Biogenic Palladium Improved Perchlorate Reduction during Nitrate Co-Reduction by Diverting Electron Flow in a Hydrogenotrophic Biofilm.

Microbial reduction of perchlorate (ClO4-) is emerging as a cost-effective strategy for groundwater remediation. However, the effectiveness of perchlorate reduction can be suppressed by the common co-contamination of nitrate (NO3-). We propose a means to overcome the limitation of ClO4- reduction: depositing palladium nanoparticles (Pd0NPs) within the matrix of a hydrogenotrophic biofilm. Two H2-based membrane biofilm reactors (MBfRs) were operated in parallel in long-term continuous and batch modes: one system had only a biofilm (bio-MBfR), while the other incorporated biogenic Pd0NPs in the biofilm matrix (bioPd-MBfR). For long-term co-reduction, bioPd-MBfR had a distinct advantage of oxyanion reduction fluxes, and it particularly alleviated the competitive advantage of NO3- reduction over ClO4- reduction. Batch tests also demonstrated that bioPd-MBfR gave more rapid reduction rates for ClO4- and ClO3- compared to those of bio-MBfR. Both biofilm communities were dominated by bacteria known to be perchlorate and nitrate reducers. Functional-gene abundances reflecting the intracellular electron flow from H2 to NADH to the reductases were supplanted by extracellular electron flow with the addition of Pd0NPs.

Moderately lipophilic 2-(Het)aryl-6-dithioacetals, 2-phenyl-1,4-benzodioxane-6-dithioacetals and 2-phenylbenzofuran-5-dithioacetals: Synthesis and primary evaluation as potential antidiabetic AMPK-activators.

Since the 1950's, AMP-kinase (AMPK) has been used as a promising target for the development of antidiabetic drugs against Type 2 diabetes mellitus (T2D). Indeed, the canonical antidiabetic drug metformin recruits, at least partially, AMPK activation for its therapeutic effect. Herein we present design and synthesis of 20 novel relatively polar cyclic and acyclic dithioacetals of 2-(Het)arylchroman-6-carbaldehydes, 2-phenyl-1,4-benzodioxane-6-carbaldehyde, and 2-phenylbenzofuran-5-carbaldehyde, which were developed as potential AMPK activators. Three of the synthesized dithioacetals demonstrated significant enhancement (≥70%) of glucose uptake in rat L6 myotubes. Noteworthy, one of the dithioacetals, namely 4-(6-(1,3-dithian-2-yl)chroman-2-yl)pyridine, exhibited high potency comparing to other molecules. It increased the rate of glucose uptake in rat L6 myotubes and augmented insulin secretion from rat INS-1E cells in pharmacological relevant concentrations (up to 2 µM). Both effects were mediated by activation of AMPK. In addition, the compound showed excellent pharmacokinetic profile in healthy mice, including maximal oral bioavailability. Such bifunctionality (increased glucose uptake and insulin secretion) can be used as a starting point for the development of a novel class of antidiabetic drugs with dual activity that is relevant for T2D treatment.

Design, synthesis, and anticancer evaluation of 1-benzo[1,3]dioxol-5-yl-3-N-fused heteroaryl indoles.

A series of 1-benzo[1,3]dioxol-5-yl-indoles bearing 3-N-fused heteroaryl moieties have been designed based on literature reports of the activity of indoles against various cancer cell lines, synthesized via a Pd-catalyzed C-N cross-coupling, and evaluated for their anticancer activity against prostate (LNCaP), pancreatic (MIA PaCa-2), and acute lymphoblastic leukemia (CCRF-CEM) cancer cell lines. A detailed structure-activity relationship study culminated in the identification of 3-N-benzo[1,2,5]oxadiazole 17 and 3-N-2-methylquinoline 20, whose IC50 values ranged from 328 to 644 nM against CCRF-CEM and MIA PaCa-2. Further mechanistic studies revealed that 20 caused cell cycle arrest at the S phase and induced apoptosis in CCRF-CEM cancer cells. These 1-benzo[1,3]dioxol-5-yl-3-N-fused heteroaryl indoles may serve as a template for further optimization to afford more active analogs and develop a comprehensive understanding of the structure-activity relationships of indole anticancer molecules.

Efficient Synthesis of Fluorescent Coumarins and Phosphorous-Containing Coumarin-Type Heterocycles via Palladium Catalyzed Cross-Coupling Reactions.

Quantum-chemical calculations on the spectral properties of some aryl substituted 3-phosphonocoumarins were performed, and the effect of the substituents in the aryl moiety was evaluated. The structures possessing promising fluorescent properties were successfully synthesized via Suzuki and Sonogashira cross-coupling. The synthetic protocol was also applied for the phosphorous chemoisomer of 3-phosphonocoumarin, 1,2-benzoxaphosphorin, and their carboxylate analogues. The optical properties of the arylated and alkynylated products were experimentally determined. The obtained quantum-chemical and experimental results give the possibility for a fine tuning of the optical properties of phosphorous-containing coumarin systems by altering the substituent at its C-6 position.

Design, Synthesis, Evaluation and Structure of Allenic 1α,25-Dihydroxyvitamin D3 Analogs with Locked Mobility at C-17.

Vitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However, hypercalcemic effects limit their therapeutical uses and call for the development of tissue-selective new analogs. We have designed and synthesized the first examples of 1α,25-dihydroxyvitamin D3 analogs bearing an allenic unit attached to the D ring to restrict the side-chain conformational mobility. The triene system was constructed by a Pd0 -mediated cyclization/Suzuki-Miyaura cross-coupling process in the presence of an allenic side chain. The allenic moiety was built through an orthoester-Claisen rearrangement of a propargylic alcohol. The biological activity and structure of (22S)-1α,25-dihydroxy-17,20-dien-24-homo-21-nor-vitamin D3 bound to binding domain of the vitamin D receptor, provide information concerning side-chain conformational requirements for biological activity.

Enabling the Facile Synthesis of Arenes by Transition Metal Catalyzed Decarbonylation Methodology.

Transition metal-catalyzed decarbonylation is an essential paradigm of synthetic organic chemistry. Decarbonylation offers a unique pathway to decoding the skeletal structure of arenes and enabling easy synthesis of structurally complicated molecules. Due to the omnipresence of carbonyl groups in a wide array of synthetically important complex molecules, the variety and scope of these transformations are enormous. As a result, the development of transition metal catalysts in such a simple decarbonylation reaction ranks among one of the most important topics in synthetic organic chemistry. Transition metals that have been employed range from 3d metals like V to second-row transition metals like Pd. The growing potential of this methodology has driven the pioneers of synthetic organic chemistry into delving into the details of this transition metal-catalyzed decarbonylation pathways. This review aims to take the readers through the employment of transition metals in various decarbonylation processes developed by our group, sticking not only to the scope and diversification of synthetically complex molecules, but also enabling the readers to understand the mechanistic insights, through computational and kinetic studies put forward in such reaction protocol, hoping to pave the way for future organic chemists to delve and hopefully solve the unique problems associated with this protocol.

Development of a novel [18 F]fluorobenzyl derivative of the AT1 receptor antagonist Candesartan.

Candesartan is a clinically approved angiotensin II type 1 receptor (AT1 R)-blocker that selectively binds AT1 Rs in high affinity. We report here the radiosynthesis and automation of the novel [18 F]fluorobenzyl derivative of Candesartan using the Sonogashira cross-coupling reaction. [18 F]Fluorobenzyl-Candesartan ([18 F]7) was developed from 4-[18 F]fluoroiodobenzene ([18 F]FIB) that was conjugated with alkyne-trityl-candesartan with the assistance of a Pd (PPh3 )4 /CuI catalyst followed by acid deprotection. The three-step two-reactor 2-HPLC purification process was automated resulting in >90% pure [18 F]7 in a RCY of 4.6 ± 1.1% (decay corrected from EOB) and molar activities of 1,406-5,513 GBq/mmol. [18 F]FIB was reproducibly obtained by direct radiofluorination of the mono-iodinated triphenylsulfonium salt in the presence of K222/K2 CO3 in an ~30% yield (decay-corrected). [18 F]7 was stable (>97%) up to 4 h in solution and up to 1 h in rat plasma at 37°C. However, the use of Sonogashira cross-coupling reaction to produce [18 F]7 in high yields and molar activities was found to be challenging for routine use in radiochemistry labs.

Regioselective Mercury(I)/Palladium(II)-Catalyzed Single-Step Approach for the Synthesis of Imines and 2-Substituted Indoles.

An efficient synthesis of ketimines was achieved through a regioselective Hg(I)-catalyzed hydroamination of terminal acetylenes in the presence of anilines. The Pd(II)-catalyzed cyclization of these imines into the 2-substituted indoles was satisfactorily carried out by a C-H activation. In a single-step approach, a variety of 2-substituted indoles were also generated via a Hg(I)/Pd(II)-catalyzed, one-pot, two-step process, starting from anilines and terminal acetylenes. The arylacetylenes proved to be more effective than the alkyl derivatives.

Imide-Fused Diazatetracenes: Synthesis, Characterization, and Application in Perovskite Solar Cells.

A series of imide-fused diazatetracenes were synthesized via Buchwald-Hartwig C-N coupling with a highly active palladium source. The introduction of an imide segment effectively lowers the LUMO levels compared with that of unsubstituted diazatetracene. By adjusting the alkyl chains of the diazatetracenes, different solid-state packings were achieved, resulting in distinct photoluminescent behaviors. Their electron-transporting properties were demonstrated in the proof-of-concept Perovskite solar cells as electron transporting layers.

Towards triptycene functionalization and triptycene-linked porphyrin arrays.

Herein, 9,10-diethynyltriptycene is investigated for its use as a rigid isolating unit in the synthesis of multichromophoric arrays. Sonogashira cross-coupling conditions are utilized to attach various porphyrins and boron dipyrromethenes (BODIPYs) to the triptycene scaffold. While there are previous examples of triptycene porphyrin complexes, this work reports the first example of a linearly connected porphyrin dimer, linked through the bridgehead carbons of triptycene. Symmetric and unsymmetric examples of these complexes are demonstrated and single crystal X-ray analysis of an unsymmetrically substituted porphyrin dimer highlights the evident linearity in these systems. Moreover, initial UV-vis and fluorescence studies show the promise of triptycene as a linker for electron transfer studies, showcasing its isolating nature.

Synthesis of novel chalcones through palladium-catalyzed CO cross-coupling reaction of bromo-chalcones with ethyl acetohydroxamate and their antiplasmodial evaluation against Plasmodium falcipuram in vitro.

An efficient method for palladium-catalyzed CO cross-coupling of ethyl acetohydroxamate (EAcHO) with 4-bromo-chalcones has been developed to synthesize novel chalcones. The two supporting ligands, namely tBuXPhos (L7), and cataCXium®PIntB (L16) were found to be effective ligands towards the Pd-catalyzed CO cross-coupling reaction to afford the desired product in moderate to excellent yields (50-99%). The coupled products were screened for in vitro blood stage antiplasmodial activity against Plasmodium falciparum (3D7) using the [3H] hypoxanthine incorporation inhibition assay. Of the twenty two compounds screened, eleven showed good antiplasmodial activity with IC50 values ranging from 6-16 µg/mL. The selected active molecules 11, 16, 22, (IC50 12 µg/mL) and 19 (IC50 6 µg/mL) were studied for their cytotoxic effect against HepG2 Cells (human hepatocellular liver carcinoma cell lines), showing the selectivity index (SI) values are greater than 4 except chalcone 22. Our result demonstrates a methodology for synthesizing novel chalcones as a new class of antiplasmodial agent.

Switchable selectivity in Pd-catalyzed [3 + 2] annulations of γ-oxy-2-cycloalkenones with 3-oxoglutarates: C-C/C-C vs C-C/O-C bond formation.

Two complementary [3 + 2] annulation protocols between 3-oxoglutarates and cyclic γ-oxy-2-cycloalkenones, simply differing on the reaction temperature, are disclosed. These domino transformations allow C-C/O-C or C-C/C-C [3 + 2] annulations at will, via an intermolecular Pd-catalyzed C-allylation/intramolecular O- or C-1,4-addition sequence, respectively. In particular, exploiting the reversibility of the O-1,4-addition step, in combination with the irreversible C-1,4-addition/decarboxylation path, the intramolecular conjugate addition step could be diverted from the kinetic (O-alkylation) to the thermodynamic path (C-alkylation) thanks to a simple temperature increase. Crucial for the success of this bis-nucleophile/bis-electrophile [3 + 2] annulation is its well-defined step chronology in combination with the total chemoselectivity of the former step. This [3 + 2] C-C/O-C bond forming annulation protocol could be also extended to 1,3,5-triketones as well as 1,3-bis-sulfonylpropan-2-one bis-nucleophiles.

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.

Dicyano-Substituted Diazaacenes.

Herein, we report the synthesis, spectroscopic, and structural properties of novel 2,3-dicyano-substituted azaacenes containing three to six annelated rings as a framework. The targets were prepared by Pd-catalyzed coupling of diamino-bis(tri-isopropylsilylethynyl)benzene, -naphthalene, and -anthracene with either 4,5-dibromophthalonitrile or 6,7-dibromonaphthalene-2,3-dicarbonitrile into the respective N,N'-dihydrodiazaacenes. Oxidation with MnO2 or PbO2 furnishes the dicyano-substituted diazaacenes in reasonable to good yields. An exception is the diazahexacene, where the N,N'-dihydrodiazaacene is difficult to oxidize. Most of the targets could be crystallized and pack in isolated pairs, stacks, and brick-wall motifs. The n-type behavior of these molecules was illustrated in a proof-of-concept organic field-effect transistor, showing mobilities up to 7×10-3  cm2 V-1 s-1 .

Highly Soluble p-Terphenyl and Fluorene Derivatives as Efficient Dopants in Plastic Scintillators for Sensitive Nuclear Material Detection.

Plastic scintillators are commonly used as first-line detectors for special nuclear materials. Current state-of-the-art plastic scintillators based on poly(vinyltoluene) (PVT) matrices containing high loadings (>15.0 wt %) of 2,5-diphenyloxazole (PPO) offer neutron signal discrimination in gamma radiation background (termed pulse shape discrimination, PSD), however, they suffer from poor mechanical properties. In this work, a series of p-terphenyl and fluorene derivatives were synthesized and tested as dopants in PVT based plastic scintillators as possible alternatives to PPO to address the mechanical property issue and to study the PSD mechanism. The derivatives were synthesized from low cost starting materials in high yields using simple chemistry. The photophysical and thermal properties were investigated for their influence on radiation sensitivity/detection performance, and mechanical stability. A direct correlation was found between the melting point of the dopants and the subsequent mechanical properties of the PVT based plastic scintillators. For example, select fluorene derivatives used as dopants produced scintillator samples with mechanical properties exceeding those of the commercial PPO-based scintillators while producing acceptable PSD capabilities. The physical properties of the synthesized dopants were also investigated to examine their effect on the final scintillator samples. Planar derivatives of fluorene were found to be highly soluble in PVT matrices with little to no aggregation induced effects.

Efficient access to ß-vinylporphyrin derivatives via palladium cross coupling of ß-bromoporphyrins with N-tosylhydrazones.

This work describes a new approach to obtain new ß-vinylporphyrin derivatives through palladium-catalyzed cross-coupling reaction of 2-bromo-5,10,15,20-tetraphenylporphyrinatozinc(II) with N-tosylhydrazones. This is the first report of the use of such synthetic methodology in porphyrin chemistry allowing the synthesis of new derivatives, containing ß-arylvinyl substituents.

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.

Symmetry-based approach to oligostilbenoids: Rapid entry to viniferifuran, shoreaphenol, malibatol A, and diptoindonesin G.

The recognition of the local symmetric image within benzofuran-based natural oligostilbenoids guided us to design a modular synthetic approach to these molecules by utilizing a three-step sequence consisting of Sonogashira coupling, iodocyclization, and Suzuki coupling. During our synthesis, the relative reactivities of ester, aldehyde, and alkoxy groups on the same aryl ring toward the neighboring alkyne in the iodine-mediated cyclization reactions were explored. Starting from the symmetrical 3,5-dimethoxybenzyl alcohol, this route allowed rapid access to 2,3-diarylbenzofuran, a key intermediate to several oligostilbenoid natural products, in good overall yields.

Palladium-Catalyzed C-H Olefination for Nucleic Acid Production.

The palladium-catalyzed direct C-H olefination of unprotected uridine, 2'-deoxyuridine, uridine monophosphate, and uridine analogues are described here. This protocol provides an efficient, atom-economical, and environmentally friendly method for the introduction of an alkenyl group at the C5 position of the uracil without pre-functionalization. A series of C5-alkenylated uridine analogues, including some biologically significant compounds and potential pharmaceutical candidates, were synthesized with exposed hydroxyl groups on the ribose. © 2023 Wiley Periodicals LLC. Basic Protocol 1: The reaction of uridine, 2'-deoxyuridine, and sofosbuvir for the C-H olefination with methyl acrylate Basic Protocol 2: The reaction of uridine and 2'-deoxyuridine for the C-H olefination with styrene.

Synthesis of 13C4-labelled oxidized metabolites of the carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene.

Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP), are ubiquitous environmental contaminants that are implicated in causing lung cancer. BaP is a component of tobacco smoke that is transformed enzymatically to active forms that interact with DNA. We reported previously development of a sensitive stable isotope dilution LC/MS method for analysis of BaP metabolites. We now report efficient syntheses of 13C4-BaP and the complete set of its 13C4-labelled oxidized metabolites needed as internal standards They include the metabolites not involved in carcinogenesis (Group A) and the metabolites implicated in initiation of cancer (Group B). The synthetic approach is novel, entailing use of Pd-catalyzed Suzuki, Sonogashira, and Hartwig cross-coupling reactions combined with PtCl2-catalyzed cyclization of acetylenic compounds. This synthetic method requires fewer steps, employs milder conditions, and product isolation is simpler than conventional methods of PAH synthesis. The syntheses of 13C4-BaP and 13C4-BaP-8-ol each require only four steps, and the 13C-atoms are all introduced in a single step. 13C4-BaP-8-ol serves as the synthetic precursor of all the oxidized metabolites of 13C-BaP implicated in initiation of cancer. The isotopic purities of the synthetic 13C4-BaP metabolites were estimated to be ≥99.9%.