Synthesis of 4‐Methyl Pyrrolo[2,3‐b]xanthone,a Novel Ring System

A short, high yielding synthesis of a novel substituted pyrrolo[2,3-b]xanthone has been developed. The synthesis begins with a copper catalyzed Ullmann coupling reaction followed by and intramolecular Friedel-Crafts acylation reaction to establish the xanthone core structure. After a regioselective nitration, a Leimgruber-Batcho synthesis establishes the final pyrrole ring.     

Genome-based deletion analysis reveals the prenyl xanthone biosynthesis pathway in Aspergillus nidulans

Xanthones are a class of molecules that bind to a number of drug targets and possess a myriad of biological properties. An understanding of xanthone biosynthesis at the genetic level should facilitate engineering of second-generation molecules and increasing production of first-generation compounds. The filamentous fungus Aspergillus nidulans has been found to produce two prenylated xanthones, shamixanthone and emericellin, and we report the discovery of two more, variecoxanthone A and epishamixanthone. Using targeted deletions that we created, we determined that a cluster of 10 genes including a polyketide synthase gene, mdpG, is required for prenyl xanthone biosynthesis. mdpG was shown to be required for the synthesis of the anthraquinone emodin, monodictyphenone, and related compounds, and our data indicate that emodin and monodictyphenone are precursors of prenyl xanthones. Isolation of intermediate compounds from the deletion strains provided valuable clues as to the biosynthetic pathway, but no genes accounting for the prenylations were located within the cluster. To find the genes responsible for prenylation, we identified and deleted seven putative prenyltransferases in the A. nidulans genome. We found that two prenyltransferase genes, distant from the cluster, were necessary for prenyl xanthone synthesis. These genes belong to the fungal indole prenyltransferase family that had previously been shown to be responsible for the prenylation of amino acid derivatives. In addition, another prenyl xanthone biosynthesis gene is proximal to one of the prenyltransferase genes. Our data, in aggregate, allow us to propose a complete biosynthetic pathway for the A. nidulans xanthones.     

Concise Approach to 1,4-Dioxygenated Xanthones via Novel Application of the Moore Rearrangement

The rapid synthesis of 1,4-dioxygenated xanthones and related natural products employing the Moore rearrangement as a key transformation has been developed. The approach features an acetylide stitching step to unite a substituted squaric acid with a protected hydroxy benzaldehyde derivative to provide a key intermediate that undergoes facile Moore rearrangement to deliver a hydroxymethyl aryl quinone. Subsequent oxidation, hydroxy group deprotection and cyclization then affords highly functionalized xanthones. The utility of the approach was demonstrated by its application to a concise and efficient synthesis of the naturally-occurring xanthone 1. The structure of a natural product that had been named dulcisxanthone C was also corrected to that of the xanthone 1.     

Efficient synthesis of fluorescent rosamines: multifunctional platforms for cellular imaging

Substituted rosamines are efficiently prepared through a new organometallic addition to an imine-substituted xanthone as a novel primary amine equivalent. The synthesis reduces the number of synthetic steps to the targeted rosamines, for convenient and facile access to potential libraries of rosamine dyes. The prepared rosamine derivatives represent unique multifunctional platforms that possess radiolabeling capability and fluorescence. Rosamines have (i) useful non-specific binding properties in mammalian cells and plant root hair, and (ii) positive uptake or binding properties in microbial systems.     

Synthesis of xanthone O-glycosides. Part III. Synthesis of 1- and 8-O-β-D-glycosides of 5-O-methyl- and de-O-methylbellidifolin

The unambiguous synthesis of three naturally occurring and biologically active xanthone 1-O and 8-O-β-D -glucosides of 5-O-methyl- and de-O-methylbellidifolin ( 2–4 ) was accomplished. The protected xanthone aglycones having only a single reactive OH group were prepared by selective benzylation, methylation, and debenzoylation reactions. An unexpected stability of the 1-MeO group towards demethylation was observed.     

Total synthesis of atroviridin

A total synthesis of atroviridin (1) based on biosynthetic principles is presented. The tetracyclic xanthone structure of the natural product was constructed by coupling aryl bromide 8 with aldehyde 7 and subsequent intramolecular conjugate addition on a quinone precursor. Bromide 8 was produced from aldehyde 9 via a sequence of steps involving Baeyer-Villiger oxidation and Claisen cyclization.     

On the relationships between molecular conformations and intermolecular contacts toward crystal self-assembly of mono-, di-, tri-, and tetra-oxygenated xanthone derivatives

Oxygenated xanthones have been extensively investigated over the years, but there are few reports concerning their crystal structure. Our chemical investigations of Brazilian plants resulted in the isolation of four natural products named 1-hydroxyxanthone (I), 1-hydroxy-7-methoxyxanthone (II), 1,5-dihydroxy-3-methoxyxanthone (III), and 1,7-dihydroxy-3,8-dimethoxyxanthone (IV). The structures of these compounds were established on the basis of single crystal X-ray diffraction. The xanthone nucleus conformation is essentially planar with the substituents adopting the orientations less sterically hindered. In addition, classical intermolecular hydrogen bonds (O–H···O) present in III and IV give rise to infinite ribbons. However, the xanthone I does not present any intermolecular hydrogen bonds, meanwhile the xanthone II presents only a non-classical one (C–H···O). The crystal packing of all xanthone structures is also stabilized by π–π interactions. The fingerprint plots, derived from the Hirshfeld surfaces, exhibited significant features of each crystal structures.     

Xanthone natural products via N-heterocyclic carbene catalysis: total synthesis of atroviridin

The total synthesis of atroviridin has been accomplished by a linear route involving the N-heterocyclic carbene (NHC)-catalyzed aroylation of the fluorobenzene derivative, Claisen cyclization of the O-propargylated benzophenones, and intramolecular 1,4-addition of the quinone intermediates. The result provides a viable route to xanthone natural products.     

Xanthone Glucosides: Isolation,Bioactivity and Synthesis

Xanthones are secondary metabolites found in plants, fungi, lichens, and bacteria from a variety of families and genera, with the majority found in the Gentianaceae, Polygalaceae, and Clusiaceae. They have a diverse range of bioactivities, including anti-oxidant, anti-bacterial, anti-malarial, anti-tuberculosis, and cytotoxic properties. Xanthone glucosides are a significant branch of xanthones. After glycosylation, xanthones may have improved characteristics (such as solubility and pharmacological activity). Currently, no critical review of xanthone glucosides has been published. A literature survey including reports of naturally occurring xanthone glucosides is included in this review. The isolation, structure, bioactivity, and synthesis of these compounds were all explored in depth.     

One-step Construction of Xanthone Scaffold Assisted by Microwave Irradiation to Optimize the Synthesis of DMXAA

An efficient and concise synthesis of 5,6-dimethylxanthenone-4-acetic acid(DMXAA) was developed. The overall yield of this 3-step procedure was 82%. The key reaction is the one-step construction of xanthone scaffold between 2,5-dibromo-3,4-dimethylbenzoic acid and 2-hydroxyphenyl-acetic acid assisted by microwave irradiation.     

Solvent-controlled leaving-group selectivity in aromatic nucleophilic substitution

A solvent-controlled inversion of leaving group ability allows selective access to either of two internal substitution products in S(N)Ar reactions of substrates with competing leaving groups. Application of this principle in a selective synthesis of the highly functionalized xanthone core of the antibiotic FD-594 is presented.     

Toward the total synthesis of citreamicin η: Synthesis of the pentacyclic core and GAB-ring annelation model studies

A short 11-step synthesis of the pentacyclic core of the polycyclic xanthone antibiotic citreamicin η has been completed. Although the basic approach was inspired by our previous explorations of polycyclic xanthone chemistry, the present report features some new insights into the Moore rearrangement and offers some improvements to our original methodology that include additions of aryllithiums to squarate esters, additions of cerium acetylides to hindered ketones utilizing PDA as an internal indicator, and the use of cyclic di-tert-butylsilyl (DTBS) ethers to protect electron-rich benzyl alcohols toward ionization under acidic conditions. We also developed an improved protocol for selective o-bromination of phenols utilizing N-bromosuccinimide (NBS) and tetramethylguanidine (TMG) that promises to be generally useful. Finally, we developed a modular approach for the synthesis of isoquinolones and dihydro-5H-oxazolo[3,2-b]isoquinoline-2,5(3H)-diones that features a novel sequence of alkoxycarbonylation, acetone arylation, transamidation.     

General and expedient synthesis of 1,4-dioxygenated xanthones

A facile entry to 1,4-dioxygenated xanthones having a variety of substitution patterns and substituents was developed that features a novel application of the Moore cyclization using substrates that were readily assembled in a highly convergent fashion by an acetylide stitching process. The practical utility of the methodology was demonstrated by an efficient synthesis of a naturally occurring xanthone and correction of the structure of dulcisxanthone C.     

Ordering the reductive and cytochrome P450 oxidative steps in demethylsterigmatocystin formation yields general insights into the biosynthesis of aflatoxin and related fungal metabolites

The biosynthesis of the potent environmental carcinogen aflatoxin B1 involves ca. 15 steps beyond the first polyketide intermediate. Central among these is the rearrangement of the anthraqinone versicolorin A to the xanthone demethylsterigmatocystin. Genetic evidence strongly suggests that two enzymes are required for this process, a cytochrome P450, AflN, and a probable NADPH-dependent oxidoreductase, AflM. Given the overall redox change evident in this skeletal rearrangement, two rounds of oxidation and a reduction necessarily occur. Earlier experiments indicated that reductive deoxygenation of versicolorin A is not the first step. In the present report we consider a mechanistic alternative that AflM-mediated reduction is instead the last of these three reactions prior to formation of the xanthone intermediate. To this end, 9-hydroxydihydrodemethylsterigmatocystin was prepared by total synthesis as was its 9-deoxy analogue, an established aflatoxin precursor. During the final isolation of the "angular" synthetic xanthone targets it was found that acid catalysis promoted their isomerization to thermodynamically favored "linear" xanthones. Whole-cell and ground-cell incubations of the 9-hydroxy- and 9-deoxyxanthones were conducted with a mutant strain of Aspergillus parasiticus blocked at the first step of the pathway and examined for their ability to support aflatoxin production. The 9-deoxyxanthone gave dramatically enhanced levels of the mycotoxin. The 9-hydroxyxanthone, on the other hand, afforded no detectable increase in aflatoxins above controls, indicating that reductive deoxygenation at C-9 of a xanthone precursor does not take place in aflatoxin biosynthesis. Constraints imposed by earlier studies and the experiments in this paper serve to eliminate simple and intuitive conversions of versicolorin A to demethylsterigmatocystin and lead inescapably to a more subtle reaction sequence of oxidation-reduction-oxidation. Previous puzzling observations of extensive A-ring hydrogen exchange in the course of the rearrangement of versicolorin A to demethylsterigmatocystin have now been explained by a new mechanism that is consistent with all extant data. We propose that P450-mediated aryl epoxidation (AflN) initially disrupts the aromatic A-ring of versicolorin A. Oxirane opening enables A-ring proton exchange, as does the subsequent AflM-mediated reductive step. A second cycle of P450 oxidation (AflN), this time a Baeyer-Villiger cleavage, enables decarboxylation and the formation of demethylsterigmatocystin. Mechanistic and stereoelectronic principles that underlie this proposal are described and may prove general as illustrated in biogenetic hypotheses for four other fungal anthraquinone --> xanthone transformations.     

Iron-mediated synthetic routes to unsymmetrically substituted, sterically congested benzophenones

A new synthetic route to unsymmetrically substituted benzophenones, relying upon iron-mediated reactions in all of the key steps, is described. The key buiding block, eta6-2-chloro-carbomethoxybenzene-eta5-cyclopentadienyl iron hexafluorophosphate (4), is reacted with a variety of substituted phenols, providing diaryl ether complexes (6). After hydrolysis of the ester functionalities, these complexes are subjected to Friedel-Crafts conditions. The efficiency of this intramolecular acylation reaction is very much dependent upon the substituents on the phenols. If these are appropriately chosen, xanthone complexes are isolated in fair to good yields. Regioselective ring-opening, using oxygen-nucleophiles, delivers substituted benzophenone complexes. After regioselective nucleophilic addition of cyanide ion, performed in the presence of DDQ, highly substituted benzophenones are isolated. To demonstrate the applicability of the new route, a formal synthesis of the benzophenone moiety of the protein kinase C inhibitor Balanol (3) is described.     

Contribution à la phytochimie du genre Gentiana,XVIII. Structure du gentiabavarutinoside,un nouveau glycoside xanthonique acylé isolé de Gentiana bavaricaL

Phytochemistry of genus Gentiana, XVIII: Structure of gentiabavarutinoside, a new acylated xanthone glycoside from Gentiana bavarica L. In a previous work [1], we isolated from Gentiana bavarica L . an acylated xanthone glycoside (1,8-dihydroxy-3-methoxy-xanthone-7-O-acetylrutinoside 1 or gentiabavarutinoside) without locating the acetyl group. By ¹³C-NMR. spectroscopy, the attach position of the acetyl is now shown to be at 4 of the rhamnose moiety. In addition, a new compound ( 2 ), the desacetyl derivative of 1 , has also been isolated and identified.     

Solid phase combinatorial synthesis of a xanthone library using click chemistry and its application to an embryonic stem cell probe

We report the first solid phase synthesis of a xanthone library CX and its application to embryonic stem cell probe development. The CX library was further derivatised with an activated ester resin to provide an acetylated CX (CXAC) library. Screening of these libraries led to the discovery of a novel fluorescent mESC probe, CDb8.     

Syntheses, structures, photoluminescence and theoretical studies of xanthone in crystalline resorcinarene-based inclusion complexes

Two new crystalline resorcinarene-based xanthone inclusion complexes, CECRxanthoneMeOH (1), and HECR2 xanthone6 MeOH (2) (CECR = C-ethylcalix[4]resorcinarene, HECR = hexaethylresorcin[6]arene) have been prepared to study the relation between photophysical properties and solid-state structure. Compared with the neat crystals, the xanthone phosphorescence is severely quenched in both solids, but the lifetime is an order of magnitude larger in 2, in which xanthone occurs as a dimer, than in 1, in which it occurs as a monomer. The electronic transitions involved in the photoluminescent process, and the relation between the energy levels of host and guest and emission quenching of the guest in the supramolecular solid have been investigated by means of time-dependent density functional theory (TDDFT) calculations.     

Biomimetic total synthesis of forbesione and desoxymorellin utilizing a tandem Claisen/Diels--Alder/Claisen rearrangement

A concise synthesis of forbesione (1) and desoxymorellin (3) is presented. Central to the strategy is a biomimetic Claisen/Diels-Alder/Claisen reaction cascade that proceeds in a regioselective manner and produces the desired scaffold exclusively. The observed regioselectivity and product distribution of the Claisen/Diels-Alder/Claisen reaction are attributed to the electronic effects of the xanthone oxygen (O10), the C9 carbonyl group and the nature of the C1 functionality.