Kye-Simeon Masters

Xanthones from Fungi, Lichens, and Bacteria: The Natural Products and Their Synthesis

Many fungi, lichens, and bacteria produce xanthones (derivatives of 9H-xanthen-9-one, “xanthone” from the Greek “xanthos”, for “yellow”) as secondary metabolites. Xanthones are typically polysubstituted and occur as either fully aromatized, dihydro-, tetrahydro-, or, more rarely, hexahydro-derivatives. This family of compounds appeals to medicinal chemists because of their pronounced biological activity within a notably broad spectrum of disease states, a result of their interaction with a correspondingly diverse range of target biomolecules. This has led to the description of xanthones as “privileged structures”.(1) Historically, the total synthesis of the natural products has mostly been limited to fully aromatized targets. Syntheses of the more challenging partially saturated xanthones have less frequently been reported, although the development in recent times of novel and reliable methods for the construction of the (polysubstituted) unsaturated xanthone core holds promise for future endeavors. In particular, the fascinating structural and biological properties of xanthone dimers and heterodimers may excite the synthetic or natural product chemist.

On the importance of an acid additive in the synthesis of pyrido[1,2-a]benzimidazoles by direct copper-catalyzed amination.

Pyrido[1,2-a]benzimidazoles1, 2a are interesting compounds both from the viewpoint of medicinal chemistry2–7 (solubility,7 DNA intercalation3) and materials chemistry8 (fluorescence). Of note among the former is the antibiotic drug Rifaximin,5 which contains this heteroaromatic core. The classical synthetic approach for the assembly of pyrido[1,2-a]benzimidazoles is by [3+3] cyclocondensation of benzimidazoles containing a methylene group at C2 with appropriate bielectrophiles.2a However, these procedures are often low-yielding, involve indirect/lengthy sequences, and/or provide access to a limited range of products, primarily providing derivatives with substituents located on the pyridine ring (A ring, Scheme 1).2–4 Theoretically, a good alternative synthetic method for the synthesis of pyrido[1,2-a]benzimidazoles with substituents in the benzene ring (C ring) should be accessible by intramolecular transition-metal-catalyzed CN bond formation in N-(2-chloroaryl)pyridin-2-amines, based on chemistry recently developed in our research group.9 These substrates themselves are easily available through SNAr or selective Pd-catalyzed amination10 of 2-chloropyridine with 2-chloroanilines.11 If a synthetic procedure that eliminated the need for preactivation of the 2-position of the 2-chloroarylamino entity could be developed, this would be even more powerful, as anilines are more readily commercially available than 2-chloroanilines. Therefore the synthesis of pyrido[1,2-a]benzimidazoles (4) by a transition-metal-catalyzed intramolecular CH amination approach from N-arylpyridin-2-amines (3) was explored (Scheme 1).

The Acetal Concept: Regioselective Access to ortho,ortho‐Diphenols via Dibenzo‐1,3‐dioxepines

Traditional methods are ill-suited for the synthesis of ortho,ortho-biphenols, a structural motif found in many polyphenolic natural products, as well as synthetically useful compounds such as the chiral ligands binol, vapol, and vanol. The new route consists of a radical-based reaction of an acetal-tethered biphenyl ether substrate and subsequent hydrolytic cleavage of the dibenzo-1,3-dioxepine intermediate.

ortho-Bromo(propa-1,2-dien-1-yl)arenes: Substrates for Domino Reactions

o-Bromo(propa-1,2-dien-1-yl)arenes exhibit novel and orthogonal reactivity under Pd catalysis in the presence of secondary amines to form enamines (concerted Pd insertion, intramolecular carbopalladation, and terminative Buchwald-Hartwig coupling) and of amides to form indoles (addition, Buchwald-Hartwig cyclization, and loss of the acetyl group). The substrates for these reactions can be accessed in a reliable and highly selective two-step process from 2-bromoaryl bromides.

Double trouble - the art of synthesis of chiral dimeric natural products

Double or nothing! Recently the total synthesis of secalonic acids A and D was reported. This work and other natural product syntheses with a dimerization step as a common feature are featured in this Highlight. The significant biological activity of the secalonic acids and the fact that their synthesis has fascinated synthetic chemists for the past forty years make this work a milestone in natural product synthesis.

TMIO-PyrImid Hybrids are Profluorescent, Site-Directed Spin Labels for Nucleic Acids

We report the synthesis of a new class of molecules which are hybrids of long-lived tetramethylisoindolinoxyl (TMIO) radicals and the pyrido[1,2-a]benzimidazole (PyrImid) scaffold. These compounds represent a new lead for noncovalently binding nucleic acid probes, as they interact with nucleic acids with previously unreported C (DNA) and C/U (RNA) complementarity, which can be detected by electron paramagnetic resonance (EPR) techniques. They also have promising properties for fluorimetric analysis, as their fluorescent spin-quenched derivatives exhibit a significant Stokes shift.

Technical Note: Preliminary investigations into the use of a functionalised polymer to reduce diffusion in Fricke gel dosimeters

PURPOSE A modification of the existing PVA-FX hydrogel has been made to investigate the use of a functionalised polymer in a Fricke gel dosimetry system to decrease Fe(3+) diffusion. METHODS The chelating agent, xylenol orange, was chemically bonded to the gelling agent, polyvinyl alcohol (PVA) to create xylenol orange functionalised PVA (XO-PVA). A gel was created from the XO-PVA (20% w/v) with ferrous sulfate (0.4 mM) and sulfuric acid (50 mM). RESULTS This resulted in an optical density dose sensitivity of 0.014 Gy(-1), an auto-oxidation rate of 0.0005 h(-1), and a diffusion rate of 0.129 mm(2) h(-1); an 8% reduction compared to the original PVA-FX gel, which in practical terms adds approximately 1 h to the time span between irradiation and accurate read-out. CONCLUSIONS Because this initial method of chemically bonding xylenol orange to polyvinyl alcohol has inherently low conversion, the improvement on existing gel systems is minimal when compared to the drawbacks. More efficient methods of functionalising polyvinyl alcohol with xylenol orange must be developed for this system to gain clinical relevance.

A Concise Approach to the Polycyclic Scaffold of Frondosin D

In a study directed at developing a concise approach to the polycyclic core of frondosin D, a Stille-Heck sequence has been identified that gives direct access to the trimethylbicyclo[5.4.0]undecane ring system common to all frondosins.

Multi-bond forming and iodo-selective base-promoted homolytic aromatic substitution

Base-promoted homolytic aromatic substitution (BHAS) has been applied as a means to effect multi-bond forming reactions. Using the dioxepine framework to illustrate the concept, BHAS was used to rapidly access regio-defined polycycles in merely 2 or 3 steps from iodophenol. Both liquid and solid arenes of an electronically-diverse nature were used as the coupling partner/solvent. DMSO additive was found to promote this multi-BHAS reaction. A pathway consistent with these observations is suggested, this hypothesis was exploited to further develop an iodo-selective BHAS reaction.

A reduction of diffusion in PVA Fricke hydrogels

A modification to the PVA-FX hydrogel whereby the chelating agent, xylenol orange, was partially bonded to the gelling agent, poly-vinyl alcohol, resulted in an 8% reduction in the post irradiation Fe3+ diffusion, adding approximately 1 hour to the useful timespan between irradiation and readout. This xylenol orange functionalised poly-vinyl alcohol hydrogel had an OD dose sensitivity of 0.014 Gy−1 and a diffusion rate of 0.133 mm2 h−1. As this partial bond yields only incremental improvement, it is proposed that more efficient methods of bonding xylenol orange to poly-vinyl alcohol be investigated to further reduce the diffusion in Fricke gels.