal

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“…Brevianamides A and B represent the most basic structural form that contains the key functional groups characteristic of this class of metabolites including: (1) the bicyclo[2.2.2]diazaoctane core and (2) the 3-spiro--indoxyl functionality. Although the chemical synthesis of Brevianamide A has recently been accomplished, 67 the various biosynthetic pathway proposals remain unresolved experimentally due to lack of access to the key enzymes. Thus, Brevianamides A and B are ideal targets for deciphering the long-standing enigma regarding the biogenesis of this important class of fungal metabolites.…”

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Cofactor-Independent Pinacolase Directs Non-Diels-Alderase Biogenesis of the Brevianamides

Ye¹,

Du²,

Zhang³

et al. 2019

Preprint

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Fungal bicyclo[2.2.2]diazaoctane indole alkaloids demonstrate intriguing structures and a wide spectrum of biological activities. Although biomimetic total syntheses have been completed for representative compounds of this structural family, the details of their biogenesis have remained largely uncharacterized. Among them, Brevianamide A represents the most basic form within this class bearing a dioxopiperazine core structure and a rare 3-spiro-psi-indoxyl skeleton. Here, we identified the Brevianamide A biosynthetic gene cluster from Penicillium brevicompacticum NRRL 864 and fully elucidated the metabolic pathway by targeted gene disruption, heterologous expression, precursor incorporation studies, and in vitro biochemical analysis. In particular, we determined that BvnE is a cofactor-independent isomerase that is essential for selective production of Brevianamide A. Based on a high resolution crystal structure of BvnE, molecular modeling, mutational analysis, and computational studies provided new mechanistic insights into the diastereoselective formation of the 3-spiro-psi-indoxyl moiety in Brevianamide A. This occurs through a biocatalyst controlled semi-Pinacol rearrangement and a subsequent spontaneous intramolecular [4+2] hetero-Diels-Alder cycloaddition.

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Chemical Synthesis of (+)-Brevianamide a Supports a Diels–Alderase-Free Biosynthesis

Cited by 2 publications

References 47 publications

Fungal-derived brevianamide assembly by a stereoselective semipinacolase

Fungal-derived brevianamide assembly by a stereoselective semipinacolase

Cofactor-Independent Pinacolase Directs Non-Diels-Alderase Biogenesis of the Brevianamides

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