Synthesis of 2,2-difluoro-1,3-diketone and 2,2-difluoro-1,3-ketoester derivatives using fluorine gas.

Solutions of 1,3-diketones and 1,3-ketoester derivatives react with fluorine to give the corresponding 2,2-difluoro-1,3-dicarbonyl derivatives in the presence of quinuclidine. Quinuclidine reacts with fluorine in situ to generate a fluoride ion that facilitates limiting enolization processes, and an electrophilic N-F fluorinating agent that is reactive towards neutral enol species.

Kinetics of Electrophilic Fluorination of Steroids and Epimerisation of Fluorosteroids.

Fluorinated steroids, which are synthesised by electrophilic fluorination, form a significant proportion of marketed pharmaceuticals. To gain quantitative information on fluorination at the 6-position of steroids, kinetics studies were conducted on enol ester derivatives of progesterone, testosterone, cholestenone and hydrocortisone with a series of electrophilic N-F reagents. The stereoselectivities of fluorination reactions of progesterone enol acetate and the kinetic effects of additives, including methanol and water, were investigated. The kinetics of epimerisation of 6ß-fluoroprogesterone to the more pharmacologically active 6α-fluoroprogesterone isomer in HCl/acetic acid solutions are detailed.

Fluorocyanoesters as Additives for Lithium-Ion Battery Electrolytes.

A range of methyl 2-fluorocyanoester derivatives were synthesized from dimethyl 2-fluoromalonate ester, and their efficacy as additives in lithium-ion battery (LIB) electrolytes was determined. The role played by the 2-fluorocyanoester additives on battery performance was explored by linear sweep cyclic voltammetry, NMR, GCMS, and XPS techniques. For all fluorocyanoester additives studied, initial reduction of the carbonyl group occurs which is then followed by formation of the corresponding radical anion. Possible degradation routes arising from loss of fluoride ion, loss of methyl radicals, and cleavage of the αß carbon-carbon bond were observed, and all affect battery performance. Electrode protection upon addition of fluorocyanoesters to the electrolyte is the main contribution to the improvement of battery stability, but improvements on the electrode protection are somewhat offset by free radical processes initiated at the anode. Longer alkyl-chain fluorocyanoesters showed the best LIB improvement with effective cathode protection.

19 F†NMR Spectroscopy Tagging and Paramagnetic Relaxation Enhancement-Based Conformation Analysis of Intrinsically Disordered Protein Complexes.

The combination of 19 F NMR spectroscopy tagging and paramagnetic relaxation enhancement (PRE) NMR spectroscopy experiments was evaluated as a versatile method to probe protein-protein interactions and conformational changes of intrinsically disordered proteins upon complex formation. The feasibility of the approach is illustrated with an application to the Myc-Max protein complex; this is an oncogenic transcription factor that binds enhancer box DNA fragments. The single cysteine residue of Myc was tagged with highly fluorinated [19 F]3,5-bis(trifluoromethyl)benzyl bromide. Structural dynamics of the protein complex were monitored through intermolecular PREs between 19 F-Myc and paramagnetic (1-oxyl-2,2,5,5-tetramethyl-Δ3-pyrroline-3-methyl)methanethiosulfonate (MTSL)-tagged) Max. The 19 F R2 relaxation rates obtained with three differently MTSL-tagged Max mutants revealed novel insights into the differential structural dynamics of Myc-Max bound to DNA and the tumour suppressor breast cancer antigen 1. Given its ease of implementation, fruitful applications of this strategy to structural biology and inhibitor screening can be envisaged.

Lewis acid promoted fluorine-alkoxy group exchange reactions for the synthesis of 5-alkoxy-4,4-difluoroisoxazoline systems.

Fluorine-alkoxy group exchange reactions of fluorinated isoxazoline derivatives promoted by Lewis acids to give various 5-alkoxylated 4,4-difluoroisoxazolines via SN1 type processes in good to excellent yields are reported. Sterically demanding phenol substrates such as 2,6-diphenylphenol gave novel aryl substituted products via electrophilic aromatic substitution.

Enolization rates control mono- versus di-fluorination of 1,3-dicarbonyl derivatives.

Fluorine-containing 1,3-dicarbonyl derivatives are essential building blocks for drug discovery and manufacture. To understand the factors that determine selectivity between mono- and di-fluorination of 1,3-dicarbonyl systems, we have performed kinetic studies of keto-enol tautomerism and fluorination processes. Photoketonization of 1,3-diaryl-1,3-dicarbonyl derivatives and their 2-fluoro analogues is coupled with relaxation kinetics to determine enolization rates. Reaction additives such as water accelerate enolization processes, especially of 2-fluoro-1,3-dicarbonyl systems. Kinetic studies of enol fluorination with Selectfluor™ and NFSI reveal the quantitative effects of 2-fluorination upon enol nucleophilicity towards reagents of markedly different electrophilicity. Our findings have important implications for the synthesis of α,α-difluoroketonic compounds, providing valuable quantitative information to aid in the design of fluorination and difluorination reactions.

A quantitative reactivity scale for electrophilic fluorinating reagents.

Electrophilic N-F fluorination agents underpin the introduction of fluorine in aliphatic systems across drug and academic research. The choice of N-F reagent is currently determined through empirical experimentation in the absence of quantitative values for electrophilicities. Here we report an experimentally-determined kinetic reactivity scale for ten N-F fluorinating reagents, including Selectfluor™, NFSI, Synfluor™ and several N-fluoropyridinium salts, in CH3CN. The reactivity scale, which covers eight orders of magnitude, employs para-substituted 1,3-diaryl-1,3-dicarbonyl derivatives to measure relative and absolute rate constants. The para-substituted 1,3-diaryl-1,3-dicarbonyl scaffold delivers a convenient, sensitive spectrophotometric reporter of reactivity that also led to the discovery of a unique form of tautomeric polymorphism.

The application of perfluoroheteroaromatic reagents in the preparation of modified peptide systems.

The perfluoroheteroaromatic reagent pentafluoropyridine has proved to be a highly reactive electrophile, undergoing SNAr arylation reactions in the presence of a range of nucleophilic peptide side chains (i.e. cysteine, tyrosine, serine and lysine) under mild conditions. Moreover, we have shown how one-step peptide-modification using perfluoroheteroaromatics can deliver enhanced proteolytic stability in pharmaceutically-relevant peptides such as oxytocin.

2,2,2-Trifluoroethanol as a solvent to control nucleophilic peptide arylation.

The SNAr arylation of peptides with perfluoroaromatics provides a route by which to install a useful chemical handle that enables both 19F-NMR analysis and further chemical modification. However, chemo-selective arylation in peptides containing multiple nucleophilic side chains currently presents a challenge to the field. Herein, we demonstrate that employing 2,2,2-trifluoroethanol (TFE) as a solvent in peptide SNAr reactions significantly improves nucleophile-selectivity when compared to N,N'-dimethylformamide (DMF).

Biotransformation of fluorophenyl pyridine carboxylic acids by the model fungus Cunninghamella elegans.

1. Fluorine plays a key role in the design of new drugs and recent FDA approvals included two fluorinated drugs, tedizolid phosphate and vorapaxar, both of which contain the fluorophenyl pyridyl moiety. 2. To investigate the likely phase-I (oxidative) metabolic fate of this group, various fluorinated phenyl pyridine carboxylic acids were incubated with the fungus Cunninghamella elegans, which is an established model of mammalian drug metabolism. 3. 19F NMR spectroscopy established the degree of biotransformation, which varied depending on the position of fluorine substitution, and gas chromatography-mass spectrometry (GC-MS) identified alcohols and hydroxylated carboxylic acids as metabolites. The hydroxylated metabolites were further structurally characterised by nuclear magnetic resonance spectroscopy (NMR), which demonstrated that hydroxylation occurred on the 4' position; fluorine in that position blocked the hydroxylation. 4. The fluorophenyl pyridine carboxylic acids were not biotransformed by rat liver microsomes and this was a consequence of inhibitory action, and thus, the fungal model was crucial in obtaining metabolites to establish the mechanism of catabolism.

Surface Energy and Work Function Control of AlOx/Al Surfaces by Fluorinated Benzylphosphonic Acids.

The performance of organic electronic devices can be significantly improved by modifying metal electrodes with organic monolayers, which alter the physical and chemical nature of the interface between conductor and semiconductor. In this paper we examine a series of 12 phosphonic acid compounds deposited on the native oxide layer of aluminum (AlOx/Al), an electrode material with widespread applications in organic electronics. This series includes dodecylphosphonic acid as a reference and 11 benzylphosphonic acids, seven of which are fluorinated, including five newly synthesized derivatives. The monolayers are experimentally characterized by contact angle goniometry and by X-ray photoemission spectroscopy (XPS), and work function data obtained by low-intensity XPS are correlated with molecular dipoles obtained from DFT calculations. We find that monolayers are formed with molecular areas ranging from 17.7 to 42.9 Å(2)/molecule, and, by the choice of appropriate terminal groups, the surface energy can be tuned from 23.5 mJ/m(2) to 70.5 mJ/m(2). Depending on the number and position of fluorine substituents on the aromatic rings, a variation in the work function of AlOx/Al substrates over a range of 0.91 eV is achieved, and a renormalization procedure based on molecular density yields a surprising agreement of work function changes with interface dipoles as expected from Helmholtz' equation. The ability to adjust energetics and adhesion at organic semiconductor/AlOx interfaces has immediate applications in devices such as OLEDs, OTFTs, organic solar cells, and printed organic circuits.

Evaluation of fluorinated biphenyl ether pro-drug scaffolds employing the chemical-microbial approach.

Incorporation of fluorine in a drug can dramatically affect its metabolism and methods to assess the effect of fluorine substitution on drug metabolism are required for effective drug design. Employing a previously developed chemical-microbial method the metabolism of a series of fluorinated biphenyl ethers was determined. The substrates were synthesized via Ullmann-type condensation reactions between bromotoluene and fluorophenol. The ethers were incubated with the fungus Cunninghamella elegans, which oxidises xenobiotics in an analogous fashion to mammals, generating a number of hydroxylated biphenyl ethers and acids. The propensity of the fluorinated ring to be hydroxylated depended upon the position of the fluorine atom, and the oxidation of the methyl group was observed when it was meta to the oxygen. The experiments demonstrate the applicability of the method to rapidly determine the effect of fluorine substitution on CYP-catalysed biotransformation of pro-drug molecules.

Synthesis and characterization of a novel N-F reagent derived from the ethano-Tröger's base: (1)J(FN) coupling constants as a signature for the N-F bond.

Methylation of 2,8-dimethyl-6H,12H-5,11-ethanodibenzo[b,f][1,5]-diazocine (ethano-Tröger's base) with methyl iodide followed by ion metathesis and fluorination with N-fluoro-2,3,4,5,6-pentachloropyridinium triflate affords a new electrophilic N-F reagent, that is more reactive than Selectfluor. 2D (19)F-(15)N HMQC experiments provide (1)JNF coupling constants which are diagnostic for the N-F functional group.

Recent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicity.

INTRODUCTION: Fluorine's unique physicochemical properties make it a key element for incorporation into pharmacologically active compounds. Its presence in a drug can alter a number of characteristics that affect ADME-Tox, which has prompted efforts at improving synthetic fluorination procedures. AREAS COVERED: This review describes the influence of fluorine on attributes such as potency, lipophilicity, metabolic stability and bioavailablility and how the effects observed are related to the physicochemical characteristics of the element. Examples of more recently used larger scale synthetic methods for introduction of fluorine into drug leads are detailed and the potential for using biological systems for fluorinated drug production is discussed. EXPERT OPINION: The synthetic procedures for carbon-fluorine bond formation largely still rely on decades-old technology for the manufacturing scale and new reagents and methods are required to meet the demands for the preparation of structurally more complex drugs. The improvement of in vitro and computational methods should make fluorinated drug design more efficient and place less emphasis on approaches such as fluorine scanning and animal studies. The introduction of new fluorinated drugs, and in particular those that have novel fluorinated functional groups, should be accompanied by rigorous environmental assessment to determine the nature of transformation products that may cause ecological damage.

Fluorotetrahydroquinolines from diethyl 2-fluoromalonate ester.

A short series of fluorotetrahydroquinolines was synthesised in two steps from diethyl fluoromalonate and appropriate ortho-nitrobenzyl bromide precursors.

Syntheses of fluorooxindole and 2-fluoro-2-arylacetic acid derivatives from diethyl 2-fluoromalonate ester.

Diethyl 2-fluoromalonate ester is utilised as a building block for the synthesis of 2-fluoro-2-arylacetic acid and fluorooxindole derivatives by a strategy involving nucleophilic aromatic substitution reactions with ortho-fluoronitrobenzene substrates followed by decarboxylation, esterification and reductive cyclisation processes.

Targeted fluorination of a nonsteroidal anti-inflammatory drug to prolong metabolic half-life.

In drug design, one way of improving metabolic stability is to introduce fluorine at a metabolically labile site. In the early stages of drug design, identification of such sites is challenging, and a rapid method of assessing the effect of fluorination on a putative drug's metabolic stability would be of clear benefit. One approach to this is to employ micro-organisms that are established as models of drug metabolism in parallel with the synthesis of fluorinated drug analogues. In this study, we have used the filamentous fungus Cunninghamella elegans to identify the metabolically labile site of the nonsteroidal anti-inflammatory drug flurbiprofen, to aid in the design of fluorinated derivatives that were subsequently synthesised. The effect of the additional fluorine substitution on cytochrome P450-catalysed oxidation was then determined via incubation with the fungus, and demonstrated that fluorine substitution at the 4'-position rendered the drug inactive to oxidative transformation, whereas substitution of fluorine at either 2' or 3' resulted in slower oxidation compared to the original drug. This approach to modulating the metabolic stability of a drug-like compound is widely applicable and can be used to address metabolic issues of otherwise good lead compounds in drug development.

Catalytic decarboxylative fluorination for the synthesis of tri- and difluoromethyl arenes.

Treatment of readily available α,α-difluoro- and α-fluoroarylacetic acids with Selectfluor under Ag(I) catalysis led to decarboxylative fluorination. This operationally simple reaction gave access to tri- and difluoromethylarenes applying a late-stage fluorination strategy. Translation to [(18)F]labeling is demonstrated using [(18)F]Selectfluor bis(triflate), a reagent affording [(18)F]tri- and [(18)F]difluoromethylarenes not within reach with [(18)F]F2.

A convenient chemical-microbial method for developing fluorinated pharmaceuticals.

A significant proportion of pharmaceuticals are fluorinated and selecting the site of fluorine incorporation can be an important beneficial part a drug development process. Here we describe initial experiments aimed at the development of a general method of selecting optimum sites on pro-drug molecules for fluorination, so that metabolic stability may be improved. Several model biphenyl derivatives were transformed by the fungus Cunninghamella elegans and the bacterium Streptomyces griseus, both of which contain cytochromes P450 that mimic oxidation processes in vivo, so that the site of oxidation could be determined. Subsequently, fluorinated biphenyl derivatives were synthesised using appropriate Suzuki-Miyaura coupling reactions, positioning the fluorine atom at the pre-determined site of microbial oxidation; the fluorinated biphenyl derivatives were incubated with the microorganisms and the degree of oxidation assessed. Biphenyl-4-carboxylic acid was transformed completely to 4'-hydroxybiphenyl-4-carboxylic acid by C. elegans but, in contrast, the 4'-fluoro-analogue remained untransformed exemplifying the microbial oxidation - chemical fluorination concept. 2'-Fluoro- and 3'-fluoro-biphenyl-4-carboxylic acid were also transformed, but more slowly than the non-fluorinated biphenyl carboxylic acid derivative. Thus, it is possible to design compounds in an iterative fashion with a longer metabolic half-life by identifying the sites that are most easily oxidised by in vitro methods and subsequent fluorination without recourse to extensive animal studies.