Synthesis of [13 C6 ]-ibrutinib.

Convenient and straightforward synthesis of ibrutinib labeled by carbon-13 isotope is reported. Isotopically labeled building block is introduced in the last step of reaction sequence affording sufficient isolated yield (7%) of [13 C6 ]-ibrutinib calculated towards starting commercially available [13 C6 ]-bromobenzene.

Asymmetric synthesis from terminal alkenes by cascades of diboration and cross-coupling.

Terminal, monosubstituted alkenes are ideal prospective starting materials for organic synthesis because they are manufactured on very large scales and can be functionalized via a broad range of chemical transformations. Alkenes also have the attractive feature of being stable in the presence of many acids, bases, oxidants and reductants. In spite of these attributes, relatively few catalytic enantioselective transformations have been developed that transform aliphatic α-olefins into chiral products with an enantiomeric excess greater then 90 per cent. With the exception of site-controlled isotactic polymerization of α-olefins, none of these catalytic enantioselective processes results in chain-extending carbon-carbon bond formation to the terminal carbon. Here we describe a strategy that directly addresses this gap in synthetic methodology, and present a single-flask, catalytic enantioselective conversion of terminal alkenes into a number of chiral products. These reactions are facilitated by a neighbouring functional group that accelerates palladium-catalysed cross-coupling of 1,2-bis(boronates) relative to non-functionalized alkyl boronate analogues. In tandem with enantioselective diboration, this reactivity feature transforms alkene starting materials into a diverse array of chiral products. We note that the tandem diboration/cross-coupling reaction generally provides products in high yield and high selectivity (>95:5 enantiomer ratio), uses low loadings (1-2 mol per cent) of commercially available catalysts and reagents, offers an expansive substrate scope, and can address a broad range of alcohol and amine synthesis targets, many of which cannot be easily addressed with current technology.

Mechanochemical Preparation of Pd(II) and Pt(II) Composites with Carbonaceous Materials and Their Application in the Suzuki-Miyaura Reaction at Several Energy Inputs.

Pd(II) and Pt(II) composites with activated carbon (AC), graphene oxide, and multiwalled carbon nanotubes were prepared by ball milling and used as catalysts for the Suzuki-Miyaura reaction, under several energy inputs (mechanical grinding, conventional heating, and microwave irradiation). The catalytic composites were characterized by ICP-MS, BET, XPS analyses, TEM, and SEM. The average particle size of the prepared composites was estimated to be in the range of 6-30 nm, while the loadings of Pd and Pt did not significantly affect the surface area of the AC support due to the tendency to agglomerate as observed by the TEM analysis. The Pd/AC composites exhibit high mechanochemical catalytic activity in cross-coupling of bromobenzene and phenylboronic acid with molar yields up to 80% with TON and TOF of 222 and 444 h-1, respectively, achieved with Pd(4.7 wt%)-AC catalyst under the liquid assisted grinding for 0.5 h at ambient conditions, using cyclohexene as an additive.

Highly efficient preparation of active S-phenyl-L-cysteine with tryptophan synthase using a chemoenzymatic method.

BACKGROUND: S-Phenyl-L-cysteine is regarded as having potential applicability as an antiretroviral/protease inhibitor for human immunodeficiency virus (HIV). In the present study, optically active S-phenyl-L-cysteine was prepared in a highly efficient manner from inexpensive bromobenzene using tryptophan synthase through a chemoenzymatic method. RESULTS: The chemoenzymatic method used a four-step reaction sequence. The process started with the reaction of magnesium and bromobenzene, followed by a Grignard reaction, and then hydrolysis and enzymatic synthesis using tryptophan synthase. Through this approach, S-phenyl-L-cysteine was chemoenzymatically synthesized using tryptophan synthase from thiophenol and L-serine as the starting material. CONCLUSIONS: High-purity, optically active S-phenyl-L-cysteine was efficiently and inexpensively obtained in a total yield of 81.3% (> 99.9% purity).

The leaching of additive-derived flame retardants (FRs) from plastics in avian digestive fluids: The significant risk of highly lipophilic FRs.

The exposure to plastic debris and associated pollutants for wildlife is of urgent concern, but little attention has been paid on the transfer of plastic additives from plastic debris to organisms. In the present study, the leaching of incorporated flame retardants (FRs), including polybrominated diphenyl ethers (PBDEs), alternative brominated FRs (AFRs), and phosphate flame retardants (PFRs), from different sizes of recycled acrylonitrile-butadiene-styrene (ABS) polymer were investigated in avian digestive fluids. The impact of co-ingested sediment on the leaching of additive-derived FRs in digestive fluids was also explored. In the recycled ABS, BDE 209 (715 µg/g) and 1, 2-bis(2,4,6-tribromophenoxy) ethane (BTBPE, 1766 µg/g) had the highest concentrations among all target FRs. The leaching proportions of FRs were higher in finer sizes of ABS. The leaching proportions of FRs from recycled ABS increased with elevated logKOW of FRs. In the tests with coexisted ABS and sediment, hexa- to deca-BDEs, BTBPE, and decabromodiphenyl ethane (DBDPE) migrated from ABS to sediment, which resulted in the less bioaccessible fractions of these FRs in gut fluids. More lipophilic chemicals tended to be adsorbed by sediment from ABS. The results suggest the migration of additive-derived FRs from plastics to other indigestible materials in digestive fluids. The findings in this study provide insights into the transfer of additive-derived FRs from plastics to birds, and indicate the significant contribution of FR-incorporated plastics to bioaccumulation of highly lipophilic FRs.

Role of Glucuronidation and P450 Oxidation in the Bioactivation of Bromfenac.

Bromfenac is a nonsteroidal anti-inflammatory drug that was approved in the United States in 1997. It was withdrawn from clinical use less than one year later, in 1998, due to hepatotoxicity. We investigate the potential of bromfenac to be metabolized to reactive intermediates to further the current understanding of bromfenac bioactivation. Incubations were conducted with hepatocytes and human, rat, and cynomolgus liver microsomes fortified with cofactors and N-acetylcysteine. One thioether adduct of hydroxylated bromfenac and three thioether adducts of hydroxylated bromfenac indolinone were detected in extracts following incubations in liver microsomes fortified with NADPH and UDPGA. These findings demonstrate a bioactivation pathway for bromfenac and contribute to the body of evidence that could advance the understanding of the toxicity associated with bromfenac.

Hierarchical Porous Phenolic Resin and Its Supported Pd-Catalyst for Suzuki-Miyaura Reactions in Water Medium.

The motivation of this work is to build micro and mesopores within phenolic resins to extend their applications to the heterogeneous catalysis field. For this purpose, porous hyper-cross-linked phenolic resin (PFN-P) with Brunauer-Emmett-Teller (BET) surface area of 775 m2 g-1 is synthesized through one-step polycondensation from tri(4-formylphenyl)phosphine and 2,5-dihydroxy-1,4-benzoquinone, which simultaneously contains abundant hydroxyl and triphenylphosphine moieties in the network. The resultant palladium-coordinated Pd@PFN-P possesses hierarchical porous structure with pore sizes ranging from 1.3 to 42.6 nm. The good hydrophilicity and broad pore sizes are advantageous for the accessibility of reactants to the catalyzing sites in the water medium for Suzuki-Miyaura reactions. As a result, high conversions for reactions between various aryl halides and phenylboronic acid are achieved under both oxygen-free and aerobic conditions. Moreover, the reaction conversions are almost unchanged after repeatedly using Pd@PFN-P for five times, showing promising potential for application in heterogeneous catalysis.

Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aß Aggregation Inhibitors.

A marine natural product, pulmonarin B (1), and a series of related tacrine hybrid analogues were synthesized and evaluated as cholinesterase (ChE) inhibitors. The in vitro ChE assay results revealed that 1 showed moderate dual acetylcholinesterase (AChE)/ butyrylcholinesterase (BChE) inhibitory activity, while the hybrid 12j proved to be the most potent dual inhibitor among the designed derivatives, being almost as active as tacrine. Molecular modeling studies together with kinetic analysis suggested that 12j interacted with both the catalytic active site and peripheral anionic site of AChE. Compounds 1 and 12j could also inhibit self-induced and AChE-induced Aß aggregation. In addition, the cell-based assay against the human hepatoma cell line (HepG2) revealed that 1 and 12j did not show significant hepatotoxicity compared with tacrine and donepezil. Taken together, the present study confirmed that compound 1 was a potential anti-Alzheimer's disease (AD) hit, and 12j could be highlighted as a multifunctional lead compound for anti-AD drug development.

Pd-Catalyzed, Highly Selective C(sp²)-Br Bond Coupling Reactions of o-(or m-, or p-) Chloromethyl Bromobenzene with Arylboronic Acids.

Highly selective C(sp²)-C(sp²) cross-coupling of dihalogenated hydrocarbons comprising C(sp²)-Br and C(sp³)-Cl bonds with arylboronic acids is reported. This highly selective coupling reaction of the C(sp²)-Br bond is successfully achieved using Pd(OAc)2 and PCy3·HBF4 as the palladium source and ligand, respectively. A series of chloromethyl-1,1'-biphenyl compounds are obtained in moderate-to-excellent yields. Moreover, this protocol can be extended to the one-pot dual arylation of 1-bromo-4-(chloromethyl)benzene with two arylboronic acids, leading to diverse unsymmetrical 4-benzyl-1,1'-biphenyl derivatives.

Synthesis of Transition-State Inhibitors of Chorismate Utilizing Enzymes from Bromobenzene cis-1,2-Dihydrodiol.

In order to survive in a mammalian host, Mycobacterium tuberculosis (Mtb) produces aryl-capped siderophores known as the mycobactins for iron acquisition. Salicylic acid is a key building block of the mycobactin core and is synthesized by the bifunctional enzyme MbtI, which converts chorismate into isochorismate via a SN2″ reaction followed by further transformation into salicylate through a [3,3]-sigmatropic rearrangement. MbtI belongs to a family of chorismate-utilizing enzymes (CUEs) that have conserved topology and active site residues. The transition-state inhibitor 1 described by Bartlett, Kozlowski, and co-workers is the most potent reported inhibitor to date of CUEs. Herein, we disclose a concise asymmetric synthesis and the accompanying biochemical characterization of 1 along with three closely related analogues beginning from bromobenzene cis-1S,2S-dihydrodiol produced through microbial oxidation that features a series of regio- and stereoselective transformations for introduction of the C-4 hydroxy and C-6 amino substituents. The flexible synthesis enables late-stage introduction of the carboxy group and other bioisosteres at the C-1 position as well as installation of the enol-pyruvate side chain at the C-5 position.

Total Synthesis of Lycoricidine and Narciclasine by Chemical Dearomatization of Bromobenzene.

The total synthesis of lycoricidine and narciclasine is enabled by an arenophile-mediated dearomative dihydroxylation of bromobenzene. Subsequent transpositive Suzuki coupling and cycloreversion deliver a key biaryl dihydrodiol intermediate, which is rapidly converted into lycoricidine through site-selective syn-1,4-hydroxyamination and deprotection. The total synthesis of narciclasine is accomplished by the late-stage, amide-directed C-H hydroxylation of a lycoricidine intermediate. Moreover, the general applicability of this strategy to access dihydroxylated biphenyls is demonstrated with several examples.

Scalable, Metal- and Additive-Free, Photoinduced Borylation of Haloarenes and Quaternary Arylammonium Salts.

We report herein a simple, metal- and additive-free, photoinduced borylation of haloarenes, including electron-rich fluoroarenes, as well as arylammonium salts directly to boronic acids. This borylation method has a broad scope and functional group tolerance. We show that it can be further extended to boronic esters and carried out on gram scale as well as under flow conditions.

Conversion of the Enzymatically Derived (1S,2S)-3-Bromocyclohexa-3,5-diene-1,2-diol into Enantiomerically Pure Compounds Embodying the Pentacyclic Framework of Vindoline.

The enzymatically derived and enantiomerically pure (1S,2S)-3-bromocyclohexa-3,5-diene-1,2-diol (7) has been elaborated over 17 steps into compounds 8 and 32, each of which embodies the pentacyclic framework and much of the functionality associated with the alkaloid vindoline (3). This work sets the stage for effecting the conversion of the related metabolite (1S,6R)-5-ethyl-1,6-dihydroxycyclohexa-2,4-diene-1-carboxylic acid (4) into compound 3, the latter being a biogenetic precursor to the clinically significant anticancer agents vinblastine and vincristine.

Identification of a Small Benzamide Inhibitor of Influenza Virus Using a Cell-Based Screening.

BACKGROUND: The zoonotic transmission of highly pathogenic avian influenza viruses and the global pandemic of H1N1 influenza in 2009 signified the need for a wider coverage of therapeutic options for the control of influenza. METHODS: An in-house compound library was screened using a cytopathic effect inhibition assay. Selected hits were then tested in vivo and used as a core skeleton for derivative synthesis. RESULTS: The hit compound (BMD-2601505) was effective [50% effective concentration (EC50) of 60-70 µM] in reducing the death rate of cells infected with human influenza A and B viruses as well as avian influenza A virus. Furthermore, BMD-2601505 reduced the weight loss and increased the survival after lethal infection. The compound was further modified to enhance its antiviral potency. Results show that one derivative with bromobenzene moiety was most effective (EC50 of 22-37 µM) against the influenza viruses tested. CONCLUSION: We identified a small benzamide compound exhibiting antiviral activity against influenza viruses. The results warrant further evaluation of antiviral activities against drug-resistant influenza isolates.

Synthesis of C2-Symmetric Benzimidazolium Salts and Their Application in Palladium-Catalyzed Enantioselective Intramolecular α-Arylation of Amides.

A series of C2-symmetric chiral benzimidazolium salts, the precursor of N-heterocyclic carbene ligands, were designed and synthesized from 1,2-dibromobenzene. In situ prepared corresponding carbenes were tested in the asymmetric palladium-catalyzed intramolecular α-arylation of amides, affording chiral diarylmethanols with high yields and moderate enantioselectivities.

Metal-free C-H amination of unactivated hydrocarbons with sulfonylimino-λ(3)-bromanes generated in situ from (diacetoxybromo)benzene.

A simple method for direct metal-free C-H amination of unactivated hydrocarbons using easy-handling diacetoxy-λ(3)-bromane and triflylamide or sulfamate esters was developed. The high 2°/3° regioselectivities and deuterium isotope effects suggest a concerted organonitrenoid transition state, analogous to C-H amination with N-triflylimino-λ(3)-bromane.

Bioactive secondary metabolites from the Red Sea marine Verongid sponge Suberea species.

In a continuation of our efforts to identify bioactive compounds from Red Sea Verongid sponges, the organic extract of the sponge Suberea species afforded seven compounds including two new dibrominated alkaloids, subereamollines C and D (1 and 2), together with the known compounds aerothionin (3), homoaerothionin (4), aeroplysinin-1 (5), aeroplysinin-2 (6) and a revised subereaphenol C (7) as ethyl 2-(2,4-dibromo-3,6-dihydroxyphenyl)acetate. The structures of the isolated compounds were assigned by different spectral data including optical rotations, 1D (1H and 13C) and 2D (COSY, multiplicity-edited HSQC, and HMBC) NMR and high-resolution mass spectroscopy. Aerothionin (3) and subereaphenol C (7) displayed potent cytotoxic activity against HeLa cell line with IC50 values of 29 and 13.3 µM, respectively. In addition, aeroplysinin-2 (6) showed potent antimigratory activity against the human breast cancer cell line MDA-MB-231 with IC50 of 18 µM. Subereamollines C and D are new congeners of the previously reported compounds subereamollines A and B with methyl ester functionalities on the side chain. These findings provide further insight into the biosynthetic capabilities of members of the genus Suberea and the chemical diversity as well as the biological activity of these compounds.

Efficient palladium-catalyzed double carbonylation of o-dibromobenzenes: synthesis of thalidomide.

We describe here a convenient and mild procedure for double carbonylation of o-dibromobenzenes with various 2-amino pyridines and naturally occurring amines, thus providing in good to excellent yields N-substituted phthalimides by using this palladium-catalyzed carbonylation procedure. Furthermore, for the first time we have applied the developed synthetic protocol for the synthesis of biologically active molecule thalidomide via a single step carbonylative cyclization reaction in excellent yield.

A facile route to 5-methyl-5H-indeno[1,2-c]quinolones via palladium-catalyzed cyclization of 2-alkynylbromobenzenes with N,N-dimethyl-2-alkynylanilines.

A tandem reaction catalyzed by palladium is developed to provide a facile and simple route for the synthesis of 5-methyl-5H-indeno[1,2-c]quinolones, which can introduce diversity and complexity into the products from readily available starting materials. This transformation proceeds well with good functional group tolerance.

Thermal decomposition of 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), a novel brominated flame retardant.

1,2-Bis(2,4,6-tribromophenoxy)ethane (BTBPE) is currently one of the most commonly applied novel brominated flame retardants. In this contribution, we analyze in detail the mechanisms pertinent to its thermal decomposition in view of analogous experimental findings. We demonstrate that a 1,3-hydrogen shift, leading to 2,4,6-tribromophenol (M9) and 1,3,5-tribromo-2-(vinyloxy)benzene (M10) molecules, dominates direct scission of O-CH2 bonds up to a temperature of ∼ 680 K. H atom abstraction from CH2 sites, followed by a fission of a C-C bond, produce a 2,4,6-tribromophenoxy radical (M2) and a M10 molecule. Bimolecular condensation reactions involving M2, M9, and M10 generate several congeners of brominated diphenyl ethers and their OH/OCHCH2 substituents, which serve as direct precursors for the formation of polybrominated dibenzo-p-dioxins. Reaction of M9 with a model compound of a hydrocarbon chain preferentially yields M2. Strong adsorption energy of the latter on a radical site of a hydrocarbon chain suggests that mechanisms such as Langmuir-Hinshelwood, Eley-Rideal, and Diels-Alder might be operating during the formation of PBDD/Fs from brominated flame retardants (BFRs). Reactions of alkyl primary/secondary radicals and diradical with the BTBPE molecule proceed via H abstraction from a -CH2- moiety.