An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

The trans‐o‐hydroxybenzylidene pyruvate aldolase‐catalysed reactions between fluoropyruvate and many (hetero)aromatic aldehydes yield aldol adducts without subsequent dehydration. Treatment of the reaction products with hydrogen peroxide yields the corresponding syn‐configured α‐fluoro β‐hydroxy carboxylic acids which have >98 % ee. The overall chemoenzymatic approach, in which fluoropyruvate serves as a fluoroacetate equivalent, may be exploited in the synthesis of polar building blocks and fragments with potential value in drug discovery.     

Synthesis and Conformation of Fluorinated β‐Peptidic Compounds

Experimental and theoretical data indicate that, for α‐fluoroamides, the F? C? C(O)? N(H) moiety adopts an antiperiplanar conformation. In addition, a gauche conformation is favoured between the vicinal C? F and C? N(CO) bonds in N‐β‐fluoroethylamides. This study details the synthesis of a series of fluorinated β‐peptides ( 1 – 8 ) designed to use these stereoelectronic effects to control the conformation of β‐peptide bonds. X‐ray crystal structures of these compounds revealed the expected conformations: with fluorine β to a nitrogen adopting a gauche conformation, and fluorine α to a C?O group adopting an antiperiplanar conformation. Thus, the strategic placement of fluorine can control the conformation of a β‐peptide bond, with the possibility of directing the secondary structures of β‐peptides.     

Synthesis of Branched‐Chain Sugars with a DHAP‐Dependent Aldolase: Ketones are Electrophile Substrates of Rhamnulose‐1‐phosphate Aldolases

Dihydroxyacetone phosphate (DHAP)‐dependent rhamnulose aldolases display an unprecedented versatility for ketones as electrophile substrates. We selected and characterized a rhamnulose aldolase from Bacteroides thetaiotaomicron (RhuABthet) to provide a proof of concept. DHAP was added as a nucleophile to several α‐hydroxylated ketones used as electrophiles. This aldol addition was stereoselective and produced branched‐chain monosaccharide adducts with a tertiary alcohol moiety. Several aldols were readily obtained in good to excellent yields (from 76 to 95 %). These results contradict the general view that aldehydes are the only electrophile substrates for DHAP‐dependent aldolases and provide a new C?C bond‐forming enzyme for stereoselective synthesis of tertiary alcohols.     

Recent Advances in the One‐Step Synthesis of Distally Fluorinated Ketones

Fluorinated ketones are intriguing compounds in synthetic chemistry and life science‐related fields. The development of efficient methodologies to obtain these compounds is of significant importance and has therefore attracted considerable attention. This Minireview highlights recent progress made in the synthesis of fluorine‐containing ketones, with an emphasis on those methods in which the construction of carbonyl groups is synergetic with distal (β‐, γ‐, δ‐, etc.) incorporation of fluorine atoms or fluorinated groups.     

Stereocontrolled Synthesis of Functionalized Azaheterocycles from Carbocycles through Oxidative Ring Opening/Reductive Ring Closing Protocols

Fluorine‐containing organic scaffolds are of significant interest in medicinal chemistry. The incorporation of fluorine into biomolecules can lead to remarkable changes in their physical, chemical, and biological properties. There are already many drugs on the market, which contain at least one fluorine atom. Saturated functionalized azaheterocycles as bioactive substances have gained increasing attention in pharmaceutical chemistry. Due to the high biorelevance of organofluorine molecules and the importance of N‐heterocyclic compounds, selective stereocontrolled procedures to the access of new fluorine‐containing saturated N‐heterocycles are considered to be a hot research topic. This account summarizes the synthesis of functionalized and fluorine‐containing saturated azaheterocycles starting from functionalized cycloalkenes and based on oxidative ring cleavage of diol intermediates followed by ring expansion with reductive amination.     

Highly Selective 1,4‐ and 1,6‐Addition of P(O)?H Compounds to p‐Quinones: A Divergent Method for the Synthesis of C‐ and O‐Phosphoryl Hydroquinone Derivatives

The reaction of P(O)? H compounds with p‐quinones could proceed through either 1,4‐ or 1,6‐addition pathways by employing different additives to selectively give the corresponding C‐ and O‐phosphoryl hydroquinone derivatives in good yields. Oxidative double 1,4‐addition of P(O)? H compounds to p‐quinones was also achieved by tuning the solvent, affording a facile synthesis of bis‐substituted hydroquinones with phosphorus functionality. Further studies on these reactions by using optically active H‐phosphinates showed that all addition reactions took place stereospecifically with retention of configuration at the phosphorus center. The findings lead to the establishment of a divergent method for the synthesis of C‐ and O‐phosphoryl hydroquinone derivatives from easily available P(O)? H compounds.     

Fluorine–proton correlation from isolated trifluoromethyl groups using unresolved J‐couplings

Fluorine‐containing compounds are rare in biological systems, so fluorine NMR spectroscopy can selectively detect and quantify fluorinated xenobiotics in crude biological extracts. The high sensitivity of fluorine NMR allows the detection of compounds containing isolated trifluoromethyl groups at nanogramme levels. However, it only provides limited structural information about trifluoromethyl‐containing compounds owing to the difficulty of interpreting fluorine chemical shifts and the low sensitivity of HOESY experiments used to correlate fluorine nuclei with protons in the same compound. This paper demonstrates that long‐range fluorine–proton J‐couplings can be used to correlate isolated trifluoromethyl groups with nearby protons with significantly higher sensitivity than HOESY. Fluorine‐observe fluorine–proton HMQC can even give correlations when the fluorine–proton J‐couplings are less than the observed fluorine resonance linewidth, so it provides a useful alternative source of structural information about fluorinated xenobiotics. Copyright © 2012 John Wiley & Sons, Ltd.     

Cover Picture: Angew. Chem. Int. Ed. 20/2002

The cover picture shows a series of ¹⁹F NMR spectra taken every hour during the monitoring of a time‐course experiment after addition of 5′‐fluoro‐5′‐deoxyadenosine (5′‐FDA) to a cell‐free extract of Streptomyces cattleya. This bacterium has the unusual capacity to biosynthesise organofluorine compounds from inorganic fluoride. The ¹⁹F NMR spectra illustrate that 5′‐FDA is a true intermediate in the biosynthesis of fluoroacetate and 4‐fluorothreonine. Other intermediates such as fluoroacetaldehyde are also observed for the first time. In a separate experiment, inorganic fluoride was converted into fluoroacetate, thus indicating that all of the enzymes involved in the fluoroacetate biosynthesis pathway are active in the cell‐free extract. These experiments report the first cell‐free biotransformations of inorganic fluoride into fluoroacetate, the most ubiquitous organic fluorine natural product, and pave the way for a biotechnological approach to organofluorine synthesis. Full details are described by O'Hagan and co‐workers on p. 3913 ff.     

One-pot Preparation of Fluorinated Polyhydrobenzoacridine-1-one Derivatives under Microwave Irradiation and Solvent-free Conditions

A facile and efficient synthesis of fluorine‐containing polyhydrobenzoacridines was accomplished by a three‐component coupling of fluorinated aldehyde, α‐naphthylamine, and 1,3‐cyclohexanedione or dimedone under microwave irradiation and solvent‐free conditions without catalyst. All new compounds were obtained in moderate to good yields and characterized by standard spectroscopic methods.     

Expedient Synthesis of C‐Aryl Carbohydrates by Consecutive Biocatalytic Benzoin and Aldol Reactions

The introduction of aromatic residues connected by a C?C bond into the non‐reducing end of carbohydrates is highly significant for the development of innovative structures with improved binding affinity and selectivity (e.g., C?aril‐sLex). In this work, an expedient asymmetric “de novo” synthetic route to new aryl carbohydrate derivatives based on two sequential stereoselectively biocatalytic carboligation reactions is presented. First, the benzoin reaction of aromatic aldehydes to dimethoxyacetaldehyde is conducted, catalyzed by benzaldehyde lyase from Pseudomonas fluorescens biovar I. Then, the α‐hydroxyketones formed are reduced by using NaBH₄ yielding the anti diol. After acetal hydrolysis, the aldol addition of dihydroxyacetone, hydroxyacetone, or glycolaldehyde catalyzed by the stereocomplementary D ‐fructose‐6‐phosphate aldolase and L ‐rhamnulose‐1‐phosphate aldolase is performed. Both aldolases accept unphosphorylated donor substrates, avoiding the need of handling the phosphate group that the dihydroxyacetone phosphate‐dependent aldolases require. In this way, 6‐C‐aryl‐L ‐sorbose, 6‐C‐aryl–L ‐fructose, 6‐C‐aryl–L ‐tagatose, and 5‐C‐aryl‐L ‐xylose derivatives are prepared by using this methodology.     

Stereoselective Synthesis of Fluorinated Galactopyranosides as Potential Molecular Probes for Galactophilic Proteins: Assessment of Monofluorogalactoside–LecA Interactions

The replacement of hydroxyl groups by fluorine atoms on hexopyranoside scaffolds may allow access to invaluable tools for studying various biochemical processes. As part of ongoing activities toward the preparation of fluorinated carbohydrates, a systematic investigation involving the synthesis and biological evaluation of a series of mono- and polyfluorinated galactopyranosides is described. Various monofluorogalactopyranosides, a trifluorinated, and a tetrafluorinated galactopyranoside have been prepared using a Chiron approach. Given the scarcity of these compounds in the literature, in addition to their synthesis, their biological profiles were evaluated. Firstly, the fluorinated compounds were investigated as antiproliferative agents using normal human and mouse cells in comparison with cancerous cells. Most of the fluorinated compounds showed no antiproliferative activity. Secondly, these carbohydrate probes were used as potential inhibitors of galactophilic lectins. The first transverse relaxation-optimized spectroscopy (TROSY) NMR experiments were performed on these interactions, examining chemical shift perturbations of the backbone resonances of LecA, a virulence factor from Pseudomonas aeruginosa. Moreover, taking advantage of the fluorine atom, the ¹⁹F NMR resonances of the monofluorogalactopyranosides were directly monitored in the presence and absence of LecA to assess ligand binding. Lastly, these results were corroborated with the binding potencies of the monofluorinated galactopyranoside derivatives by isothermal titration calorimetry experiments. Analogues with fluorine atoms at C-3 and C-4 showed weaker affinities with LecA as compared to those with the fluorine atom at C-2 or C-6. This research has focused on the chemical synthesis of “drug-like” low-molecular-weight inhibitors that circumvent drawbacks typically associated with natural oligosaccharides.     

Nickel(0) Complexes with Fluorinated Alkyne Ligands and their Reactivity towards Semihydrogenation and Hydrodefluorination with Water

The current work describes the synthesis and full characterization of zerovalent nickel complexes of the type [(dippe)Ni(η²‐C,C‐F_n‐alkyne)] (dippe=1,2‐bis(di‐isopropylphosphino‐ethane), F_n‐alkyne=fluorinated aromatic alkyne, n=1, 3, 5; 3a , 3b , 3c ) and [{(dippe)Ni}₂(μ²‐C,C‐F_n‐alkyne)] ( 4 ). Reactions with complexes 3a , 3b , 3c , and water as the hydrogen source, yield selective semihydrogenation of the bound alkyne to the corresponding alkene, accompanied by partial hydrodefluorination of the aromatic ring. Different alkynes were tested; on using the alkyne with five fluorine atoms over the aromatic ring, partial defluorination was achieved under the mildest reaction conditions, followed in reactivity by the alkyne with three fluorine atoms. The alkyne with only one fluorine atom was barely defluorinated. The use of triethylsilane as a sacrificial hydride source resulted in an overall increase in reactivity towards defluorination.     

Facile and Regioselective Synthesis of Substituted 1H‐Pyrazolo[3,4‐b]quinolines from 2‐Fluorobenzaldehydes and 1H‐Pyrazol‐5‐amines

The present article concerns the scope and limitations of the regioselective condensation of 2‐fluorobenzaldehydes with 1H‐pyrazol‐5‐amines, leading to the synthesis of substituted 1H‐pyrazolo[3,4‐b ]quinolines ( PQ ), in the presence of a base catalyst (DABCO and 2,4,6‐trimethylpyridine). A method to obtain these nitrogen heterocycles with fluorine or trifluoromethyl substituents in different positions in the carbocyclic ring was developed as a part of a systematic research on the influence of fluorine‐containing substituents on the parameters of PQ . Those compounds, characterized by high‐fluorescence intensity, have been tested as emitters for the organic light‐emitting diodes since 1997. The functionalization of PQ causes changes in various parameters, for example, HOMO and LUMO levels, which are important for the adjustment of fabricated organic light‐emitting diodes. One of the easiest methods of PQ preparation, namely, the condensation of substituted anilines with 5‐chloro‐1H‐pyrazole‐4‐carbaldehydes, is not regioselective. The method described in this study allows synthesizing of 1H‐pyrazolo[3,4‐b ]quinolines with good yields and high selectivity – only the expected isomer is obtained. As various different 2‐fluorobenzaldehydes are commercially available, and 1H‐pyrazol‐5‐amines with different substituents are easy to prepare, the method could be a good alternative to the already known procedures. All possible mechanisms of the reaction were also thoroughly studied.     

Synthesis of Fluorine‐Containing Multisubstituted Phenanthridines by Rhodium‐Catalyzed Alkyne [2+2+2] Cycloaddition and Tandem sp2 C?H Difluoromethylenation

A highly efficient method for the synthesis of fluorine‐containing multisubstituted phenanthridines through Rh‐catalyzed alkyne [2+2+2] cycloaddition reactions has been developed. This method exhibits excellent functional‐group compatibility. When a bromodifluoromethyl group, rather than a trifluoromethyl group, was employed in the cycloaddition reaction, more‐complicated polycyclic compounds were obtained through tandem Rh‐catalyzed cycloaddition/C? H difluoromethylenation. This route provides convenient access to fluorine‐containing polycyclic compounds.     

Synthesis of Selectively gem-Difluorinated Molecules; Chiral gem-Difluorocyclopropanes via Chemo-Enzymatic Reaction and gem-Difluorinated Compounds via Radical Reaction

The incorporation of fluorine atoms into an organic compound can alter the chemical reactivity or biological activity of the resulting compound due to the strong electron withdrawing nature of the fluorine atom. We have synthesized many original gem-difluorinated compounds and described the results in four sections. The first section describes the synthesis of optically active-gem-difluorocyclopropanes via the chemo-enzymatic reaction; we applied these compounds to liquid crystalline molecules, then further discovered a potent DNA cleavage activity for the gem-difluorocyclopropane derivatives. The second section describes the synthesis of selectively gem-difluorinated compounds via a radical reaction; we synthesized fluorinated analogues of a sex pheromone of the male African sugarcane borer, Eldana saccharina, and used the compounds as proof for investigating the origin of pheromone molecule recognition on the receptor protein. The third involves the synthesis of 2,2-difluorinated-esters by visible light-driven radical addition of 2,2-difluoroacetate with alkenes or alkynes in the presence of an organic pigment. The last section describes the synthesis of gem-difluorinated compounds via the ring-opening of gem-difluorocyclopropanes. We further developed a novel method of synthesizing gem-difluorohomoallylic alcohols via the ring-opening of gem-difluorocyclopropane and aerobic oxidation by photo-irradiation in the presence of an organic pigment. Since gem-difluorinated compounds that were prepared by the present method have two olefinic moieties with a different reactivity at the terminal position, we accomplished the synthesis of four types of gem-difluorinated cyclic alkenols via the ring-closing-metathesis (RCM) reaction.     

Advancements in the Synthesis and Applications of Cationic N‐Heterocycles through Transition Metal‐Catalyzed C−H Activation

Cationic N‐heterocycles are an important class of organic compounds largely present in natural and bioactive molecules. They are widely used as fluorescent dyes for biological studies, as well as in spectroscopic and microscopic methods. These compounds are key intermediates in many natural and pharmaceutical syntheses. They are also a potential candidate for organic light‐emitting diodes (OLEDs). Because of these useful applications, the development of new methods for the synthesis of cationic N‐heterocycles has received a lot of attention. In particular, many C?H activation methodologies that realize high step‐ and atom‐economies toward these compounds have been developed. In this review, recent advancements in the synthesis and applications of cationic N‐heterocycles through C?H activation reactions are summarized. The new C?H activation reactions described in this review are preferred over their classical analogs.     

Application of Copper(I) Iodide/Diorganoyl Dichalcogenides to the Synthesis of 4‐Organochalcogen Isoquinolines by Regioselective C?N and C?Chalcogen Bond Formation

A copper‐catalyzed cyclization of (ortho‐alkynyl)benzaldimines with diorganoyl dichalcogenides allowed the synthesis of 4‐organochalcogen isoquinolines, whereas the presence of base in the reaction medium inhibited the product formation producing the undesirable isoquinoline without the organochalcogen atom at the 4‐position. The cyclization reaction was carried out by using CuI (20 %) as a catalyst with diorganoyl dichalcogenides (1.5 equiv) in the presence of DMF at 100 °C. Furthermore, the reaction did not require an argon atmosphere and was carried out in an open flask. The cyclization reaction tolerated a variety of functional groups both in ortho‐alkynylbenzaldimines and diorganoyl dichalcogenides, such as trifluoromethyl, chloro, fluorine, and methoxyl, to give the six‐membered heterocyclic ring exclusively through a 6‐endo‐dig cyclization process. The organochalcogen group present at the 4‐position of the isoquinoline ring was further subjected to a selective chalcogen–lithium exchange reaction followed by the addition of aldehydes to afford the desired secondary alcohols in good yields. The obtained isoquinolines also proved to be suitable substrates for the Suzuki and Sonogashira coupling conditions affording the corresponding products through C? C bond formation.     

Synthesis and Chromatographic Evaluation of Perfluorooctyl Stationary Phase for Separation of Basic Compounds

Fluorinated stationary phases provide unique separation effect on basic compounds, due to the fluorine atoms, and pentafluorophenyl stationary phases (PFPs) are the most widely used. Considering that some fluoroalkyls have higher fluorine contents than PFPs do, it is speculated that fluoroalkyl stationary phases should have potential new applications. Herein, we synthesized a silica-based stationary phase bonding perfluoroctyl (FC8) proved by characterization through elemental analysis and solid-state ¹³C cross-polarization/magic-anglespinning nuclear magnetic resonance. The chromatographic behavior of the stationary phase was evaluated with test compounds. In addition, to further study the applicability of FC8 materials, Corydalis decumbens (Thunb.) Pers. fraction, considered as a challenging medicine on reversed-phase chromatography columns, was chosen as a test sample. Results demonstrated that the FC8 stationary phase had better and more satisfactory separation performance than the PFP stationary phase on basic compounds.

     

Nitroxy/Azido‐Functionalized Triazoles as Potential Energetic Plasticizers

The synthesis of a series of nitroxy‐ and azido‐functionalized compounds, based on 4‐amino‐3,5‐di(hydroxymethyl)‐1,2,4‐triazole, for possible use as an energetic plasticizers is described. All compounds were fully characterized. Two of them were further confirmed by X‐ray single crystal diffraction. Energetic performance was calculated by using EXPLO5 v6.01 based on calculated heats of formation (Gaussian 03) and experimentally determined densities at 25 °C. The results show that the nitration product 1‐nitro‐3,5‐di(nitroxymethyl)‐1,2,4‐triazole, containing a nitro group and two nitroxy groups, exhibits good detonation properties (D=8574 m s^?1, P=32.7 GPa). In addition, its low melting point makes it very attractive as an energetic plasticizer in solid propellants.     

Copper‐Catalyzed Cascade Cyclization Reaction of 2‐Haloaryltriazenes and Sodium Azide: Selective Synthesis of 2 H‐Benzotriazoles in Water

A new approach to the synthesis of 2 H‐benzotriazoles is described. This strategy is based on the copper‐catalyzed C?N coupling of 2‐haloaryltriazenes or 2‐haloazo compounds with sodium azide and the intramolecular addition of nitrene to N?N bonds. This approach allows the synthesis of various N‐amino‐ and N‐aryl‐2 H‐benzotriazoles in water, in good to excellent yields. The procedure is simple and the starting materials and catalyst are easily available, offering a practical and convenient synthetic route to 2‐substituted benzotriazoles.