C(sp)-C(sp) Lever-Based Targets of Orientational Chirality: Design and Asymmetric Synthesis.

In this study, the design and asymmetric synthesis of a series of chiral targets of orientational chirality were conducted by taking advantage of N-sulfinylimine-assisted nucleophilic addition and modified Sonogashira catalytic coupling systems. Orientational isomers were controlled completely using alkynyl/alkynyl levers [C(sp)-C(sp) axis] with absolute configuration assignment determined by X-ray structural analysis. The key structural element of the resulting orientational chirality is uniquely characterized by remote through-space blocking. Forty examples of multi-step synthesis were performed, with modest to good yields and excellent orientational selectivity. Several chiral orientational amino targets are attached with scaffolds of natural and medicinal products, showing potential pharmaceutical and medical applications in the future.

Synthesis of Nano-Structured Conjugated Polymers with Multiple Micro-/Meso-Pores by the Post-Crosslinking of End-Functionalized Hyperbranched Conjugated Polymers.

A nano-structured conjugated polymer with multiple micro-/meso-pores was synthesized by post-crosslinking of an end-functionalized hyperbranched conjugated prepolymer. Firstly, an AB2 monomer 3-((3,5-dibromo-4-(octyloxy)phenyl)ethynyl)-6-ethynyl-9-octyl-9H-carbazole (PECz) was synthesized and polymerized by Sonogashira reaction to give the -Br end-functionalized hyperbranched conjugated prepolymer hb-PPECz. The photophysical and electrochemical properties of hb-PPECz were investigated. The λmax of absorption and emission of hb-PPECz in tetrahydrofuran (THF) solution was 313 and 483 nm, respectively. The optical energy bandgap, highest occupied molecular orbital (HOMO), and lowest unoccupied molecular orbital (LUMO) energy levels of hb-PPECz were 2.98, -5.81, and -2.83 eV, respectively. Then, the prepolymer hb-PPECz was post-crosslinked by Heck reaction with divinylbenzene to give the porous conjugated polymer c-PPECz. The effects of hb-PPECz concentration and added dispersant polyvinylpyrrolidone (PVP K-30) on the morphology and porosity of c-PPECz were investigated. The resulting c-PPECzs showed multiple porous structures mainly constructed by micropores and mesopores. Under a higher hb-PPECz concentration (4 wt/v%), a bulky gel product was obtained. Under lower hb-PPECz concentrations (0.6 wt/v%~2 wt/v%), the resulting c-PPECzs were mainly composed of nano-sized particles. Nearly spheric nanoparticles (200~300 nm) (c-PPECz-5) were obtained under the concentration of 1 wt/v% in the presence of PVP (10 wt% of hb-PPECz). The Brunauer-Emmett-Teller (BET) surface area, pore volume, average pore size, and percentage of pore size below 10 nm of c-PPECz-5 were 10.7781 m2·g-1, 0.0108 cm3·g-1, 4.0081 nm, and 94.47%, respectively.

Design and Asymmetric Control of Orientational Chirality by Using the Combination of C(sp2)-C(sp) Levers and Achiral N-Protecting Group.

New chiral targets of orientational chirality have been designed and asymmetrically synthesized by taking advantage of N-sulfinyl imine-directed nucleophilic addition/oxidation, Suzuki-Miyaura, and Sonogashira cross-coupling reactions. Orientation of single isomers has been selectively controlled by using aryl/alkynyl levers [C(sp2)-C(sp) axis] and tBuSO2- protecting group on nitrogen as proven by X-ray diffraction analysis. The key structural characteristic of resulting orientational products is shown by remote through-space blocking manner. Seventeen examples of multi-step synthesis were obtained with modest to good chemical yields and complete orientational selectivity.

Unique biomedical application of fluorescence derivatization based on palladium-catalyzed coupling reactions for HPLC analysis of pharmaceuticals and biomolecules.

Palladium-catalyzed coupling reactions are versatile and powerful tools for the construction of carbon-carbon bonds in organic synthesis. Although these reactions have favorable features that proceed selectively in mild reaction conditions using aqueous organic solvents, no attention has been given to their application in the field of biomedical analysis. Therefore, we focused on these reactions and evaluated the scope and limitations of their analytical performance. In this review, we describe the pros and cons and future trends of fluorescence derivatization of pharmaceuticals and biomolecules based on palladium-catalyzed coupling reactions such as Suzuki-Miyaura coupling, Mizoroki-Heck coupling, and Sonogashira coupling reactions for HPLC analysis.

Upper Rim-Bridged Calix[4]arenes via Cyclization of meta Alkynyl Intermediates with Diphenyl Diselenide.

A Sonogashira coupling of meta-iodocalix[4]arene with various terminal acetylenes confirmed that the meta position of calixarene is well addressable, and that both thermal and microwave protocols led to good yields of alkynylcalixarenes. Alkynes thus obtained were subjected to the ferric chloride and diphenyl diselenide-promoted electrophilic closure. It turns out that the calix[4]arenes give completely different bridging products than those described for the non-macrocyclic starting compounds. This can be demonstrated not only by the isolation of products with a six-membered ring (6-exo-dig), but mainly by the smooth formation of the 5-endo-dig cyclization, which has never been observed in the aliphatic series. An attempt at electrocyclization led to a high yield of the 1,2-diketone (oxidation of the starting alkyne), again in contrast to the reaction described for the acyclic derivatives. The structures of the unexpected products were unequivocally established by X-ray analysis and clearly demonstrate how the preorganized macrocyclic skeleton favors a completely different regioselectivity of cyclization reactions compared to common aliphatic compounds.

Aryl Radical Enabled, Copper-Catalyzed Sonogashira-Type Cross-Coupling of Alkynes with Alkyl Iodides.

Despite the success of Sonogashira coupling for the synthesis of arylalkynes and conjugated enynes, the engagement of unactivated alkyl halides in such reactions remains historically challenging. We report herein a strategy that merges Cu-catalyzed alkyne transfer with the aryl radical activation of carbon-halide bonds to enable a general approach for the coupling of alkyl iodides with terminal alkynes. This unprecedented Sonogashira-type cross-coupling reaction tolerates a broad range of functional groups and has been applied to the late-stage cross-coupling of densely functionalized pharmaceutical agents as well as the synthesis of positron emission tomography tracers.

Synthesis and Studies of Mono-functionalized Telluradithiasapphyrins and Covalently Linked Porphyrin- Telluradithiasapphyrin Dyads.

A series of mono-functionalized aromatic 22π telluradithiasapphyrins containing functional groups such as p-bromophenyl, p-iodophenyl, p-nitrophenyl and p-trimethylsilylethynyl phenyl groups at one of the meso-positions were synthesized by condensing appropriately functionalized unsymmetrical bithiophene diol and 16-telluratripyrrane in CH2 Cl2 under acid-catalyzed conditions. To demonstrate the reactivity of mono-functionalized telluradithiasapphyrins, we synthesized the first examples of covalently linked diphenyl ethyne bridged four novel 18π porphyrin/metalloporphrin-22π telluradithiasapphyrin dyads by coupling meso-ethynyl phenyl porphyrin with telluradithiasapphyrin containing meso-iodophenyl group under Pd(0) coupling conditions followed by metalation of porphyrin unit by treating free base dyad with appropriate metal salts. The dyads were characterized and studied by mass, 1D & 2D NMR, absorption, cyclic voltammetry, fluorescence and DFT techniques. The DFT analysis showed that the porphyrin/metalloporphyrin and sapphyrin units in dyads orient with each other in different angles and Zn(II) porphyrin-sapphyrin dyad (Zn-dyad) showed minimum whereas the free base dyad showed maximum angle of deviation. NMR, absorption, and redox studies indicated that the dyads exhibit the overlapping features of their constituted monomers and maintain their individual characteristic features. The steady-state fluorescence studies revealed that the fluorescence of the porphyrin/metalloporphyrin unit was significantly quenched due to possible energy/electron transfer from the porphyrin/metalloporphyrin unit to non-emissive sapphyrin unit in dyads.

Synthesis, Pharmacological Evaluation, and Molecular Modeling of Lappaconitine-1,5-Benzodiazepine Hybrids.

Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, have long interested scientists due to their medicinal uses and infamous toxicity which has limited the clinical application of the native compound. Alkaloid lappaconitine extracted from various Aconitum and Delphinium species has displayed extensive bioactivities and active ongoing research to reduce its adverse effects. A convenient route to construct hybrid molecules containing diterpenoid alkaloid lappaconitine and 3H-1,5-benzodiazepine fragments was proposed. The key stage involved the formation of 5'-alkynone-lappaconitines in situ by acyl Sonogashira coupling of 5'-ethynyllappaconitine, followed by cyclocondensation with o-phenylenediamine. New hybrid compounds showed low toxicity and outstanding analgesic activity in experimental pain models, which depended on the nature of the substituent in the benzodiazepine nucleus. An analogous dependence was also shown for the antiarrhythmic activity in the epinephrine arrhythmia test in vivo. Studies on the isolated atrium have shown that the mechanism of action of the new compounds is included the blockade of beta-adrenergic receptors and potassium channels. Molecular docking analysis was conducted to determine the binding potential of target molecules with the voltage-gated sodium channel NaV1.5. All obtained results provide a basis for future rational modifications of lappaconitine, reducing side effects, while retaining its therapeutic effects.

Rhodium-Catalyzed Trans-Bis-Silylation Reactions of 2-Ethynyl-3-pentamethyldisilanylpyridines.

Rhodium-catalyzed reactions of 2-ethynyl-3-pentamethyldisilanylpyridine derivatives (1 and 2) are reported. The reactions of compounds 1 and 2 in the presence of catalytic amounts of rhodium complexes at 110 °C gave the corresponding pyridine-fused siloles (3) and (4) through intramolecular trans-bis-silylation cyclization. The reaction of 2-bromo-3-(1,1,2,2,2-pentamethyldisilanyl)pyridine with 3-phenyl-1-propyne in the presence of PdCl2(PPh3)2-CuI catalysts afforded 1:2 bis-silylation adduct 6. DFT calculations were also performed to understand the reaction mechanism for the production of compound 3 from compound 1.

Trinuclear PdII Complexes with a C3 -Symmetric Triethynylbenzene-Based Tris-NHC Ligand: Catalytic Benefits.

A new C3 -symmetric tris-imidazolium tribromide salt 3, featuring 1,3,5-substituted triethynylbenzene, was used for the preparation of a trinuclear PdII pyridine-enhanced precatalyst preparation stabilization and initiation-type (PEPPSI) complex by triple C2 deprotonation followed by the addition of PdCl2 . Trinuclear PdII complex possessing a combination of NHC and PPh3 ligands has also been synthesized. The corresponding mononuclear palladium(II) complexes have also been synthesized for the comparison purpose. All these complexes have been characterized by using NMR spectroscopy and ESI mass spectrometry. The molecular structure of the trinuclear palladium(II) complex bearing mixed carbene and pyridine donor ligands has been established by using single crystal XRD. All the palladium(II) complexes have been used as pre-catalysts, which gave good to excellent yields in intermolecular α-arylation of 1-methyl-2-oxindole and Sonogashira coupling reaction. Catalytic studies indicate an enhanced activity of the trinuclear PdII complex in comparison to the corresponding mononuclear PdII complex for both catalytic transformations. The better performance of the trinuclear complex has also been further supported by preliminary electrochemical measurements. A negative mercury poison test was observed for both the aforementioned catalyses and therefore, it is likely that these organic transformations proceed homogeneously.

1-Phospha-Butadienes and 1H-Phospholes via Alkynylation of Acetylenic Phosphaalkenes.

Carbon-rich motifs are important building blocks for the fabrication of functional and opto-electronic materials. Electronic tuning can be achieved by alteration of bonding topologies but also via incorporation of heteroelements, for example phosphorus. Herein we present the palladium/copper mediated formation of branched 1-phospha-butadiene derivatives through an unusual alkynylation of a phospha-enyne fragment. Structural and NMR studies provide mechanistic insights into this alkynylation. Furthermore, we disclose a complex cyclisation of the thus obtained 3-yne-1-phosphabutadiene motifs to give highly substituted phosphole derivatives identified by 2D NMR and SC-XRD analysis.

Synthesis and structure-activity relationship of kujigamberol B, a dinorlabdane diterpenoid isolated from an ancient Kuji amber.

The versatile methodology was developed for synthesizing kujigamberol B, a dinorlabdane diterpenoid isolated from the methanol extract of Kuji amber. A highly efficient intramolecular cyclization is followed by a Sonogashira-coupling reaction during the total synthesis. The synthesized compounds were evaluated for the growth-restoring activity against the mutant yeast (zds1Δ erg3Δ pdr1Δ pdr3Δ) and for the degranulation of RBL-2H3 cells. We found that in both activities, primary alcohol and secondary alcohol analogs are as active as kujigamberol B.

Synthesis of 6-Alkynylated Purine-Containing DNA via On-Column Sonogashira Coupling and Investigation of Their Base-Pairing Properties.

Synthetic unnatural base pairs have been proven to be attractive tools for the development of DNA-based biotechnology. Our group has very recently reported on alkynylated purine-pyridazine pairs, which exhibit selective and stable base-pairing via hydrogen bond formation between pseudo-nucleobases in the major groove of duplex DNA. In this study, we attempted to develop an on-column synthesis methodology of oligodeoxynucleotides (ODNs) containing alkynylated purine derivatives to systematically explore the relationship between the structure and the corresponding base-pairing ability. Through Sonogashira coupling of the ethynyl pseudo-nucleobases and CPG-bound ODNs containing 6-iodopurine, we have demonstrated the synthesis of the ODNs containing three NPu derivatives (NPu1, NPu2, NPu3) as well as three OPu derivatives (OPu1, OPu2, OPu3). The base-pairing properties of each alkynylated purine derivative revealed that the structures of pseudo-nucleobases influence the base pair stability and selectivity. Notably, we found that OPu1 bearing 2-pyrimidinone exhibits higher stability to the complementary NPz than the original OPu, thereby demonstrating the potential of the on-column strategy for convenient screening of the alkynylated purine derivatives with superior pairing ability.

Synthesis of Cy5-Labelled C5-Alkynyl-modified cytidine triphosphates via Sonogashira coupling for DNA labelling.

New applications of palladium-catalyzed Sonogashira-type cross-coupling reaction between C5-halogenated 2'-deoxycytidine-5'-monophosphate and novel cyanine dyes with a terminal alkyne group have been developed. The present methodology allows to synthesize of fluorescently labeled C5-nucleoside triphosphates with different acetylene linkers between the fluorophore and pyrimidine base in good to excellent yields under mild reaction conditions. Modified 2'-deoxycytidine-5'-triphosphates were shown to be good substrates for DNA polymerases and were incorporated into the DNA by polymerase chain reaction.

Synthesis, Structures, and Complexation with Phenolic Guests of Acridone-Incorporated Arylene-Ethynylene Macrocyclic Compounds.

Acridone units were incorporated into the arylene-ethynylene structure as polar arene units. Cyclic trimers consisting of three acridone-2,7-diyl units and three 1,3-phenylene units were synthesized by Sonogashira couplings via stepwise or direct route. X-ray analysis revealed that the trimer had a nearly planar macrocyclic framework with a cavity surrounded by three carbonyl groups. In contrast, the corresponding tetramer had a nonplanar macrocyclic framework. 1 H NMR measurements showed that the trimer formed a 1 : 1 complex as a macrocyclic host with dihydric phenol guests, and the association constants were determined to be ca. 1.0×103  L mol-1 for hydroquinone or resorcinol guests in CDCl3 at 298 K. The calculated structures of these complexes by the DFT method supported the presence of two sets of OH⋅⋅⋅O=C hydrogen bonds between the host and guest molecules. The spectroscopic data of the cyclic trimers and tetramers are compared with those of reference acridone compounds.

Panchromatic Absorbers Tethered for Bioconjugation or Surface Attachment.

The syntheses of two triads are reported. Each triad is composed of two perylene-monoimides linked to a porphyrin via an ethyne unit, which bridges the perylene 9-position and a porphyrin 5- or 15-position. Each triad also contains a single tether composed of an alkynoic acid or an isophthalate unit. Each triad provides panchromatic absorption (350-700 nm) with fluorescence emission in the near-infrared region (733 or 743 nm; fluorescence quantum yield ~0.2). The syntheses rely on the preparation of trans-AB-porphyrins bearing one site for tether attachment (A), an aryl group (B), and two open meso-positions. The AB-porphyrins were prepared by the condensation of a 1,9-diformyldipyrromethane and a dipyrromethane. The installation of the two perylene-monoimide groups was achieved upon the 5,15-dibromination of the porphyrin and the subsequent copper-free Sonogashira coupling, which was accomplished before or after the attachment of the tether. The syntheses provide relatively straightforward access to a panchromatic absorber for use in bioconjugation or surface-attachment processes.

Functionalized 10-Membered Aza- and Oxaenediynes through the Nicholas Reaction.

The scope and limitations of the Nicholas-type cyclization for the synthesis of 10-membered benzothiophene-fused heterocyclic enediynes with different functionalities were investigated. Although the Nicholas cyclization through oxygen could be carried out in the presence of an ester group, the final oxaenediyne was unstable under storage. Among the N-type Nicholas reactions, cyclization via an arenesulfonamide functional group followed by mild Co-deprotection was found to be the most promising, yielding 10-membered azaendiynes in high overall yields. By contrast, the Nicholas cyclization through the acylated nitrogen atom did not give the desired 10-membered cycle. It resulted in the formation of a pyrroline ring, whereas cyclization via an alkylated amino group resulted in a poor yield of the target 10-membered enediyne. The acylated 4-aminobenzenesulfonamide nucleophilic group was found to be the most convenient for the synthesis of functionalized 10-membered enediynes bearing a clickable function, such as a terminal triple bond. All the synthesized cyclic enediynes exhibited moderate activity against lung carcinoma NCI-H460 cells and had a minimal effect on lung epithelial-like WI-26 VA4 cells and are therefore promising compounds in the search for novel antitumor agents that can be converted into conjugates with tumor-targeting ligands.

Isoquinoline Antimicrobial Agent: Activity against Intracellular Bacteria and Effect on Global Bacterial Proteome.

A new class of alkynyl isoquinoline antibacterial compounds, synthesized via Sonogashira coupling, with strong bactericidal activity against a plethora of Gram-positive bacteria including methicillin- and vancomycin-resistant Staphylococcus aureus (S. aureus) strains is presented. HSN584 and HSN739, representative compounds in this class, reduce methicillin-resistant S. aureus (MRSA) load in macrophages, whilst vancomycin, a drug of choice for MRSA infections, was unable to clear intracellular MRSA. Additionally, both HSN584 and HSN739 exhibited a low propensity to develop resistance. We utilized comparative global proteomics and macromolecule biosynthesis assays to gain insight into the alkynyl isoquinoline mechanism of action. Our preliminary data show that HSN584 perturb S. aureus cell wall and nucleic acid biosynthesis. The alkynyl isoquinoline moiety is a new scaffold for the development of potent antibacterial agents against fatal multidrug-resistant Gram-positive bacteria.

Co-operative halogen bonds and nonconventional sp-C-H...O hydrogen bonds in 1:1 cocrystals formed between diethynylpyridines and N-halosuccinimides.

The rapid evaporation of 1:1 solutions of diethynylpyridines and N-halosuccinimides, that react together to form haloalkynes, led to the isolation of unreacted 1:1 cocrystals of the two components. The 1:1 cocrystal formed between 2,6-diethynylpyridine and N-iodosuccinimide (C4H4INO2·C9H5N) contains an N-iodosuccinimide-pyridine I...N halogen bond and two terminal alkyne-succinimide carbonyl C-H...O hydrogen bonds. The three-dimensional extended structure features interwoven double-stranded supramolecular polymers that are interconnected through halogen bonds. The cocrystal formed between 3,5-diethynylpyridine and N-iodosuccinimide (C4H4INO2·C9H5N) also features an I...N halogen bond and two C-H...O hydrogen bonds. However, the components form essentially planar double-stranded one-dimensional zigzag supramolecular polymers. The cocrystal formed between 3,5-diethynylpyridine and N-bromosuccinimide (C4H4BrNO2·C9H5N) is isomorphous to the cocrystal formed between 3,5-diethynylpyridine and N-iodosuccinimide, with a Br...N halogen bond instead of an I...N halogen bond.

Development of a selective fluorescence derivatization strategy for thyroid hormones based on the Sonogashira coupling reaction.

A new fluorescence derivatization technique for the determination of the thyroid hormones, 3,3',5-triiodo-L-thyronine (T3, triiodothyronine) and 3,3',5,5'-tetraiodo-L-thyronine (T4, L-thyroxine), in human serum was developed based on the Sonogashira coupling reaction. This derivatization reaction was recently utilized by our research group as a promising solution for the derivatization of ortho-substituted aryl halides that suffer from steric hindrance. T3 and T4 possess amino groups that could be derivatized by many reagents; however, these reagents are not useful in the case of biological analysis as they could non-selectively react with many biogenic amines and amino acids. Thus, herein we aimed at labeling the iodo-phenyl group of T3 and T4 as a selective fluorescence labeling approach suitable for biological analysis. The fluorescent alkyne, 2-(4-ethynylphenyl)-4,5-diphenyl-1H-imidazole (DIB-ET), can label the ortho-substituted aryl halides T3 and T4 in the presence of palladium and copper as catalysts, overcoming the steric hindrance of ortho-substitution. Furthermore, the application of the proposed method for the selective analysis of T3 and T4 in biological samples was successfully performed even in the presence of numerous biological components. The formed fluorescent derivatives produced from the reaction of DIB-ET and T3 and T4 could be determined by an HPLC system with fluorescence detection. The proposed method was successfully applied for the selective and sensitive determination of T3 and T4 in human serum with detection limits (S/N = 3) of 4.0 and 6.1 ng/mL and the recovery rate in the ranges of 84.3-92.1% and 81.3-84.9%, respectively. Therefore, the proposed method could be used as a new simple tool for the simultaneous determination of T3 and T4 in biological samples.