Three‐Component One‐Pot Total Syntheses of Glyantrypine, Fumiquinazoline F, and Fiscalin B Promoted by Microwave Irradiation.

Liu, Jifeng; Zhang, Bailin; Bi, Grace; Sargent, Katie; Yu, Libing; Yohannes, Daniel; Baldino, Carmen M.

doi:10.1002/chin.200551186

Cited by 5 publications

(10 citation statements)

References 1 publication

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“…The crude reaction mixture was purified by silica-gel flash chromatography (solvent system as described for FQF) to yield GAT plus its enantiomer. Data supporting the identity of the synthetic GAT: high-resolution ESI/MS ([M+H] + expected, 345.1346; observed, 345.1364), UV-Vis, and 1 H-NMR data (30) (see Figures S12C and S14)…”

Section: Methodsmentioning

confidence: 83%

“…The ee of FQF was determined to be 14% by analytical chiral HPLC (same column and gradient as previous, 1 mL/min flow); enantiopure FQF was prepared by injecting multiple samples of the scalemic mixture on the Chiralcel column and collecting the appropriate peak. Data supporting the identity of the synthetic FQF includes high-resolution ESI/MS ([M+H] + expected, 359.1503; observed, 359.1492), UV-Vis, and 1 H-NMR data (5, 30) (see Figures S5 and S6). …”

Section: Methodsmentioning

confidence: 89%

“…Under these conditions 3 , FQA, FQF, and 4 , eluted at 18.2, 20.6, 21.9, and 24.8 min respectively. Data supporting the identity of the enzymatically prepared FQA includes high-resolution ESI/MS ([M+H] + expected, 446.1818; observed, 446.1823), UV-Vis, and 1 H-NMR data (5, 30) (see Figures S10 and S11). …”

Section: Methodsmentioning

confidence: 92%

“…The synthesis of FQF and GAT followed a previously described three-component one-pot microwave assisted protocol (30). For the synthesis of FQF, anthranilic acid (140 mg, 200 μmol), N -Boc-L-Ala (190 mg, 200 μmol) and triphenyl phosphite (315 μL, 220 μmol) were combined with anhydrous pyridine (5 mL) in a round-bottom flask and heated in an oil bath for 16 hrs at 55°C.…”

Section: Methodsmentioning

confidence: 99%

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Enzymatic Processing of Fumiquinazoline F: A Tandem Oxidative-Acylation Strategy for the Generation of Multicyclic Scaffolds in Fungal Indole Alkaloid Biosynthesis

2010

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Aspergillus fumigatus Af293 is a known producer of quinazoline natural products including the antitumor fumiquinazolines, of which the simplest member is fumiquinazoline F (FQF) with a 6-6-6 tricyclic core derived from anthranilic acid, tryptophan, and alanine. FQF is the proposed biological precursor to fumiquinazoline A (FQA) where the pendant indole side chain has been modified via oxidative coupling of an additional molecule of alanine, yielding a fused 6-5-5 imidazoindolone. We recently identified fungal anthranilate-activating non-ribosomal peptide synthetase (NRPS) domains through bioinformatics approaches. One domain previously identified is part of the trimodular NRPS Af12080, which we predict is responsible for FQF formation. We now show that two adjacent A. fumigatus ORFs, a monomodular NRPS Af12050 and a flavoprotein Af12060, are necessary and sufficient to convert FQF to FQA. Af12060 oxidizes the 2',3'-double bond of the indole side chain of FQF, and the three-domain NRPS Af12050 activates L-Ala as the adenylate, installs it as the pantetheinyl thioester on its carrier protein domain and acylates the oxidized indole for subsequent intramolecular cyclization to create the 6-5-5 imidazolindolone of FQA. This work provides experimental validation of the fumiquinazoline biosynthetic cluster of A. fumigatus A293, and describes an oxidative annulation biosynthetic strategy likely shared among several classes of polycyclic fungal alkaloids.

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Section: Methodsmentioning

confidence: 83%

Section: Methodsmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

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Enzymatic Processing of Fumiquinazoline F: A Tandem Oxidative-Acylation Strategy for the Generation of Multicyclic Scaffolds in Fungal Indole Alkaloid Biosynthesis

2010

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“…18,[20][21][22][23][24] One report containing a footnote explaining that ELS detectors are unreliable for measuring enantiomeric purity for one class of non-UV active compounds has been published. 25,26 In another case, a compound with an enantiomeric ratio of 99:1 based on UV detection appeared to be enantiomerically pure by ELS detection, but this fact was attributed to the lower sensitivity of the ELSD.…”

Section: Introductionmentioning

confidence: 98%

HPLC determinations of enantiomeric ratios

Wipf¹,

Werner²,

Twining³

et al. 2006

Chirality

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Evaporative light-scattering detection (ELSD) is widely applied in the HPLC analysis of organic compounds lacking a UV chromophore. However, this detection method is generally unsuitable for determination of enantiomeric ratios (er). The er calculated from a UV trace and an ELS trace of the same compound differs significantly. Because of the nonlinear concentration response of the ELS detector, a compound with an er of 95:5 appears to be enantiomerically pure by ELS detection. It is possible to obtain a calibration curve and to calculate a correction factor, but this procedure is time consuming and therefore not very practical for routine analyses. In contrast, a charged aerosol detector allows a very accurate determination of the enantiomeric ratios. Like the ELS detection, the CA detection is independent of the chromophore properties of the substrate. Therefore, we recommend the use of CA instead of ELS detection for determination of the enantiomeric ratios of non-UV active compounds.

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Co-ordination between BrlA regulation and secretion of the oxidoreductase FmqD directs selective accumulation of fumiquinazoline C to conidial tissues inAspergillus fumigatus

et al. 2014

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SUMMARY Aerial spores, crucial for propagation and dispersal of the Kingdom Fungi, are commonly the initial inoculum of pathogenic fungi. Natural products (secondary metabolites) have been correlated with fungal spore development and enhanced virulence in the human pathogen Aspergillus fumigatus but mechanisms for metabolite deposition in the spore are unknown. Metabolomic profiling of A. fumigatus deletion mutants of fumiquinazoline (Fq) cluster genes reveal that the first two products of the Fq cluster, FqF and FqA, are produced to comparable levels in all fungal tissues but the final enzymatically-derived product, FqC, predominantly accumulates in the fungal spore. Loss of the sporulation-specific transcription factor, BrlA, yields a strain unable to produce FqA or FqC. Fluorescence microscopy showed FmqD, the oxidoreductase required to generate FqC, was secreted via the Golgi apparatus to the cell wall in an actin-dependent manner. In contrast, all other members of the Fq pathway including the putative transporter, FmqE – which had no effect on Fq biosynthesis – were internal to the hyphae. The coordination of BrlA-mediated tissue specificity with FmqD secretion to the cell wall presents a previously undescribed mechanism to direct localization of specific secondary metabolites to spores of the differentiating fungus.

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Three‐Component One‐Pot Total Syntheses of Glyantrypine, Fumiquinazoline F, and Fiscalin B Promoted by Microwave Irradiation.

Cited by 5 publications

References 1 publication

Enzymatic Processing of Fumiquinazoline F: A Tandem Oxidative-Acylation Strategy for the Generation of Multicyclic Scaffolds in Fungal Indole Alkaloid Biosynthesis

Enzymatic Processing of Fumiquinazoline F: A Tandem Oxidative-Acylation Strategy for the Generation of Multicyclic Scaffolds in Fungal Indole Alkaloid Biosynthesis

HPLC determinations of enantiomeric ratios

Co-ordination between BrlA regulation and secretion of the oxidoreductase FmqD directs selective accumulation of fumiquinazoline C to conidial tissues inAspergillus fumigatus

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