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The development of synthetic methodology allowing for a strategic incorporation of fluorine into target compounds is in a high demand in many areas of the chemical and pharmaceutical industries. In this regard, application of fluorinated chiral sulfinimine reagents, in particularly, N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine, is one of the most general and practical approaches for preparation of compounds containing pharmacophoric fluoro-amino-keto/hydroxy moieties. This article provides a timely and comprehensive overview of the recent synthetic applications of fluorinated chiral sulfinimine reagents for asymmetric synthesis of fluoro-containing polyfunctional amino-compounds of biological interest. Where it is possible, we emphasize the synthetic versatility and practicality of the reported methods.

Mannich-type addition of 1,3-dicarbonyl compounds to (SS)-N-tert-butanesulfinyltrifluoroacetaldimine has been carried out under dramatically different conditions. The stereochemical outcome was quite different when the reaction was carried out under solvent-free conditions, at high temperature and without any catalyst or additive, compared with the DBU catalyzed reaction in dichloromethane solution at low temperature. Mechanistic aspects of the reaction under both the conditions are discussed. In this respect, vibrational (VCD) and electronic circular dichroism (ECD) and optical rotatory dispersion (ORD) experiments proved to be valuable tools for determining the absolute configurations of the reaction products.

Antibiotic resistance represents a worldwide concern, especially regarding the outbreak of methicillin-resistant Staphylococcus aureus, a common cause for serious skin and soft tissues infections. A major contributor to Staphylococcus aureus antibiotic resistance is the NorA efflux pump, which is able to extrude selected antibacterial drugs and biocides from the membrane, lowering their effective concentrations. Thus, the inhibition of NorA represents a promising and challenging strategy that would allow recycling of substrate antimicrobial agents. Among NorA inhibitors, the indole scaffold proved particularly effective and suitable for further optimization. In this study, some unexplored modifications on the indole scaffold are proposed. In particular, for the first time, substitutions at the C5 and N1 positions have been designed to give 48 compounds, which were synthesized and tested against norA-overexpressing S. aureus. Among them, 4 compounds have NorA IC50 values lower than 5.0 μM proving to be good efflux pump inhibitor (EPI) candidates. In addition, preliminary data on their ADME (absorption, distribution, metabolism, and excretion) profile is reported.

Electronic and vibrational circular dichroism (ECD and VCD) spectra and specific optical rotation measurements at the sodium D-line (OR) have been taken for thirteen chiral [2]paracyclo[2](5,8)quinolinophane derivatives and calculated by density functional theory. Besides the planar chirality from the paracyclophane moiety in all molecules, some of the investigated compounds also exhibit central chirality due to an asymmetric carbon atom in the side-chain bound at C-2 of the heterocyclic ring. Characteristic bands for each type of chirality were clearly identified in the VCD spectra in the CH-stretching and mid-IR regions, allowing assignment of absolute and relative configurations. ECD was found to be sensitive mostly, if not exclusively, to planar chirality, whereas OR was also very sensitive to central chirality. Configurational assignment of the different diastereomers by the present method provided results that are in agreement with those inferred from NOE-NMR experiments.

At the beginning of this article an in-depth comparison of electrophilic and nucleophilic aromatic and heterocyclic substitution processes examines their scopes of applicability in a new light. In the subsequent parts, recent progress in the area of halide and hydride displacement from pyridines is highlighted. Particular attention is paid to the leaving group aptitudes of fluoride and chloride, to the effect of 'passive' substituents on the reaction rates, and to the control of the relative reactivity at halogen-bearing 4-versus 2-(or 6-)positions.

The absorption IR and vibrational circular dichroism (VCD) spectra of both enantiomers of 4-X-[2.2]paracyclophanes (X = F, CH(2)F, COCF(3)) have been recorded in the mid-IR and CH stretching regions. The electronic CD (ECD) spectra have been collected as well. VCD spectra in the two IR regions, 900-1700 cm(-1) and 2700-3200 cm(-1), have been compared with the corresponding DFT calculated spectra. The absolute configuration assignment was confirmed as previously determined. We have shown that, to various extents, the VCD and ECD spectra bear some information on the relative mobility of the two phenyl rings and on the existence of different conformers for the X group. It has been observed that X = F and X = CH(2)F groups do not change the conformational and electronic properties of the parent X = H and X = CH(3) molecules. The X = COCF(3) group brings in a large perturbation to the [2.2]paracyclophanes, and the role of fluorine is less important than that of oxygen.

Two novel homologous [2]paracyclo[2](5,8)quinolinophane-derived P,N-bidentate planar chiral ligands have been synthesised and their effectiveness in asymmetric catalysis tested in palladium-catalysed allylic malonylation of 1,3-diphenylpropenyl acetate. The extent of asymmetric induction depends linearly on the ligand/metal molar ratio, indicating the involvement of P,P-type and chelate P,N-type π-allylpalladium complexes in equilibrium. The length of the chain that binds the diphenylphosphine group to the quinolinophane moiety, while appreciably affecting the P,N-complex stability, has little effect on the extent of asymmetric induction, which is due to the greater reactivity of the [PN]- exo–syn–syn – ([PN] xss ) with respect to the [PN]- endo – syn – syn – ([PN] nss ) π-allylpalladium complex.

Lipases from Candida rugosa , Candida antartica B and Carica papaya are employed as the biocatalyst for the hydrolytic resolution of methyl 2-fluoro-2-arylpropionates in water-saturated isooctane, in which excellent to good enantioselectivity without the formation of byproducts is obtained for the papaya lipase when using ( R , S )-2-fluoronaproxen methyl ester ( 1 ) and methyl ( R , S )-2-fluoro-2-(4-methoxyphenyl)propionate ( 2 ), but not methyl ( R , S )-2-fluoro-2-(naphth-1-yl)propionate ( 3 ) as the substrates. The thermodynamic analysis indicates that the enantiomer discrimination for the papaya lipase is driven by the difference in activation enthalpy for compound 1 , 2 or ( R , S )-naproxen methyl ester ( 4 ). The kinetic analysis also demonstrates that in comparison with ( S )- 4 , the insertion of the 2-fluorine moiety in ( R )- 1 has increased k 2 , but not K m , and consequently the lipase activity.

The enzymatic hydrolysis of methyl 2-fluoro-2-arylpropionates was performed using lipases from Candida rugosa and Candida cylindracea (OF-360). A careful analysis of the reaction products revealed that racemic 2-hydroxy-2-arylpropionic acid and traces of 2-arylacrylic acid are formed, in addition to the expected 2-aryl-2-fluoropropionic acid. The presence of powerful electron-releasing groups in the aromatic ring of the substrate increase the amount of 2-hydroxypropionic acid. A mechanistic hypothesis has been formulated according to which the enzyme facilitates the elimination of fluoride ion from the hydrolysed acid with the formation of an α-carboxy-stabilized carbocation which provides 2-hydroxypropionic acids by nucleophilic attack of H2O and 2-arylacrylic acids by a β-elimination process.

A systematic study to assess the contribution of planar and central chirality to the asymmetric induction in the diethylzinc addition to aromatic and aliphatic aldehydes has been carried out using planar chiral quinolinophanylcarbinols ( R p )- 1 and ( R p )- 11 and diastereomeric quinolinophanylcarbinols ( R p , R )- and ( R p , S )- 5 – 8 , exhibiting both planar and central chirality as catalysts. The stereochemistry of the addition process leading to aryl- or 1-alkylpropanols seems to be mostly controlled by the central chirality. Nevertheless, the planar chirality shows a remarkable cooperative effect on the degree of asymmetric induction, which turns out to be positive or negative depending on the configuration of the stereogenic carbon of the catalyst.

Atropisomeric (R,R)-2,2'-bi([2]paracyclo[2](5,8)quinolinophane) [(R,R)-1] and (R,R)-1,1'-bi([2]paracyclo[2](5,8)isoquinolinophane) [(R,R)-2] have been prepared in moderate overall yield (17 and 9%, respectively) by a four-step sequence starting from (R)-(-)-4-amino[2.2]paracyclophane and (R)-(-)-4-carboxy[2.2]paracyclophane, respectively. The structures have been determined on the basis of NOE (1)H NMR analysis and molecular mechanics (MM) calculations performed with a Spartan02 program, using the MMF94s force field. A preliminary, qualitative analysis of the chiroptical properties of these two compounds has also been attempted. The main spectral data can be interpreted in terms of an almost planar 2,2'-bisquinoline chromophore inserted in a paracyclophane structure in the case of (R,R)-1, while in the case of (R,R)-2, the main role is played by a distorted 1,1'-bisisoquinoline chromophore. On the basis of the above structural results, a hypothesis about the enantioselection capability of these two molecules has also been formulated.

Tetraethyl vinylidenebis(phosphonate) (VBP) reacts smoothly with substituted 1,3-dienes at 90-110 degrees C without solvent to give the corresponding cyclohex-3-ene-1,1-bis(phosphonates) in good yields (60-85%). With nonsymmetrically substituted dienes, mixtures of regioisomers are obtained, the regioisomeric ratio being exclusively controlled by electronic effects. Danishefsky's diene allows tetraethyl 4-oxocyclohex-2-ene-1,1-bis(phosphonate) to be obtained in an 81% overall yield after the acid-catalyzed hydrolysis of the Diels-Alder cycloadduct. With 2,3-dimethoxy-1,3-butadiene, a mixture of regioisomeric dimethoxycyclohexene-1,1-bis(phosphonates) is formed by the VBP-catalyzed isomerization of the normal Diels-Alder cycloadduct. The mixture converges into tetraethyl 3,4-dimethoxycyclohex-2-ene-1,1-bis(phosphonate) at prolonged reaction times.

(+)-(R)-[2.2]Paracyclophane[4,5-d]-1,3-oxazol-2(3H)-one exhibiting planar chirality has been used as a chiral auxiliary in asymmetric Diels-Alder, Michael, and aldol reactions of alpha,beta-unsaturated carboxy and enolate imides, respectively. The endo-exo- and face-diastereoselectivity is good and is controlled by the spatial relationship between the prochiral center and the C9-C10 ethylene bridge of the [2.2]paracyclophane moiety. The chiral auxiliary is easily removed and quantitatively recovered.

The 4th edition of the Fluorine Days held in Bordeaux from 6th to 10th July 2014 showed, as it was previously the case in Perugia (2001 and 2010) and Valencia (2012), that this concept for a conference on fluorine chemistry is very successful. Manfred Schlosser was born on June 12th, 1934 in Ludwigshafen am Rhein (Germany). After his chemistry studies, and, to some extent, medicine at the prestigious University of Heidelberg between 1952 and 1957, he was awarded ‘‘Diplom-Chemiker’’ (comparable with M.Sc.). In 1957 he started then his Ph.D. work under the supervision of the famous Nobel Prize laureate Georg Wittig and received in May 1960 his doctor degree ‘‘Doctor rerum naturarum’’ (comparable with Ph.D.). He spent then 1 year (from May 1962 to April 1963) in Brussels (Belgium) where he was appointed as a Research Fellow at the European Research Associates, sponsored by the Union Carbide Co. On August 1966 he was then awarded ‘‘Doctor habilitus’’ (coupled with the conferment of the ‘‘venia legendi’’) from the University of Heidelberg. After his habilitation, Prof. Schlosser accepted a position as ‘‘Oberarzt’’ (Senior Physician) at the Heidelberg Faculty of Medicine, where he was group leader at the German Cancer Research Center. He was at the same time a ‘‘Privatdozent’’ (Assistant Professor) at the Heidelberg Faculty of Science before

(R)-4-Hydroxy-, -4-fluoro-, -4-bromo-, and -4-iodo[2.2]paracyclophanes have been prepared and their absolute configuration assigned on the basis of chemical correlations. Different relationships between the specific optical rotation and the group polarizability have been found depending on the ability of the substituents to conjugate with the aromatic ring. At least for 4,7-disubstituted [2.2]paracyclophanes, the effects of the substituents on the specific rotation seem to be additive, independent of the wavelength used. An equation has been derived which allows to predict, to a satisfactory approximation, the [α] values of 4-X-7-methyl[2.2]paracyclophanes whenever the group polarizability of the substituents is known.

A new chiroptical compound, (E)-(R(p),R(p))-1,2-bis{4-methyl-[2]paracyclo[2](5,8)quinolinophan-2-yl}ethene (trans-RPQE) has been synthesized, and its photoresponse has been investigated through steady state and time-resolved absorption and emission spectroscopies and theoretical calculations. To elucidate the relaxation mechanism of trans-RPQE after photoexcitation, the photophysics of the 2,4-dimethyl-[2]paracyclo[2](5,8)quinolinophane chromophore has also been studied. The quantum yields of the different relaxation paths for trans-RPQE have been determined. It emerges that in addition to thermal and radiative routes, trans-RPQE also photoisomerizes with a quantum yield of 8%. Trans- and cis-RPQE isomers are pseudoenantiomers exhibiting appreciably different CD spectra, whereby RPQE can be a model for the design of new promising chiroptical photoswitches.

Regioselectively fluorinated 1-(naphth-2-ylmethyl)imidazoles 1a-h have been synthesized starting from the corresponding (naphth-2-yl)methanols (2). 2a-d have been obtained by LiAlH4-promoted reduction of fluorinated 1-methyl-2-naphthaldehydes. The latter were easily prepared in fairly good overall yields by ceric ammonium nitrate (CAN)-promoted oxidative addition of the suitable 3-(fluoroaryl)-1-trimethylsilyloxy-1-butenes to ethyl vinyl ether in methanol followed by cyclization of the resulting acetals in strongly acidic medium in the presence of DDQ. 2e-h were prepared by LiAlH4-promoted reduction of the corresponding fluorinated methyl 2-naphthoates. The latter were more profitably obtained by reacting the suitable benzyl bromide with the sodium salt of dimethyl 2-(2,2-dimethoxyethyl)malonate in DMF followed by demethoxycarbonylation and acid catalysed cyclization of the resulting acetals. Compared with the nonfluorinated parent compounds 1i-1, fluorinated 1-(naphth-2-yl)methylimidazoles 1a-h turned out to be potent inhibitors of CYP17 and CYP19 enzymes. The most active inhibitor of CYP17 is 1c, whereas CYP19 is strongly inhibited by 1b, 1e, and 1g. Interestingly, 1g is a potent dual inhibitor also being very active towards CYP19.

3-Acyl- and 3-carboalkoxyfurans can be prepared in 30–55% yield by the oxidative addition of 1,3-dicarbonyl compounds to vinylic acetates induced by eerie ammonium nitrate.