Mid-IR and CH stretching vibrational circular dichroism spectroscopy to distinguish various sources of chirality: The case of quinophaneoxazoline based ruthenium(II) complexes.

Five diastereomers of ruthenium(II) complexes based on quinolinophaneoxazoline ligands were investigated by vibrational circular dichroism (VCD) in the mid-IR and CH stretching regions. Diastereomers differ in three sources of chirality: the planar chirality of the quinolinophane moiety, the central chirality of an asymmetric carbon atom of the oxazoline ring, and the chirality of the ruthenium atom. VCD, allied to DFT calculations, has been found to be effective in disentangling the various forms of chirality. In particular, a VCD band is identified in the CH stretching region directly connected to the chirality of the metal. The analysis of the calculated VCD spectra is carried out by partitioning the complexes into fragments. The anharmonic analysis is also performed with a recently proposed reduced-dimensionality approach: such treatment is particularly important when examining spectroscopic regions highly perturbed by resonances, like the CH stretching region.

Fluorine-Containing Drugs Approved by the FDA in 2018.

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.

Chemistry of detrifluoroacetylatively in situ generated fluoro-enolates.

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.

CF3: an overlooked chromophore in VCD spectra. A review of recent applications in structural determination.

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.

Mannich-type addition of 1,3-dicarbonyl compounds to chiral tert-butanesulfinyltrifluoroacetaldimines. Mechanistic aspects and chiroptical studies.

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.

Solvent-free, uncatalyzed asymmetric "ene" reactions of N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimines: a general approach to enantiomerically pure α-(trifluoromethyl)tryptamines.

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.

Indole Based Weapons to Fight Antibiotic Resistance: A Structure-Activity Relationship Study.

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.

Long-range bonding/nonbonding interactions: a donor-acceptor resonance studied by dynamic NMR.

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.

Importance of C*-H based modes and large amplitude motion effects in vibrational circular dichroism spectra: the case of the chiral adduct of dimethyl fumarate and anthracene.

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.

Optimization of small-molecule inhibitors of influenza virus polymerase: from thiophene-3-carboxamide to polyamido scaffolds.

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.

Cationic half-sandwich quinolinophaneoxazoline-based (η6-p-cymene)ruthenium(II) complexes exhibiting different chirality types: synthesis and structural determination by complementary spectroscopic methods.

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.

Rotational barriers of biphenyls having heavy heteroatoms as ortho-substituents: experimental and theoretical determination of steric effects.

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.

Stereochemical characterization of fluorinated 2-(phenanthren-1-yl)propionic acids by enantioselective high performance liquid chromatography analysis and electronic circular dichroism detection.

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 α(1)-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.

Electrical and mechanical anharmonicities from NIR-VCD spectra of compounds exhibiting axial and planar chirality: the cases of (S)-2,3-pentadiene and methyl-d(3) (R)- and (S)-[2.2]paracyclophane-4-carboxylate.

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.

The biphenyl-monitored effective size of unsaturated functional or fluorinated ortho substituents.

The size of a series of typical substituents has been probed by dynamic NMR measurements of the barriers to aryl-aryl rotation of the corresponding biphenyls. The resulting B values are meaningful because only mono-ortho substituted compounds were investigated and thus the results are not compromised by the non-additivity of multiple steric effects. On the basis of the chosen model system ethynyl and cyano groups were found to be slightly smaller than a phenyl ring. In contrast, vinyl and, in particular, formyl groups proved to be larger than phenyl. The latter difference is due to the loss of conjugation forces at the planar transition state. Alpha-Hydroxyhexafluoroisopropyl is slightly more bulky than tert-butyl. Pentafluorophenyl and trifluoromethoxy exhibit nearly the same effective size as phenyl and methoxy, respectively. Trifluoromethyl is somewhat smaller than isopropyl.

The torsional barriers of 2-hydroxy- and 2-fluorobiphenyl: small but measurable.

By making use of a novel diastereotopicity probe, namely C(CF(3))(2)OH, it has been possible to measure by very low temperature (19)F NMR spectroscopy the elusive aryl-aryl rotation barriers of biphenyls bearing an OH or F group in one ortho position. The experimental values (5.4 and 4.4 kcal mol(-1), respectively) are matched by those from ab initio calculations (5.3 and 4.3 kcal mol(-1), respectively).

Study of the photobehavior of a newly synthesized chiroptical molecule: (E)-(R(p),R(p))-1,2-bis{4-methyl-[2]paracyclo[2](5,8)quinolinophan-2-yl}ethene.

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.

Electronic and vibrational circular dichroism spectra of chiral 4-X-[2.2]paracyclophanes with X containing fluorine atoms.

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.

B values as a sensitive measure of steric effects.

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.