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This review article comprehensively profiles all literature reports (2015-2018) related to the detrifluoroacetylative in situ generation of fluorine-containing enolates and their reactions with electrophilic reagents. The innovative facets of this unconventional methodology and its synthetic generality for the preparation of fluorine-containing compounds of high medicinal value are highlighted.

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.

In recent years, a large number of in silico and in vitro assays have been developed for safety assessment in early drug discovery. These methods are usually validated using datasets of known drugs with large chemical diversity, while application to homologous series has been rarely explored. Here we report a case study about phospholipidosis (PLD) risk evaluation for a dataset of nine compounds, designed and synthesized to modulate the physico-chemical properties typical of cationic amphiphilic compounds (CADs), representing the main class of PLD inducers. Our aim was to investigate the effect of structure modification on PLD induction according to a number of standard in silico and in vitro methods. As a result, we found that different in silico methods lead to conflicting results when applied to our series of weak PLD inducers, thus the apparently easy-to-use definition of CADs requires special attention. Moreover, when weak inducers are tested in vitro, the revealed PLD effect may vary based on the purity grade of the tested compound and the features of the selected assay. Finally, we have shown that slight modifications on a chemical scaffold can have an impact on the PLD effect. This study also exemplifies that current in silico methods possibly overestimate the PLD induction effect of cationic amphiphilic compounds compared to the in vitro, with the risk of discarding promising compounds based on incorrect safety liabilities.

The VCD spectra of several chiral compounds containing the CF

The VCD spectra of several chiral compounds containing the CF3 group are reviewed and analyzed. The list of compounds contains pharmaceutically relevant molecules as well as simple model molecules, having the value of case studies. In particular we point out the importance of the sign of the VCD band relative to some stretching normal mode of CF3 in the region 1110–1150 cm−1, as diagnostic of the configuration of stereogenic carbons C* to which the CF3 group is bound: the correspondence (−) ↔ (R) and (+) ↔ (S) holds for 100% of 1-aryl-2,2,2-trifluoroethanols. DFT calculations confirm these conclusions, but for the rule established here they serve just as a check. This rule is tested on two new compounds, namely N-tert-butanesulfinyl-1-(quinoline-4-yl)-2,2,2-trifluoroethylamine, 8, and 4-[2-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile, 10, both containing two stereogenic elements, one of them being an asymmetric carbon C* of unknown configuration binding a CF3 group. Discussion of the general validity of the rule is provided and some further tests are run on compounds in well-established drugs.

Over the last two decades, fluorine substitution has become one of the essential structural traits in modern pharmaceuticals. Thus, about half of the most successful drugs (blockbuster drugs) contain fluorine atoms. In this review, we profile 17 fluorine-containing drugs approved by the food and drug administration (FDA) in 2018. The newly approved pharmaceuticals feature several types of aromatic F and CF3 , as well as aliphatic (CF2 ) substitution, offering advances in the treatment of various diseases, including cancer, HIV, malarial and smallpox infections.

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.

The role played by the C*-H based modes (C* being the chiral carbon atom) and the large amplitude motions in the vibrational absorption (VA) and vibrational circular dichroism (VCD) spectra is investigated. The example of an adduct of dimethyl fumarate and anthracene, i.e., dimethyl-(+)-(11R,12R)-9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboxylate, and two deuterated isotopomers thereof specially synthesized for this goal, are considered. By comparing the experimental and DFT calculated spectra of the undeuterated and deuterated species, we demonstrate that the C*-H bending, rocking, and stretching modes in the VA and VCD spectra are clearly identified in well defined spectroscopic features. Further, significant information about the conformer distribution is gathered by analyzing the VA and VCD data of both the fingerprint and the C-H stretching regions, with particular attention paid to the band shape data. Effects related to the large amplitude motions of the two methoxy moieties have been simulated by performing linear transit (LT) calculations, which consists of varying systematically the relative positions of the two methoxy moieties and calculating VCD spectra for the partially optimized structures obtained in this way. The LT method allows one to improve the quality of calculated spectra, as compared to experimental results, especially in regard to relative intensities and bandwidths.

A novel approach to regioselectively substituted and stereoselectively α-trifluoromethylated tryptamines is reported based on the ene reaction of Boc-protected 3-methyleneindolines with optically pure (R)- or (S)-tert-butanesulfinyltrifluoroacetaldimine. Boc- and sulfinylamido-protected α-trifluoromethyltryptamines are obtained in 60-70% yield and 85/15 dr by just heating equimolar amounts of the two reaction partners at 80-90 °C for 2-3 h without a solvent. The absolute configuration of the amino α-carbon has been assigned based on the vibrational circular dichroism (VCD) spectral analysis. The two protecting group can be chemoselectively removed allowing further regio- and stereoselective elaboration of the ene products to various biologically interesting compounds.

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.

Someone who says "A" should be prepared to also say "B": In contrast to cyclohexane model-based A values, biphenyl model-derived B values are powerful tools to quantify steric repulsion in and conformational behavior of ortho-substituted aromatic compounds.Torsional barriers of 15 ortho-substituted biphenyls have been determined computationally using the B3LYP density functional and experimentally by variable-temperature ("dynamic") nuclear magnetic resonance. Taking advantage of the 3'-isopropyldimethylsilyl group as a novel and superior diastereotopicity probe and tracking coalescence temperatures down to -173 degrees C (100 K), activation energies of aryl-aryl rotation as small as 5 kcal mol(-1) can be assessed. The 2-X/2'-H repulsion increments thus derived are powerful parameters for rationalizing and predicting the conformational behavior of aromatic compounds carrying ortho substituents.

The vibrational absorption spectra and vibrational circular dichroism (VCD) spectra of both enantiomers of 4-X-[2.2]paracyclophanes (X = COOCD3, Cl, I) have been recorded for a few regions in the range of 900-12000 cm(-1). The analysis of the VCD spectra for the two IR regions, 900-1600 cm(-1) and 2800-3200 cm(-1), is conducted by comparing with DFT calculations of the corresponding spectra; the latter region reveals common motifs of vibrational modes for the three molecules for aliphatic CH stretching fundamentals, whereas in the mid-IR region, one is able to identify specific signatures arising from the substituent groups X. In the CH stretching region between 2900 and 2800 cm(-1), we identify and interpret a group of three IR VCD bands due to HCH bending overtone transitions in Fermi resonance with CH stretching fundamental transitions. The analysis of the NIR region between approximately 8000 and approximately 9000 cm(-1) for X = COOCD3 reveals important features of the aromatic CH stretching overtones that are of value since the aromatic CH stretching fundamentals are almost silent. The intensifying of such overtones is attributed to electrical anharmonicity terms, which are evaluated here by ab initio methods and compared with literature data.

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.

Long-range bonding interactions were evaluated using variable-temperature NMR spectroscopy and suitable 2'-CH2X-substituted phenylpyridines (X = Me, NMe2, OMe, F). It was found that the arylpyridyl rotational barriers were lower when electronegative atoms were bound to the α carbon of the 2' moiety. This effect was ascribed to a stabilizing interaction in the transition state due to the lone pair of the heterocyclic nitrogen with the α carbon. Computational support for this hypothesis came from CCSD(T)/6-31+G(d) calculations. Steric effects of the X moiety were ruled out by comparison of the rotational barriers of analogous biphenyls.

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.

Diethyl 2-alkyl-2-hydroxymalonates react with DAST almost exclusively at the ester carbonyl giving a mixture of ethyl 2-(ethoxydifluoromethyl)-2-hydroxyalkanoates, 1,1-bis(ethoxydifluoromethyl)alkan-1-ols when administered at room temperature in dichloromethane. The reaction was exploited in the synthesis of nucleus- and side-chain polyfluorinated indoles. The fluorination of substituted diethyl 2-[(1- tert -butoxycarbonylindol-3-yl)methyl]-2-hydroxymalonates with DAST gave a mixture of ethyl 2-(ethoxydifluoromethyl)-2-hydroxy-3-(1- tert -butoxycarbonylindol-3-yl)propionate, diastereomeric 1′- tert -butoxycarbonyl-2′-hydroxy-2,2-diethoxycarbonylspiro(cyclopropane-1,3′-indoline) and only traces of 1,1-bis(ethoxydifluoromethyl)-2-(1- tert -butoxycarbonylindol-3-yl)ethanol. The composition of these mixtures changes depending on the reaction conditions. Regioselectively substituted ethyl 2-hydroxy-2-[(1- tert -butoxycarbonylindol-3-yl)methyl]-3,3,3-trifluoropropionate reacts with DAST at 0 °C in dichloromethane giving satisfactory yields of the corresponding 1-ethoxy-2-[(1- tert -butoxycarbonylindol-3-yl)methyl]-1,1,3,3,3-pentafluoropropan-2-ols as the exclusive reaction products. In the same reaction conditions, ethyl 3-(1- tert -butoxycarbonylindol-3-yl)-2-hydroxypropionate mainly provides 1′- tert -butoxycarbonyl-2′-hydroxy-2,2-diethoxycarbonylspiro(cyclopropane-1,3′-indoline) together with the “normal” fluorination product ethyl 3-(1-tert-butoxycarbonylindol-3-yl)-2-fluoropropionate. A plausible mechanism of this process is proposed in the following.

(+)-(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.

Influenza virus infections represent a serious concern to public health, being characterized by high morbidity and significant mortality. To date, compounds targeting the viral ion-channel M2 or the viral neuraminidase are the drugs available for treatment of influenza, but the emergence of drug-resistant viral mutants renders the search for novel targets and their possible inhibitors a major priority. Recently, we demonstrated that the viral RNA-dependent RNA polymerase (RdRP) complex can be an optimal target of protein–protein disruption by small molecules, with thiophene-3-carboxamide derivatives emerging as promising candidates for the development of new anti-influenza drugs with broad-spectrum activity. Here, we report a further dissection of the thiophene-3-carboxamide structure. By using a GRID molecular interaction field (MIF)-based scaffold-hopping approach, more potent and nontoxic polyamido derivatives were identified, highlighting a new space in the chemical variability of RdRP inhibitors. Finally, a possible pharmacophoric model highlighting the key features required for RdRP inhibition is proposed.

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

The CD spectra of a new series of 4-substituted [2.2]paracyclophanes 1b – e have been measured down to 185 nm. Polarizability calculations within the DeVoe model satisfactorily reproduce the CD features over all the spectral range. In addition, the analysis of the complete CD spectrum allowed a phenomenological interpretation of the dependence of the sign of [α] D on the nature of the substituents, at least for X=F, OH, I.

Novel, optically pure 2-{4-methyl[2]paracyclo[2](5,8)quinolinophan-2-yl}-4-aryl/alkyloxazolines (QUIPHANOX) exhibiting both planar and central chirality have been prepared by reacting (Rp)- and (Sp)-2-cyano-4-methyl[2]paracyclo[2](5,8)quinolinophane with 2-aryl/alkyl-2-aminoethanols. The reaction of each of the above N,N-ligands with [Ru(η(6)-p-cymene)Cl2]2 in methanol, in the presence of either NH4PF6 or NaBPh4, gave the corresponding half-sandwich [(η(6)-p-cymene)Ru(QUIPHANOX)Cl](+)Y(-), (Y(-) = PF6(-), BPh4(-)) as stable complex salts exhibiting planar and carbon- and metal-centered chirality. The unknown absolute configuration (AC) at the metal was determined by (1)H NMR and by theoretical calculations of electronic circular dichroism (ECD) spectra and subsequently confirmed by crystallographic X-ray analysis. (Rp) and (Sp)-ligands afforded (RRu)- and (SRu)-configured complexes, respectively, independent of the AC at the chiral carbon of the oxazoline moiety.

The enzymatic kinetic resolution of (±)-4-acetoxy[2.2]paracyclophane by Candida cylindracea lipase was investigated in water and in a two-phase aqueous organic system. The (+)-(R)-4-hydroxy- and (+)-(S)-4-acetoxy[2.2]-paracyclophanes were isolated in excellent yields and high enantiomeric excesses. The resolution was carried out on multi-gram scale in hexane-water at 40° C.

(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 survey of some recent synthetic approaches to regioselectively fluorinated six member condensed homo- and heteropolycyclic aromatic compounds by complementary cyclization methods is reported.

A survey of some recent synthetic approaches to regioselectively fluorinated six member condensed homo- and heteropolycyclic aromatic compounds by complementary cyclization methods is reported.

Accepted Manuscript version. The Published Journal Article is available on the Journal of Chromatography A, Volume 1232, pages 128–133 (DOI: https://doi.org/10.1016/j.chroma.2011.10.090). Supplementary Material available free of charge on the article webpage. © 2011. This Manuscript version is made available under the CC-BY-NC-ND 4.0 license. https://creativecommons.org/licenses/by-nc-nd/4.0/ ABSTRACT Enantioselective high performance liquid chromatography (HPLC) coupled with a detection system based on the simultaneous measurement of UV absorption and electronic circular dichroism (ECD) allows a complete stereochemical characterization of chiral compounds, once the relationship between sign of the chiroptical properties and absolute configuration is determined. In the present communication, the development of enantioselective HPLC methods for the resolution of a series of fluorinated 2-phenanthrenylpropionic acids (1-6) is reported. Different chiral stationary phases (CSPs) were tested: Chiralcel® OJ, Chiralcel® OD, Chiralpak® AD, (S,S)-Whelk-O® 1, Chirobiotic™ T and α1-acid glycoprotein (AGP). The results allow the application of the methods to a reliable determination of the enantiomeric excess for all the examined compounds; the highest enantioselectivity values were obtained with the Hibar® [(S,S)-Whelk-O® 1] column for some of the examined compounds. In the case of rac-2-(6-fluorophenanthren-1-yl)propionic acid (1), the relationship between circular dichroism and absolute configuration of the enantiomeric fractions was determined by ECD analysis and time-dependent density functional theory (TD-DFT) calculations. The experimental ECD spectrum of the second-eluted fraction of 1 on the Hibar® [(S,S)-Whelk-O® 1] column was found to be in excellent agreement with the theoretical ECD spectrum of (S)-1; therefore, the absolute configuration of the first- and second-eluted enantiomers on the (S,S)-Whelk-O® 1 CSP was assessed as (R) and (S), respectively, and the elution orders of the enantiomeric forms of 1 were determined on all the different CSPs.

The free energies of activation for the aryl-aryl rotation of 17 biphenyl derivatives, bearing a heavy heteroatom (S, Se, Te, P, Si, Sn) as ortho substituent, have been measured by variable temperature NMR. These numbers, so called B values, represent a meaningful measure of the steric hindrance exerted by the selected substituents. DFT computations match quite satisfactorily the experimental barriers and the ground state geometries as well (determined, in two cases, by X-ray diffraction). The present values extend the available list of B values and thus provide an enlarged basis for the compilation of the space requirements of standard substituents, based solely on experimental determinations.

The IR and Near infrared (NIR) vibrational circular dichroism (VCD) spectra of molecules endowed with noncentral chirality have been investigated. Data for fundamental, first, and second overtone regions of (S)-2,3-pentadiene, exhibiting axial chirality, and methyl-d(3) (R)- and (S)-[2.2]paracyclophane-4-carboxylate, exhibiting planar chirality have been measured and analyzed. The analysis of NIR and IR VCD spectra was based on the local-mode model and the use of density functional theory (DFT), providing mechanical and electrical anharmonic terms for all CH-bonds. The comparison of experimental and calculated spectra is satisfactory and allows one to monitor fine details in the asymmetric charge distribution in the molecules: these details consist in the harmonic frequencies, in the principal anharmonicity constants, in both the atomic polar and axial tensors and in their first and second derivatives with respect to the CH-stretching coordinates.

Silyloxycyclopropanes are easily oxidized by ceric ammonium nitrate to generate β-carbonylalkyl radicals which are able to add to 1,3-butadiene to give a mixture of 4-(γ-carbonylalkyl)-substituted 3-nitroxy-1-butenes and 4-(γ-carbonylalkyl) substituted (E)-1-nitroxy-2-butenes (1,2- and 1,4-adducts) in ca. 1:1 molar ratio. The crude mixture, subjected to palladium-catalyzed alkylation by a variety of carbon nucleophiles, affords mainly δ,g3-unsaturated carbonyl compounds with high regio- and stereoselectivity and in satisfactory overall yield.

Trimethylsilyl dienol ethers are easily oxidized by ceric ammonium nitrate to give α-carbonylallyl radicals which are able to add to enolic carbon-carbon double bonds with very high γ regioselectivity, allowing the method to be applied to the synthesis of 6-oxo-α,β-unsaturated carbonyl compounds.

1-Oxa-2,3-cyclohexadiene (I) can be readily generated by treatment of 5-bromo-3,4-dihydro-2H-pyran with potassium tert-butoxide in the presence of 18-crown-6 and can be trapped with dienes or olefins. Thus, the treatment of I with furan gave 50% yield of Diels-Alder adduct II, whereas with 1,1-diphenylethylene I gave 43% of the [2+2]cycloadduct III. The remarkable regio- and stereoselectivities with which [4+2] and [2+2] adducts are formed suggests a concerted, non-radical cycloaddn. mechanism. [on SciFinder (R)]

Trimethylsilyl dienol ethers are easily oxidized by ceric ammonium nitrate to give α-carbonylallyl radicals which are able to add to enolic carbon-carbon double bonds with very high γ regioselectivity, allowing the method to be applied to the synthesis of 6-oxo-α,β-unsaturated carbonyl compounds.

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.

Organic sulfides are selectively oxidized to the corresponding sulfoxides in high yields and under very mild conditions using 35% hydrogen peroxide in CHCl3 in the presence of catalytic amounts of 1, 1, 1-trifluoroacetone.