Unusual KIE and dynamics effects in the Fe-catalyzed hetero-Diels-Alder reaction of unactivated aldehydes and dienes

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Апрель 15, 2020

Abstract Hetero-Diels-Alder (HDA) reaction is an important synthetic method for many natural products. An iron(III) catalyst was developed to catalyze the challenging HDA of unactivated aldehydes and dienes with high selectivity. Here we report extensive density-functional theory (DFT) calculations molecular dynamics simulations that show effects iron (including its coordinate mode and/or spin state) on this reaction: considerably enhancing dynamically stepwise process, broadening entrance channel narrowing exit from concerted asynchronous transition states. Also, our combined computational experimental secondary KIE studies reveal unexpectedly large values five-coordinate pathway even considerable C–C bond forming, due equilibrium isotope effect change in metal coordination. Moreover, steric electronic are computationally shown dictate C=O chemoselectivity α,β-unsaturated aldehyde, which verified experimentally. Our mechanistic study may help design homogeneous, heterogeneous biological catalysts reaction.

Язык: Английский

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Secondary metabolite biosynthetic diversity in the fungal family Hypoxylaceae and Xylaria hypoxylon

Studies in Mycology, Год журнала: 2021, Номер 99(1), С. 100118 - 100118

Опубликована: Июнь 1, 2021

To date little is known about the genetic background that drives production and diversification of secondary metabolites in Hypoxylaceae . With recent availability high-quality genome sequences for 13 representative species one relative ( Xylaria hypoxylon ) we attempted to survey diversity biosynthetic pathways these organisms investigate their true potential as metabolite producers. Manual search strategies based on accumulated knowledge biosynthesis fungi enabled us identify 783 across 14 studied species, majority which were arranged gene clusters (BGC). The similarity BGCs was analysed with BiG-SCAPE engine organised into 375 cluster families (GCF). Only ten GCFs conserved all indicating speciation accompanied by changes metabolism. From compounds produced family members some can be directly correlated identified highlighted herein azaphilone, dihydroxynaphthalene, tropolone, cytochalasan, terrequinone, terphenyl brasilane giving insights evolution those compound classes. Vice versa , products various predicted through homology analysis from other shown ergot alkaloid, trigazaphilone, curvupallide, viridicatumtoxin swainsonine BGCs. However, had no obvious links or well-studied fungi. These findings highlight number strongly underrepresents a tremendous unidentified still hidden. Moreover, increasing numbers genomes further becoming available, likelihood revealing new encode new, potentially useful will significantly improve. Reaching better understanding biology producers, development methods manipulation, crucial access treasures.

Язык: Английский

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Flavin-Dependent Monooxygenase-Mediated 1,2-Oxazine Construction via Meisenheimer Rearrangement in the Biosynthesis of Paeciloxazine

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(9), С. 4269 - 4276

Опубликована: Фев. 22, 2022

The [1,2]-Meisenheimer rearrangement is well known as the [1,2]-migration of an O-substituted hydroxylamine from a tertiary amine N-oxide, and it frequently employed in organic synthesis to enforce adjacent carbon oxidation or install 1,2-oxazine core, which prevalent structural feature pharmacophore many bioactive natural products. Although was proposed occur biosynthesis number 1,2-oxazine-containing products, has never been proved biosynthetically. Here, we identified biosynthetic gene cluster insecticidal product, paeciloxazine (1), Penicillium janthinellum characterized flavin-dependent monooxygenase, PaxA, first example that mediates formation moiety via Meisenheimer rearrangement. In vitro biochemical assays, site-directed mutations, docking molecular dynamics simulations, density functional theory calculations support mechanism PaxA catalyzes N-oxidation form N-oxide intermediate, undergoes with assistance amino acid proton transfer property. This study expands repertoire reactions during products provides new strategy for discovering N-O tethers by genome mining.

Язык: Английский

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The evolutionary origin of naturally occurring intermolecular Diels-Alderases from Morus alba

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 20, 2024

Abstract Biosynthetic enzymes evolutionarily gain novel functions, thereby expanding the structural diversity of natural products to benefit host organisms. Diels-Alderases (DAs), functionally unique catalysing [4 + 2] cycloaddition reactions, have received considerable research interest. However, their evolutionary mechanisms remain obscure. Here, we investigate origins intermolecular DAs in biosynthesis Moraceae plant-derived Diels-Alder-type secondary metabolites. Our findings suggest that these evolved from an ancestor functioning as a flavin adenine dinucleotide (FAD)-dependent oxidocyclase (OC), which catalyses oxidative cyclisation reactions isoprenoid-substituted phenolic compounds. Through crystal structure determination, computational calculations, and site-directed mutagenesis experiments, identified several critical substitutions, including S348L, A357L, D389E H418R alter substrate-binding mode enable OCs DA activity during evolution. This work provides mechanistic insights into rationale paves way for mining engineering new other protein families.

Язык: Английский

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Hunting for the Intermolecular Diels–Alderase

Accounts of Chemical Research, Год журнала: 2024, Номер 57(15), С. 2166 - 2183

Опубликована: Июль 12, 2024

ConspectusThe Diels-Alder reaction is well known as a concerted [4 + 2] cycloaddition governed by the Woodward-Hoffmann rules. Since Prof. Otto Diels and his student Kurt Alder initially reported intermolecular between cyclopentadiene quinone in 1928, it has been recognized one of most powerful chemical transformations to build C-C bonds construct cyclic structures. This named widely used synthesizing natural products drug molecules. Driven synthetic importance reaction, identifying enzyme that stereoselectively catalyzes become an intriguing research area product biosynthesis biocatalysis. With significant progress sequencing bioinformatics, dozens Diels-Alderases have characterized microbial biosynthesis. However, few are evolutionally dedicated catalyzing with mechanism.This Account summarizes our endeavors hunt for naturally occurring Diels-Alderase from plants. Our journey started biomimetic syntheses D-A-type terpenoids flavonoids, showing plants use both nonenzymatic enzymatic cycloadditions create complex Inspired syntheses, we identify hidden biosynthetic pathway mulberry Diels-Alder-type cycloadducts using intermediate probe-based target identification strategy. enzyme, MaDA,

Язык: Английский

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