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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.

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.

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.

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.

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.

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.

(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.

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.

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.

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.

The addition reactions of 1,3-dicarbonylalkyl radicals to ring-substituted styrenes have been kinetically investigated in MeOH and/or MeCN. It ha^ been observed that the rate effect of ring substituenta ie nearly identical in the reactions of MeCOCHCOMe (11, MeOCOCHCOMe (2) and MeOCOCHCOOMe (4, the p value, in MeOH being 4.96, -1.01 and -1.06, respectively. Since the three radicals are relatively strong oxidants and have similar reduction potentials, an important contribution of the charge transfer structure RCOCHCORCH&HAf+ to the addition transition state is suggested. It has also be found that in the reactions of 1 and 4 with a-alkyl-substituted styrenes the rate of addition is strongly influenced by the nature of the alkyl group, decreasing in the order: Me > Et > 'Pr > tBu. The observed effecta are much larger than those reported for the corresponding reactions of the nucleophilic cyclohexyl radical. It is suggested that the a-alkyl substituents exert an effect of steric inhibition of resonance thereby ring delocalization of the charge and/or unpaired electron in the transition state is significantly reduced. Delocalization may be more important in the reactions of 1 and 4 than in those of the cyclohexyl radical since it is possible that the former utilizes a transition state occurring later along the reaction coordinate and/or characterized by a larger extent of charge transfer.

The relative rates for the addition reactions of the malonyl radical to substituted styrenes induced by cerium(IV) ammonium nitrate (CAN) and tributyltin hydride have been determined. The two processes exhibit practically identical ρ + values (−1.05 and 1.06), thus suggesting that the coordination between the metal and the radical does not play a significant role in the CAN-promoted oxidative additions

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.

Les reactions du titre sont realisees sous diverses conditions: a) reaction avec le nitrate d'ammonium cerique (CAN) dans l'acide acetique et l'acetonitrile aqueux ; b) oxydation electrochimique dans l'acetone aqueuse et dans AcOH−CH 3 CN ; c) autooxydation photochimique en presence d'anthracenedicarbonitrile-9,10 ou CAN dans CH 3 CN ; d) oxydation photochimique par CAN dans CH 3 CN

Etude cinetique et etude des produits de l'elimination a partir des meso-dichloro-1,2 diphenyl-1,2 ethane, erythro-chloro-1 fluoro-2 diphenyl-1,2 ethane et meso-difluoro-1,2 diphenyl-1,2 ethane par t-BuOK dans t-BuOH en presence et en l'absence de 18-crown-6.