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The use of fluorine-18 as a radionuclide for positron emission tomography (PET) has become increasingly popular over the last two decades and cancer and neurology clinical centres worldwide are increasingly establishing competence in this modality for diagnostic imaging. Progress has been particularly impressive for small molecule pharmaceutical candidates and low molecular weight affinity peptides, where clearance rates of the peptides in the body are compatible with the half-life of fluorine-18 (t 1/2 = 110 min). However high molecular weight proteins present challenges as they circulate and clear much more slowly. This review focuses on the methods used to radiolabel antibodies and their derivatives with fluorine-18 as tracers for PET. The very high specificity of these biomolecules for disease indicators at the molecular level makes labelling them attractive, however antibodies can circulate for days within the blood, with slow clearance times due to their high molecular weights, and this is inconsistent with the relatively short half-life of fluorine-18. Thus, lower molecular weight fragments of antibodies present more realistic targets for labelling. This review describes the approaches and protocols which have been successfully used to radiolabel antibodies and particularly antibody fragments with fluorine-18, and highlights this challenging aspect of fluorine-18 labelling for PET imaging.

The role of organo-fluorine compounds in modern health, food and energy related industries is widely-appreciated. The unique properties that fluorine imparts to organic molecules, stemming from its high electronegativity and stability when bound to carbon, finds it increasingly being used in the development of new bioactivities. Around 25 % of the current blockbuster drugs contain fluorine and this number is increasing to well above 30 % for recent FDA approvals. In this Review we highlight a selection of the most successful organo-fluorine drugs, that have achieved blockbuster status, namely, sitagliptin (diabetes), sofosbuvir (hepatitis C), emtricitabine (HIV), glecaprevir/pibrentasvir (hepatitis C), elvitegravir (HIV), dolutegravir (HIV), bictegravir (HIV), efavirenz (HIV), enzalutamide (prostate cancer), aubagio (immunomodulatory) and paliperidone palmitate (schizophrenia). For each compound we discuss their discovery, their relevant disease state and how they are made, emphasizing the source of fluorine-containing moieties, and where known, their mode of action.

Fluorine has been used widely to tune the pharmacokinetic properties of bioactive compounds as they progress through development. Accordingly, selective fluorination has had a major impact in the pharmaceuticals and agrochemicals industries and therefore on human health and well being, though in this context it is notable that fluorine has no presence at all in the flavours and fragrance industries. There does not appear to be an obvious molecular basis for this exclusion. It may be that costs have become prohibitive in this market and it may also be that there are negative perceptions of safety for products that will have intimate contact with healthy individuals, though given the impresssive track record of fluorine to influence the properties of bioactives for health improvement it is a striking omission. It seemed timely therefore to bring to the surface the literature that does exist in this area, if for no other purpose than to begin to explore prospects. We extend the survey to literature in the related area of insect pheromone and semiochemical analogues, as such analogues have the lucrative potential to be used in the field in traps and in small quantities to monitor insect populations. On the face of it, it would appear that there are genuine prospects to develop improved molecules for these purposes using fluorine, however the area remains underdeveloped. In this review we collate those studies which have prepared fluorinated analogues of flavours, fragrance and pheromone molecules and, where known, we discuss their efficacy.

Of the herbicides licensed worldwide, currently around 25% contain at least one fluorine atom and many contain multiple fluorines in the form of difluoro- and trifluoromethyl groups. Fluorine-containing compounds have made a significant contribution to the development of products for the agrochemicals industry and many organofluorine entities have found stable market positions. In this review we highlight the most important fluorinated herbicides in terms of their global use. The compounds are grouped by mode of action. A synthesis route is described for each compound although the synthesis presented may not actually be the industrial process.

An improved synthetic route for the synthesis of the 2,3,4-trideoxy-2,3,4-trifluoro hexose analogue of d -glucose has been developed. The newly reported synthesis features improved fluorination reactions and simpler chromatographic separations.

Organic fluorine compounds have had a profound impact on the development of bioactives for the modern pharmaceuticals market. It is estimated that up to 20% of pharmaceuticals prescribed or administered in the clinic contain a fluorine atom and 30% of the leading 30 blockbuster drugs by sales contain a fluorine. In this Highlight review, the top 10 fluorine containing pharmaceuticals (by US Sales in 2008) are highlighted. By this measure, these are currently the most significant fluorinated compounds impacting on health care. They embrace statins (Lipitor, Crestor, Vytorin, Zetia/Ezetimibe), anti-inflammatories (fluticasone propionate, Celebrex), antacids (Prevacid), antidepressants (Lexapro), neuroleptics (Risperdal) and antibiotics (Levaquin). In each case the structures and modes of action of these important drugs compounds are reviewed and representative synthetic routes are highlighted.

A range of dehydroxyfluorination reagents was reacted with separate diastereoisomers of a chiral allylic alcohol to explore both the regio- and stereoselectivity ratios of direct versus allylic fluorination. The allylic alcohol stereoisomers gave the same predominant fluorinated diastereoisomer indicating that the reaction proceeds with a significant SN1 component via an allylic carbocation intermediate, which is quenched by fluoride ion, predominantly from the least hindered face. None of the reagents displayed very high regio- or stereoselectivity, although in all cases the allylic fluorination products predominated.

Aldol reaction utilising Evans N-(α-fluoropropyl)-2-oxazolidinones with TiCl4 have been explored. Reactions of N-(α-fluoropropyl)-2-oxazolidinones with aliphatic aldehydes generated α-fluoro-β-hydroxy-aldol products with high diastereoselectivities. When (αR)- and (αS)-N-(α-fluoropropyl)-2-(4S)-oxazolidinones were explored as substrates they gave rise to identical aldol diastereoisomer products. Examination of the enolates formed in each case by 19F NMR, after treatment with TiCl4, indicated that both preparations gave the same predominant enolate. This was assumed to be the E-enolate. The α-fluoro-β-hydroxy-aldol products were removed from the auxiliary either by alcoholysis or reduction and converted to the corresponding α,β-difluoro products by treatment with Deoxofluor™.

This is a summary of a lecture presented at the 100th Anniversary, Moissan Symposium in Paris on Friday, 10 November 2006. The lecture highlighted recent developments on the enzyme structure, mechanism and biotransformation prospects of the fluorinase enzyme identified in 2002 from the bacterium Streptomyces cattleya . Over-expression of the enzyme has allowed it to be used as a catalyst for 18 F-incorporation during the synthesis of potential ligands for positron emission tomography (PET) applications.

In this review those fluorinated compounds which have found a role as anti-cancer agents are summarized. The emphasis is to highlight the important drugs but also to highlight the latest developments on emerging compounds. This has been done as comprehensively as possible with the objective of informing readers of some of the latest developments in this area.

A series of long chain fatty acids is prepared with alternating blocks of fluorocarbon and hydrocarbon. This hybrid construction provides three domains (fluorous, hydrocarbon, hydrophilic) on the same molecule. The ability of the monocarboxylic acids to form monolayers on water is explored and, in selected cases, X-ray structure analysis of the dicarboxylic acids provides information on the conformation and solid state organisation of these molecules. The hybrid molecules display surface behaviour and show packing distances which are intermediate between alkyl and perfluoroalkyl chains.

The conformation of 2-fluoro- N -(2-fluoroethyl)-propionamide 4 in the solid state indicates the influence of both a β-fluorine-amide gauche effect and an α -fluoroamide effect. The structure reveals the influence of two recently observed stereoelectronic effects associated with the CF bond, which has resulted in the successful prediction of the solid state conformation of amide 4. A gauche relationship (−69.9°) was observed for atoms N(1)C(4)C(5)F and a syn planar (2.0°) relationship was observed for N(1)C(3)C(2)F. The paper demonstrates the predictive power of using the CF bond as a tool in influencing the conformation of amides and peptides.

The acylase from Aspergillus melleus was able to hydrolyse the amide bond of ( S )-phenylalanine- N -2-( R , S )-fluoropropionamide and discriminate the diastereoisomers such that the ( S , S )-diastereoisomer was hydrolysed by an order of magnitude faster than the ( S , R )-diasteroisomer. The origin of the kinetic discrimination is attributed to both binding and kinetic effects.

It is now more than 50 years since the first fluorinated natural product was identified. In that time only about a dozen fluorinated natural products have been isolated, the last one over a decade ago. Very little is known about the mechanism of biological fluorination although significant progress has been made in elucidating the pathway by which biosynthesis of fluoroacetate and 4-fluorothreonine occurs in the bacterium Streptomyces cattleya . In this article we review the fluorinated natural products and the current status of our understanding of fluorometabolite biosynthesis.

An efficient synthesis of 6-fluoro- d -olivose 5 (2,6-dideoxy-6-fluoro- d -arabino-hexopyranose) starting from d -glucose is reported. Key features of the synthesis involve the early introduction of the fluorine atom at C-6 and the Fischer reductive elimination as a strategy to achieve C-2 deoxygenation. The route, the first to this compound, is efficient providing gramme quantities of 5 for biotransformation studies.

The CF 2 containing 6,6- and 10,10-difluorooctadecanoic acids 7 and 8 , respectively have been synthesised and their Langmuir isotherms evaluated. In marked contrast to the behaviour of octadecanoic acid (stearic acid) 1 it is demonstrated that spreading on an aqueous subphase generates an unstable monolayer which reorganises to a more stable bilayer structure. Grazing incidence X-ray scattering and ellipsometric measurements after deposition of 8 from the subphase onto a silicon wafer, confirmed a bilayer structure. These observations reinforce our earlier conclusions with 12,12-difluorooctadecanoic acid that substitution of CH 2 by CF 2 leads to increased conformational flexibility of a hydrocarbon chain.

Stork enamine reactions are explored with mono-fluorinated enamines derived from α-fluoroacetophenones and pyrrolidine. The resulting enamines react under mild conditions with Michael acceptors (acrylonitrile, methyl acrylate, methyl methacrylate, methyl vinyl ketone and cyclohexenone) to generate a variety of substituted α-fluoroketones.

The reaction of α-lithium-α-fluoro-α-trimethylsilyl-methylphosphonate 2 with aldehydes 3a-f leads to α-fluorovinylphosphonates 4a-f by a Peterson type olefination reaction.

Diethyl difluoromethylphosphonylcadmium bromide reacts with allyl and benzyl halides in THF to give the corresponding difluoromethylenephosphonate derivatives. The reaction with allyl bromide affords a versatile synthetic intermediate which undergoes a variety of synthetic transformations and therefore becomes a key compound in the preparation of elaborated difluoromethylenephosphonates of biological significance.

A method is outlined for the preparation of monofluorocarboxylic acids using Ishikawa's reagent, (C 2 H 5 ) 2 NCF 2 CHFCF 3 (PPDA), directly from hydroxyesters, or indirectly from monofluorinated alkylbenzenes, followed by the oxidation of the phenyl ring to a carboxylic acid. The chiral fluorocarboxylic acids, (2S) and (2R)-3-fluoro-2-methylpropionates (>99% ee) and (2S)-2-fluoropropionic acid (55% ee) are prepared as are 3-fluoropropionate and 4-fluorobutyrate.