•Chiroptical Spectra performed on Thia-bridged Triarylamino Heterohelicenes (TBTA-HELI).•TBTA-HELI are configurationally more stable than plain helicenes of the same size.•TBTA-HELI exhibit larger CPL than plain helicenes.•Excited states of TBTA-HELI are dissymmetric, while ground states are symmetric.

Oxadiazolo[3,4-c][1,4]thiazin-3-ones are cardiovascular agents that block L-type calcium channels. Previous data of cardiac and vasorelaxant activity on guinea-pig for several derivatives indicated the two positions ortho to the thiazine's sulphur as crucial for modulating the activity; but these positions are likely susceptible to metabolic biotransformations, as indicated by in silico predictions. We designed new derivatives, and obtained three negative inotropic agents with EC50 in the low nanomolar range, more potent than all the precursors published so far. In particular, benzocondensation at the thiazine ring led to 3a (EC50 = 0.013 μM) and 3b (EC50 = 0.006 μM). Besides negative inotropy, we also observed relaxant activity on nonvascular muscle in the micromolar range. We resolved the new derivatives by chiral chromatography, and determined their absolute configuration by comparing experimental and calculated chiroptical properties (VCD, ECD and ORD): they hold the same absolute configuration-optical rotation relationship, (S)-(+)/(R)-(-). Both cardiac and nonvascular activity are majorly or mostly retained in the R-form for all the compounds, but for the nonvascular activity we observed a strong stereoselectivity for 3a, with the R-form in the nanomolar range (IC50 = 0.020 μM) and 259-fold more potent than the S-one.

The theoretical prediction of x-ray absorption spectra (XAS) has become commonplace in electronic structure theory. The ability to better model and understand L-edge spectra is of great interest in the study of transition metal complexes and a wide variety of solid state materials. However, until recently few first-principles works have modeled L-edge XAS due to the presence of strong spin–orbit coupling in the 2p orbitals, which splits the observed peaks into multiple groups of features. Therefore, a proper description of spin–orbit coupling is vital for the successful prediction of L-edge spectra. A number of new approaches that incorporate spin–orbit coupling have recently made advances in the computation of L-edge spectra. In this review, we describe recent work in computational L-edge XAS and how these methods may continue to improve in the future. Comparison of the advantages and disadvantages of the various approaches are considered, with special attention to not only the computational cost of the level of theory but also the various approaches that can be used to compute the absorption spectra with a large number of high energy excited states.

Density functional theory (DFT) calculations of sodium d line specific rotation and of vibrational circular dichroism (VCD) have been used to assign the absolute configuration of a recently prepared (1S,4R)-norcamphor-derived furyl hydroperoxide, (+)-3, introduced as a stereoselective oxidant. Both approaches give the same absolute configuration to the newly generated stereogenic carbon at position 2, i.e., (1S,2S,4R)-(+)-3, thus providing a confident assignment in a case made difficult by the large conformational flexibility and the small difference between the computed optical rotations of the two possible diastereoisomers. Although the computed IR absorption spectra of (1S,2S,4R)-3 and (1S,2R,4R)-3 are practically indistinguishable, a number of significant differences in the VCD spectra of these two nonmirror-image isomers can be observed, which allows the structural identification of the synthesized compound. This is clearly shown here for the first time.

We studied the stereoselective behavior of 1-[(4-chlorophenyl)sulfonyl]-2-(2-thienyl)pyrrolidine, a recently described blocker of cardiovascular L-type calcium channels that binds to the diltiazem site. Given the stereocenter at C-2 of the pyrrolidine ring, the two enantiomers were separated by chiral HPLC and, using VCD in conjunction with DFT calculations of chiroptical properties, the absolute configuration was assigned as R-(+)/S-(-). For both forms, functional, electrophysiological, and binding properties were studied and the three-dimensional superimpositions of the two enantiomers over diltiazem were obtained in silico. The significant differences observed for the two enantiomers well agreed with the experimental data, and molecular regions were hypothesized as responsible for the cardiac stereoselectivity and vascular stereospecificity.

Phosphoryl-transfer reactions have long been of interest due to their importance in maintaining numerous cellular functions. A phosphoryl-transfer reaction results in two possible stereochemical outcomes: either retention or inversion of configuration at the transferred phosphorus atom. When the product is phosphate, isotopically-labeled [O-16, O-17, O-18]-phosphate derivatives can be used to distinguish these outcomes; one oxygen must be replaced by sulfur or esterified to achieve isotopic chirality. Conventionally, stereochemical analysis of isotopically chiral phosphate has been based on P-31 NMR spectroscopy and involves complex chemical or enzymatic transformations. An attractive alternative would be direct determination of the enantiomeric excess using chiroptical spectroscopy. (S)-Methyl-[O-16, O-17, O-18]-phosphate (MePi(+)), 7 and enantiomeric [O-16, O-17, O-18]-thiophosphate (TPi(+)), 10, were previously reported to exhibit weak electronic circular dichroism (ECD), although with 10 the result was considered to be uncertain. We have now re-examined the possibility that excesses of 7 and 10 enantiomers can be detected by ECD spectrometry, using both experimental and theoretical approaches. 7 and both the (R) and (S) enantiomers of 10 (10a, 10b) were synthesized by the 'Oxford route' and characterized by H-1, P-31 and O-17 NMR, and by MS analysis. Weak ECD could be found for 7, with suboptimal S/N. No significant ECD could be detected for the 10 enantiomers.Time-dependent DFT (TDDFT) calculations of the electronic excitation energies and rotational strengths of the same three enantiomers were carried out using the functional B3LYP and the basis set 6-311G(++). The isotopically-perturbed geometries were predicted using the anharmonic vibrational frequency calculational code in GAUSSIAN 03. In the case of 10, calculations were also carried out for the hexahydrated complex to investigate the influence of the aqueous solvent. The predicted excitation wavelengths are greater than the observed wavelengths, a not unusual result of TDDFT calculations. The predicted anisotropy ratios are 2.9 x 10(-5) for 7, -5.3 x 10(-6) for 10a/b, and 1.7 x 10(-6) for 10a/b center dot(H2O)(6). For 7 the predicted anisotropy ratio approximates that observed in this work, 4.5 x 10(-5) at 208 nm. For 10a/b, the upper limits of the experimental anisotropy ratios (<5 x 10(-6) at 225 nm, pH 9; <5 x 10(-6) at 236 nm, pH 12) are comparable to the predicted magnitude of the value for 10a/b. The lower predicted value for 10a/b center dot(H2O)(6) suggests that the aqueous environment affects the ECD significantly. Altogether, the TDDFT calculations together with a stereochemical analysis based on NMR and the MS data support the conclusion that the experimental ECD results for MePi(+) and TPi(+) may be reliable in order of magnitude. (C) 2010 Published by Elsevier Inc.

The absolute configuration (AC) of the antiprotozoal lactone, Klaivanolide, 1, from Uvaria klaineana, has been determined using Vibrational Circular Dichroism (VCD) spectroscopy. The experimental VCD spectrum of the (+) enantiomer of 1 was measured. To analyze the AC of (+)-1, the conformationally-averaged VCD spectrum of 7-S-1 was calculated using density functional theory (DFT) and the GAUSSIAN 03 program. The B3PW91/TZ2P conformationally-averaged VCD spectrum of 7-S-1 proves that the AC of 1 is 7-S-(+).

Comparison of theoretical and experimental vibrational circular dichroism (VCD) spectra of an enantiopure synthetic sample of the obscure mealybug sex pheromone allowed the determination of the absolute configuration of the insect's pheromone.

The (+) and (−) enantiomers of the isotopically chiral sulfoxide, perdeuteriophenyl-phenyl-sulfoxide, 1, have been synthesized by the reaction of the diastereomers of O-menthyl benzenesulfinate with C6D5MgBr. Their absolute configurations have been determined by comparison of the vibrational circular dichroism (VCD) spectra of (R)-1 and (S)-1, predicted using ab initio DFT, to the experimental VCD spectrum of 1. The absolute configuration of 1 is shown to be (S)(+)/(R)(−). This is the first application of VCD to the determination of the absolute configuration of an isotopically chiral sulfoxide.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The vibrational circular dichroism (VCD) spectra of the two enantiomers of a chiral molecule are of equal magnitude and opposite sign: i.e. mirror-image enantiomers give mirror-image VCD spectra. In principle, the absolute configuration (AC) of a chiral molecule can therefore be determined from its VCD spectrum. In practice, the determination of the AC of a chiral molecule from its experimental VCD spectrum requires a methodology which reliably predicts the VCD spectra of its enantiomers. The only reliable methodology developed to date uses the Stephens quantum-mechanical theory of the rotational strengths of fundamental vibrational transitions, developed in the early 1980s, implemented using ab initio density functional theory in the GAUSSIAN program in the mid 1990s. This methodology has by now been widely used in determining ACs from experimental VCD spectra. In this article we discuss the protocol for determining the ACs of chiral molecules with optimum reliability and its implementation for a variety of molecules, including the D3 symmetry perhydrotriphenylene, a thiazino-oxadiazolone recently shown to be a highly active calcium entry channel blocker, the alkaloid natural products schizozygine, iso-schizogaline, and iso-schizogamine, and the iridoid natural products plumericin, iso-plumericin, and prismatomerin. The power of VCD spectroscopy in determining ACs, even for large organic molecules and for substantially conformationally-flexible organic molecules is clearly documented.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The vibrational circular dichroism (VCD) spectra of the two enantiomers of a chiral molecule are of equal magnitude and opposite sign: i.e., mirror-image enantiomers give mirror-image VCD spectra. In principle, the absolute configuration (AC) of a chiral molecule can therefore be determined from its VCD spectrum. In practice, the determination of the AC of a chiral molecule from its experimental VCD spectrum requires a methodology that reliably predicts the VCD spectra of its enantiomers. The only reliable methodology developed to date uses the Stephens quantum-mechanical theory of the rotational strengths of fundamental transitions, developed in the early 1980s, implemented using ab initio density functional theory in the GAUSSIAN program in the mid-1990s. This methodology has by now been widely used in determining ACs from experimental VCD spectra. This article discusses the protocol for determining the ACs of chiral molecules with optimum reliability and its implementation for a variety of molecules, including the D3 symmetry perhydrotriphenylene; a thiazino-oxadiazolone recently shown to be a highly active calcium channel blocker; the alkaloid natural products schizozygine, isoschizogaline, and isoschizogamine; and the iridoid natural products plumericin, isoplumericin, and prismatomerin. The power of VCD spectroscopy in determining ACs, even for large organic molecules and for confomationally flexible organic molecules, is clearly documented.