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Authors thank the Engineering and Physical Sciences Research Council (EPSRC) for funding and we are grateful to the EPSRC Mass Spectroscopy Service at the University of Swansea for carrying out some of the accurate mass analysis of prepared compounds. A series of five 12-dodecanolides have been synthesised containing CF2 groups at C5, C6, C7, C8 and in one case a double substitution at C5 & C8, as a strategy to bias the conformational space accessed by these macrocycles, and to assess if the analogues may act as mimetics for 12-decenolide pheromones associated with the Emerald Ash Borer. Accordingly individual syntheses of 5,5-difluoro- 5, 6,6-difluoro- 6, 7,7-difluoro- 7, 8,8-difluoro- 8 and 5,5,8,8-tetrafluoro- 9, 12-decanolides is outlined and X-ray structural data was obtained for three (5, 8 and 9) of these compounds. The structures show clearly that the CF2 groups occupy ‘corner’ locations in the macrocycle consistent with their ability to bias accessible conformations. The fluorine containing 12-dodecanolides all generated an electro-antennogram response in female beetles. Postprint

A series of analogues of the integrin binding aspartic acid-glycine-arginine (RGD) peptide sequence were synthesised conjugated to nitric oxide (NO) donating functional groups. Also the cytotoxicity of abiraterone, a prostate cancer drug, was explored when it was conjugated in three part constructs to RGD sequences and NO releasing heterocycles. In general the analogues showed integrin binding affinity comparable to RGD reference compounds, and all released NO by the Griess test assay. Two analogues exhibited significant cytotoxic effects against PC3 and MCF7 cell lines.

A protocol for the preparation of a series of liquid crystals is presented, where the structures carry a central propyleneoxy motif carrying two vicinal threo-C–F bonds. The negative dielectric anisotropy (−Δɛ) of the resultant liquid crystals has been explored. The stereoelectronic relationship between the vicinal C–F bonds was anticipated to orientate the fluorine atoms gauche to each other when the propylene chain is extended. This is shown to be the case. This orientation of the C–F bonds generates a net dipole perpendicular to the molecular axis, a prerequisite for the design of dielectrically negative liquid crystals. However the molecules adopt a conformation where one C–F bond reinforces the net molecular dipole, and the other has a counter effect, thus the introduction of the motif has an almost neutral effect on dielectric anisotropy (Δɛvirt) of these candidate liquid crystals. However, introduction of the difluoro motif raises the melting points of the liquid crystals and increases their conformational rigidity.

Epidemiological studies indicate that flavonoid intake is inversely associated with the risk of coronary heart disease, yet the mechanisms responsible for their bioactivity are still a matter of debate. Based on the rapid and extensive metabolism of most flavonoids, their health effects most likely result from the biological activity of their metabolites. However, a lack of commercially available compounds/standards has prevented the study of metabolite bioactivity and resulted in a focus on non-physiologically relevant precursor/parent structures. This paper details the synthesis of a series of phenolic glucuronide 1a–e and sulfate 2a–e derivates as candidate metabolites for use as reference compounds in metabolic profiling studies and for the exploration of flavonoid bioactivity.

DFT derived conformational energy profiles of a series of β-substituted α-fluoroethanes (F–CH 2 CH 2 –X) have been explored where the substituent X was varied as NH 3 + , OCOH, NCO, NO 2 , NHCHO, F, N 3 , CH NH, NCS, CH C CH 2 , CH 3 , CH CH 2 , NC, CN, CHO, and CCH. Comparisons were correlated relative to 1,2-difluoroethane, a compound which exhibits a well known gauche preference. Only four of the compounds displayed an anti preference, with the large majority preferring a gauche conformation. In particular the influence of steric and electrostatic attraction/repulsion between the fluorine atom and the X-substituent was explored by evaluating rotational energy profiles for all compounds and separately NBO correlations were evaluated to assess the contribution of hyperconjugation to the minimised gauche and anti conformers. In the event the gauche preference for 1,2-difluoroethane was shown to have an origin due largely to σ(C–H)→σ*(C–F) hyperconjugative interactions, whereas the conformational preference for the remaining structures is rationalised by hyperconjugative as well as steric and electrostatic contributions. The anti preferred compounds 13 , 14 and 16 possessed triple bonds and the preference arose due to fluorine/ p -orbital repulsion.

1-Deoxy-D-xylulose is a key intermediate in bacterial co-factor biosynthesis. We report the synthesis of the 1-fluoro- and 1,1-difluoro- analogues of 1-deoxy-D-xylulose as potential antimetabolites of bacterial 1-deoxy- d -xylulose metabolism.

The acyltetramic acid 6 previously proposed as a putative intermediate in tenellin biosynthesis in Beauveria bassiana has been synthesised in two isotopically labelled forms. This compound was not incorporated into tenellin and was not identifiable in extracts of B. bassiana and is unlikely to be involved in tenellin biosynthesis. On the other hand a re-evaluation of the role of tyrosine reveals that it is a good precursor to tenellin and is probably generated in vivo by the action of a phenylalanine hydroxylase directly from L-phenylalanine. Thus the long held contention that acyltetramic acid 6 undergoes oxidative ring expansion to a pyridone no longer appears a valid hypothesis for tenellin biosynthesis.

This study is aimed at evaluating organic fluorine as a hydrogen bonding acceptor. A review of short F…H contacts from all of the organofluorine compounds deposited in the Cambridge Structural Database System (CSDS) was carried out and in parallel a theoretical estimate of the energy of such contacts with inter nuclear distance was executed. A total of 548 structures emerged which contained 1163 unique CF bonds and only 166 of these fluorine atoms posessed short CF…HX contacts of ≤ 2.35A. Contacts between fluorine and hydrogen bound to carbon (CF…HC) represent the major category of short contacts however these were not judged to be hydrogen bonds as they are weak with energies similar to those of van der Waals complexes. Short contacts between F and the acidic hydrogens of HO or HN are rare in the CSDS with only 12 and 28 occurring respectively. There was only one contact below 2.0A. Ab initio calculations have evaluated the relative stability and optimum distance of CF…HO bonds between water and fluoromethane and fluoroethene. It emerges that the C(sp 3 )F fluorine in fluoromethane can enter into stronger hydrogen bonds than C(sp 2 )F of fluoroethene. The X-ray data reinforces the conclusion that C(sp 3 )F fluorine is a better hydrogen bond acceptor than C(sp 2 )F fluorine. The C(sp 3 )F…HO bond is less than half the strength (2.38 kcal mol −1 ) of a CO…HO and the C(sp 2 )F…HO bond (1.48 kcal mol −1 ) is about half as weak again. Overall however short contacts in the Database which are consistent with an optimal F…H bond are extremely rare.

The synthesis of the cyclohexylammonium salts of (1 RS , 3S)-3,4-dihydroxy-1-fluorobutylphosphonic acid 3 and (S)-difluoro-3,4-dihydroxybutylphosphonic acid 4 is reported. These compounds are fluorinated phosphonate analogues of sn -glycerol-3-phosphate where the bridging phosphate ester oxygen is replaced by CHF and CF 2 respectively. Kinetic studies are presented for oxidation with NADH linked glycerol-3-phosphate dehydrogenase, which reveal that the CHF-phosphonate 3 performs similarly to the natural substrate sn -glycerol-3-phosphate, and is a better substrate than the CF 2 -phosphonate 4 . The study also reveals that the diastereoisomers of 3 ( 3a and 3b ) are processed at different rates suggesting that the enzyme can discriminate the CHF stereogenic centres. A synthesis and X-ray crystal structure of 2-amino-1-fluoroethylphosphonic acid 7 is described which allows comparison of the geometry and conformation of CHF-phosphonate with that of analogous CH 2 - and CF 2 -phosphonates.

The preparation of difluoromethylenephosphonate analogues of the glycolytic intermediates, glycerol-3-phosphate and 3-phosphoglycerate are described. Attempts to prepare the corresponding analogue of dihydroxyacetone phosphate failed due the facile elimination of hydrogen fluoride from the target molecule. Finally the synthesis of a difluoromethylenephosphonate possessing inhibitory activity against RNA transcriptase from the influenza virus is described.

Structural and stereochemical similarities transcending the polyether and macrolide antibiotic classes are outlined. Significant correlations are highlighted between the macrolides mycinamicins I–V and the polyethers norboritomycins A and B and antibiotic X-14766A over a structural sequence derived from seven biosynthetic subunits. The analogy is extended by comparison of a model which describes the stereochemistry of all the 16-membered macrolides with the Cane-Celmer-Westley PAPA prototype which summarises the stereochemistry of all the monovalent bisdispiroketal polyether antibiotics. Although the subunit constitution varies in individual cases the absolute configuration maintains its consistency at five of six asymmetric centres over the seven subunit sequence.