Fluorocarbon-DNA Conjugates for Enhanced Cellular Delivery: Formation of a Densely Packed DNA Nano-Assembly.

Forming nano-assemblies is essential for delivering DNA conjugates into cells, with the DNA density in the nano-assembly playing an important role in determining the uptake efficiency. In this study, we developed a strategy for the facile synthesis of DNA strands bearing perfluoroalkyl (R) groups (R-DNA conjugates) and investigated how they affect cellular uptake. An R-DNA conjugate bearing a long R group at the DNA terminus forms a nano-assembly with a high DNA density, which results in greatly enhanced cellular uptake.

Cellular Penetration and Intracellular Dynamics of Perfluorocarbon-Conjugated DNA/RNA as a Potential Means of Conditional Nucleic Acid Delivery.

Nucleic acid-based therapeutics represent a novel approach for controlling gene expression. However, a practical delivery system is required that overcomes the poor cellular permeability and intercellular instability of nucleic acids. Perfluorocarbons (PFCs) are highly stable structures that can readily traverse the lipid membrane of cells.

Fluoroalkylated hypervalent sulfur fluorides: radical addition of arylchlorotetrafluoro-λ-sulfanes to tetrafluoroethylene.

Fluorinated groups are essential hydrophobic groups in drug design. Combining a carbon-free tetrafluoro-λ-sulfanyl (SF) group with a polyfluoroalkyl group (R) provides SFR groups, exhibiting high hydrophobicity with a short carbon chain. In this study, various aryltetrafluoro(polyfluoroalkyl)-λ-sulfanes (ArSFR) were synthesized through the radical addition of arylchlorotetrafluoro-λ-sulfanes (ArSFCl) to tetrafluoroethylene.

Synthesis of Short Peptides with Perfluoroalkyl Side Chains and Evaluation of Their Cellular Uptake Efficiency.

With an increasing demand for macromolecular biotherapeutics, the issue of their poor cell-penetrating abilities requires viable and relevant solutions. Herein, we report tripeptides bearing an amino acid with a perfluoroalkyl (R ) group adjacent to the α-carbon. R -containing tripeptides were synthesized and evaluated for their ability to transport a conjugated hydrophilic dye (Alexa Fluor 647) into the cells.

-Fluorobenzenesulfonimide (NFSI) analogs with deprotectable substituents: synthesis of β-fluoroamines catalytic aminofluorination of styrenes.

The palladium-catalyzed aminofluorination of styrenes using novel -fluorobenzenesulfonimide (NFSI) derivatives with deprotectable substituents, and the selective deprotection and transformation of the resulting products into amines under mild reaction conditions are herein disclosed.

An -Fluorinated Imide for Practical Catalytic Imidations.

Catalytic imidation using NFSI as the nitrogen source has become an emerging tool for oxidative carbon-nitrogen bond formation. However, the less than ideal benzenesulfonimide moiety is incorporated into products, severely detracting its synthetic value. As a solution to this challenge, we report herein the development of a novel -fluorinated imide, -fluoro--(fluorosulfonyl)carbamate (NFC), by which the attached imide moiety acts as a modular synthetic handle for one-step derivatization to amines, sulfonamides, and sulfamides.

Methyl to trifluoromethyl substitution as a strategy to increase the membrane permeability of short peptides.

Here, we investigated the effect of CH to CF substitution on the membrane permeability of peptides. We synthesized a series of peptides with CF groups and corresponding nonfluorinated peptides and measured the membrane permeability of the peptides. As a result, we demonstrated that CH to CF substitution is useful for increasing the membrane permeability of di-/tri-peptides.

Bench-Stable Electrophilic Fluorinating Reagents for Highly Selective Mono- and Difluorination of Silyl Enol Ethers.

Efficient methods for the synthesis of fluorinated compounds have been intensively studied, recently. Development of practical fluorinating reagents is indispensable for this purpose. Herein, bench-stable electrophilic fluorinating reagents were synthesized as N-fluorobenzenesulfonimide (NFSI) substitutes.

Copper-catalyzed asymmetric methylation of fluoroalkylated pyruvates with dimethylzinc.

The catalytic asymmetric methylation of fluoroalkylated pyruvates is shown with dimethylzinc as a methylating reagent in the presence of a copper catalyst bearing a chiral phosphine ligand. This is the first catalytic asymmetric methylation to synthesize various α-fluoroalkylated tertiary alcohols with CF, CFH, CFBr, and -C F ( = 2, 3, 8) groups in good-to-high yields and enantioselectivities. Axial backbones and substituents on phosphorus atoms of chiral phosphine ligands critically influence the enantioselectivity.

Copper-Catalyzed Difluoromethylation of Aryl Iodides with (Difluoromethyl)zinc Reagent.

The combination of difluoroiodomethane and zinc dust or diethylzinc can readily lead to (difluoromethyl)zinc reagents. Therefore, the first copper-catalyzed difluoromethylation of aryl iodides with the zinc reagents is accomplished to afford the difluoromethylated arenes. The reaction proceeds efficiently through the ligand/activator-free operation without addition of ligands for copper catalyst (e.

Palladium-Catalyzed Negishi Cross-Coupling Reaction of Aryl Halides with (Difluoromethyl)zinc Reagent.

The palladium-catalyzed Negishi cross-coupling reaction of aryl iodides and bromides with (difluoromethyl)zinc reagent bearing a diamine such as TMEDA is achieved to provide the difluoromethylated aromatic compounds in good to excellent yields. The advantages of (difluoromethyl)zinc reagent are that (1) the derivatives, which possess different stability and reactivity, can be readily prepared via ligand screening and (2) transmetalation of a difluoromethyl group from the zinc reagent to palladium catalyst efficiently proceeds without an activator.

Dynamic Chirality Control of tropos DPCB-digold Skeleton by Chiral Binaphthyldicarboxylate.

The planar 3,4-diphosphinidenecyclobutene (DPCB) can be remarkably twisted into a C2 -type helical structure by dual coordination of a AuCl moiety. A prompt chirality control of the twisted DPCB skeleton ligated by the digold units affords the enantiopure structure by exchanging the chloride ligands for chiral [1,1'-binaphthalene]-2,2'-dicarboxylate. The chirality of the diaurated 2,2'-bis(diphenylphosphanyl)-1,1'-biphenyl (BIPHEP) system can be controlled prior to that of DPCB.

Carbon-carbon bond cleavage for Cu-mediated aromatic trifluoromethylations and pentafluoroethylations.

This short review highlights the copper-mediated fluoroalkylation using perfluoroalkylated carboxylic acid derivatives. Carbon-carbon bond cleavage of perfluoroalkylated carboxylic acid derivatives takes place in fluoroalkylation reactions at high temperature (150-200 °C) or under basic conditions to generate fluoroalkyl anion sources for the formation of fluoroalkylcopper species. The fluoroalkylation reactions, which proceed through decarboxylation or tetrahedral intermediates, are useful protocols for the synthesis of fluoroalkylated aromatics.

Lewis Acid Catalyzed Asymmetric Three-Component Coupling Reaction: Facile Synthesis of α-Fluoromethylated Tertiary Alcohols.

A chiral dicationic palladium complex is found to be an efficient Lewis acid catalyst for the synthesis of α-fluoromethyl-substituted tertiary alcohols using a three-component coupling reaction. The reaction transforms three simple and readily available components (terminal alkyne, arene, and fluoromethylpyruvate) to valuable chiral organofluorine compounds. This strategy is completely atom-economical and results in perfect regioselectivities and high enantioselectivities of the corresponding tertiary allylic alcohols in good to excellent yields.

Development of (Trifluoromethyl)zinc Reagent as Trifluoromethyl Anion and Difluorocarbene Sources.

The trifluoromethylation of carbonyl compounds is accomplished by the stable (trifluoromethyl)zinc reagent generated and then isolated from CF3I and ZnEt2, which can be utilized as a trifluoromethyl anion source (CF3(-)). The reaction proceeds smoothly with diamine as a ligand and ammonium salt as an initiator, providing the corresponding trifluoromethylated alcohol products. Moreover, the (trifluoromethyl)zinc reagent can also be employed as a difluorocarbene source (:CF2) not only for gem-difluoroolefination of carbonyl compounds with phosphine but also for gem-difluorocyclization of alkenes or alkynes via the thermal decomposition, respectively.

Catalytic Asymmetric Synthesis of Tertiary Alcohols and Oxetenes Bearing a Difluoromethyl Group.

The catalytic asymmetric ene reaction with difluoropyruvate as an electrophile in the presence of a dicationic palladium complex is shown. This is the reliable and practical catalytic asymmetric synthesis for various α-CF2H tertiary alcohols in high yields and enantioselectivities. The reaction with isobutene can be catalyzed efficiently under solvent-free conditions with low catalyst loading (up to S/C 2000).

α-Difluoromethylation on sp(3) Carbon of Nitriles Using Fluoroform and Ruppert-Prakash Reagent.

Difluoromethylation on sp(3) carbon of various nitrile compounds with lithium base and fluoroform (CF3H), which is an ideal difluoromethylating reagent, is shown to provide the α-difluoromethylated nitrile products with an all-carbon quaternary center in moderate to high yields. The Ruppert-Prakash reagent (CF3TMS) is also applicable to the reaction, affording the α-siladifluoromethylated nitrile products, which can be utilized for sequential carbon-carbon bond-forming reactions. These reactions using 1.

Stable but reactive perfluoroalkylzinc reagents: application in ligand-free copper-catalyzed perfluoroalkylation of aryl iodides.

The aromatic perfluoroalkylation catalyzed by a copper(I) salt with bis(perfluoroalkyl)zinc reagents Zn(RF)2(DMPU)2, which were prepared and then isolated as a stable white powder from perfluoroalkyl iodide and diethylzinc, was accomplished to provide the perfluoroalkylated products in good-to-excellent yields. The advantages of this reliable and practical catalytic reaction are 1) air-stable and easy-to-handle bis(perfluoroalkyl)zinc reagents can be utilized, 2) the reagent is reactive and hence the operation without activators and ligands is simple, and 3) not only trifluoromethylation but also perfluoroalkylation can be attained.

Direct synthesis of pentafluoroethyl copper from pentafluoropropionate as an economical C2F5 source: application to pentafluoroethylation of arylboronic acids and aryl bromides.

The direct synthesis of pentafluoroethyl copper (CuC2F5) from a cuprate reagent and ethyl pentafluoropropionate as one of the most economical and useful pentafluoroethyl sources was accomplished. The advantages of this method are; all the reagents employed are low-cost and operationally simple, and the CuC2F5 reagent is prepared in virtually quantitative yield. Furthermore, the CuC2F5 reagent prepared was successfully applied to two types of pentafluoroethylations with arylboronic acids and aryl bromides to provide the pentafluoroethylated aromatic products in good-to-excellent yields, including large scale operations.

Direct α-siladifluoromethylation of lithium enolates with Ruppert-Prakash reagent via C-F bond activation.

The direct α-siladifluoromethylation of lithium enolates with the Ruppert-Prakash reagent (CF3 TMS) is shown to construct the tertiary and quaternary carbon centers. The Ruppert-Prakash reagent, which is versatile for various trifluoromethylation as a trifluoromethyl anion (CF3 (-) ) equivalent, can be employed as a siladifluoromethyl cation (TMSCF2 (+) ) equivalent by CF bond activation due to the strong interaction between lithium and fluorine atoms.

Paradigm shift from alkaline (earth) metals to early transition metals in fluoroorganometal chemistry: perfluoroalkyl titanocene(III) reagents prepared via not titanocene(II) but titanocene(III) species.

Perfluoroalkyl (RF) titanocene reagents [Cp2Ti(III)RF] synthesized via [Cp2Ti(III)Cl] rather than [Cp2Ti(II)] show new types of perfluoroalkylation reactions. The [Cp2Ti(III)RF] reagents exhibit a wide variety of reactivity with carbonyl compounds including esters and nitriles, and selectivities far higher than those reported for conventional RFLi and RFMgX reagents.

Cu-catalyzed trifluoromethylation of aryl iodides with trifluoromethylzinc reagent prepared in situ from trifluoromethyl iodide.

The trifluoromethylation of aryl iodides catalyzed by copper(I) salt with trifluoromethylzinc reagent prepared in situ from trifluoromethyl iodide and Zn dust was accomplished. The catalytic reactions proceeded under mild reaction conditions, providing the corresponding aromatic trifluoromethylated products in moderate to high yields. The advantage of this method is that additives such as metal fluoride (MF), which are indispensable to activate silyl groups for transmetallation in the corresponding reactions catalyzed by copper salt by using the Ruppert-Prakash reagents (CF3SiR3), are not required.

Asymmetric catalysis based on tropos ligands.

All enantiopure atropisomeric (atropos) ligands essentially require enantiomeric resolution or synthetic transformation from a chiral pool. In sharp contrast, the use of tropos (chirally flexible) ligands, which are highly modular, versatile, and easy to synthesize without enantiomeric resolution, has recently been the topic of much interest in asymmetric catalysis. Racemic catalysts bearing tropos ligands can be applied to asymmetric catalysis through enantiomeric discrimination by the addition of a chiral source, which preferentially transforms one catalyst enantiomer into a highly activated catalyst enantiomer.