Control of the helical chirality of enantiopure sulfinyl (Z)-azobenzene-based photoswitches.

A new class of enantiopure ortho,ortho-disubstituted azobenzene photoswitches has been synthesized from (S)-2-(p-tolylsulfinyl)benzoquinone and arylhydrazines. The sulfoxide acts as a unidirectional controller of the helical chirality that arises in the Z isomer after photoisomerization. Highly congested E-azobenzenes 5 c showed two atropisomeric diastereoconformers in the solid state that converged upon irradiation into a unique Z isomer with defined helicity (M), as evident in the X-ray structure.

Central-to-axial chirality transfer revealed by liquid crystals: a combined experimental and computational approach for the determination of absolute configuration of carboxylic acids with an α chirality centre.

The conversion into 6,7-dihydro-5H-dibenz[c,e]azepine (DAZ) N-protected amides is a viable route for the determination of the absolute configuration of chiral 2-substituted carboxylic acids. The biphenyl moiety of DAZ, besides being a probe of chirality for the electronic circular dichroism (ECD) spectroscopy, makes these systems suitable for configuration assignment by exploiting the chirality amplification which occurs in nematic liquid crystals. To assess the reliability of the liquid crystal method in detecting the absolute stereochemistry of chiral amides bound to a biphenyl group, we measured the helical twisting power of a series of DAZ-N-protected amides and compared these data with the results obtained from ECD measurements.

Absolute configuration assignment of inherently chiral calix[4]arenes using DFT calculations of chiroptical properties.

The racemate of an inherently chiral meta-substituted calix[4]arene derivative 3 has been resolved via enantioselective HPLC. Measured optical rotation dispersion and electronic circular dichroism have been compared with DFT theoretical predictions. The comparison indicates that the absolute configuration of the dextrorotatory enantiomer (+)-3 is cS.

Absolute configuration through the DFT simulation of the optical rotation. importance of the correct selection of the input geometry: a caveat.

In ab initio calculation of ORs of flexible molecules, the input geometries and conformer populations obtained at different levels of theory can yield opposite OR values. Therefore, when at the commonly used DFT/B3LYP/6-31G* level several conformers result, even showing the same sign of OR, additional geometry optimization at a higher level of theory will be absolutely required.

A vibrational circular dichroism approach to the determination of the absolute configuration of flexible and transparent molecules: fluorenone ketals of 1,n-diols.

The infrared absorption (IR) and vibrational circular dichroism (VCD) spectra for five ketal molecules, three of which obtained from 1,2-diols and two from 1,3-diols, were recorded in the mid-IR region. The spectra have been satisfactorily reproduced by DFT calculations, even with not too large wavefunction basis sets, especially due to the low number of conformers to be considered. The mobility of some moieties provides a recognizable signature.

Assignment of the absolute configuration at the sulfur atom of thioridazine metabolites by the analysis of their chiroptical properties: the case of thioridazine 2-sulfoxide.

Thioridazine (THD) is a commonly prescribed phenotiazine neuroleptic drug, which is extensively biotransformed in the organism producing as main metabolites sulfoxides and a sulfone by sulfur oxidation. Significant differences have been observed in the activity of the THD enantiomers as well as for its main metabolites, and enantioselectivity phenomena have been proved in the metabolic pathway. Here the assignment of the absolute configuration at the sulfur atom of enantiomeric THD-2-sulfoxide (THD-2-SO) has been carried out by circular dichroism (CD) spectroscopy.

Synthesis, chiroptical properties, and their theoretical simulation of some highly rotating benzotricamphor derivatives.

The large molecules 1-3 (69, 90, and 102 atoms, respectively), prepared by cyclotrimerization of enantiomerically pure derivatives of (-)-bornyl acetate, show intense ECD spectra, high optical rotation (OR) values (200-1300, in absolute value) dominated in sign and order of magnitude by the lowest-energy Cotton effects, that is, they are the ideal candidates to test the reliability of our "approximate" (TDDFT/B3LYP/6-31G* or smaller basis set) approach to the calculation of chiroptical properties. As a matter of fact, a correct simulation of the OR values and ECD spectra of 1 and 2 can be obtained even using STO-3G basis set and semiempirical or molecular mechanics input geometries: for 1, at the TDDFT/B3LYP/STO-3G level, the OR values are of the order of 500-550, versus an experimental value ranging between 660 and 690, depending on the solvent. On the contrary, the case of 3 (exp.

A new efficient enantioselective synthesis of (+)-cis-2-methyl-4-propyl-1,3-oxathiane, a valuable ingredient for the aroma of passion fruit.

A new simple route to (+)-cis-2-methyl-4-propyl-1,3-oxathiane, the main component responsible of the passion fruit aroma is shown. Such a procedure consists in the sequence of the asymmetric conjugated addition of a thiol to trans-2-hexenal/cleavage of sulfide moiety, which allows to prepare, in only two steps, its immediate precursor, (R)-3-mercaptohexan-1-ol. Various procedures have been investigated for both the steps, using benzyl and tert-butyl mercaptan as thiols.

A new case of induced helical chirality in a bichromophoric system: absolute configuration of transparent and flexible diols from the analysis of the electronic circular dichroism spectra of the corresponding di(1-naphthyl)ketals.

Di(1-naphthyl)ketals of 1, n-diols show couplet effects allied to the (1)B naphthalene transition in their CD spectra. This means that they assume a conformation with a prevailing sense of twist of the naphthalene rings, imposed by the absolute configuration (AC) of the starting diols and by the nature of the R 1 groups. A positive couplet for aliphatic diols is a probe of ( R, R), AC while the opposite sign is found for ( R, R) aromatic diols.

A chemical/computational approach to the determination of absolute configuration of flexible and transparent molecules: aliphatic diols as a case study.

By reacting flexible and optically transparent in UV-vis molecules such as 1,2-, syn- and anti-1,3-diols, 1,3-sulfanylalcohols of known absolute configuration (AC) with fluorenone dimethyl acetal, the corresponding ketals are obtained. They are conformationally well-defined (only one conformer in most cases) compounds exhibiting medium-high optical rotation (OR) values, which are independent of the solvent, and electronic circular dichroism (ECD) spectra, which show several (up to five) Cotton effects in the 350-200 nm range due to valence shell pi-->pi* transitions. These features allow simulation of the chiroptical properties of these compounds at the TDDFT/B3LYP/6-31G* level of theory to obtain, using the known ACs of these compounds, a satisfactory reproduction of the OR values (sign and order of magnitude; quantitatively, the predicted values are twice the experimental ones), and a more than satisfactory reproduction of the ECD spectra (sign, intensity, and position of the lowest-energy four Cotton effects) for all the compounds studied.

Enantioselective oxidation of sulfides catalyzed by titanium complexes of 1,2-diarylethane-1,2-diols: effect of the aryl substitution.

The effects of the substitution on the aryl moiety on the asymmetric oxidation of sulfides mediated by Ti-complexes of chiral 1,2-diarylethane-1,2-diols were investigated. The substitution of the aryl ring of the diol with both EWG and EDG substituents generally decreased the enantioselectivity with respect to the use of unsubstituted 1,2-diphenylethane-1,2-diol (1a). Only in the presence of 1,2-di(4-t-butyl)phenyl-1,2-diol (1g) were higher ee's obtained with aryl methyl and aryl benzyl sulfides affording ee's up to 90 and 99%, respectively.

Structure, conformation, stereodynamics, dimer formation, and absolute configuration of axially chiral atropisomers of hindered biphenyl carbinols.

NMR spectra of biphenyl derivatives bearing a single CR2OH substituent in the ortho position indicate that they exist as sp (more stable) and ap (less stable) conformers, due to the restricted rotation about the Ar-CR2OH bond. When R = Et (compound 2) the corresponding rotation barrier was determined (7.5 kcal mol-1) by line shape simulation of the low-temperature NMR spectra.

Absolute configuration of natural cyclohexene oxides by time dependent density functional theory calculation of the optical rotation: the absolute configuration of (-)-sphaeropsidone and (-)-episphaeropsidone revised.

The optical rotatory power of some natural cyclohexene oxides, such as (+)-chaloxone, 1, (+)-epiepoformine, 2, (+)-epoformine, 3, (+)-epoxidone, 5, (-)-sphaeropsidone, 6, (-)-episphaeropsidone, 7, and the synthetic compound (+)-epitheobroxide, 4, has been calculated by means of the TDDFT/B3LYP method using the 6-31G(d) and aug-cc-pVDZ basis sets, both in the gas phase and in solution by means of the polarizable continuum model. For compounds 1 and 2, which possess high (about 300 units) optical rotations, gas-phase calculations with the smaller basis set are able to reproduce the experimental values both in sign and order of magnitude. By contrast, a larger basis set is required to satisfactorily simulate the OR values of 3 and 4, which show smaller (about 100 units or less) rotations.

Origin of enantioselectivity in palladium-catalyzed asymmetric allylic alkylation reactions using chiral N,N-ligands with different rigidity and flexibility.

The chiral bidentate-N,N ligands, (S(a))-1, (S(a))-2, (S,S)-3 and (S,S)-4, were synthesized. They were shown to contain rigid 2-pyridinyl or 8-quinolinyl building blocks and the C(2)-symmetric chiral frameworks trans-2,5-dimethylpyrrolidinyl or (S)-(+)-2,2'-(2-azapropane-1,3-diyl)-1,1'-binaphthalene. In the (S(a))-2, and (S,S)-4 ligands pair, the 8-quinolinyl skeleton is directly bonded to the C(2)-symmetric chiral frameworks (S)-(+)-2,2'-(2-azapropane-1,3-diyl)-1,1'-binaphthalene or trans-2,5-dimethylpyrrolidinyl.

Determination of the absolute configurations of flexible molecules: synthesis and theoretical simulation of electronic circular dichroism/optical rotation of some pyrrolo[2,3-b]indoline alkaloids--a case study.

The paper describes the synthesis and chiroptical properties of (-)-1,2,3,3a,8,8a,-hexahydro-1,3a-dimethyl-pyrrolo[2,3-b]indole, (-)-1, one of the monomeric units of many flexible polypyrroloindoline alkaloids and (-)-chimonanthine, (-)-2. The aim of this investigation is to show that, under certain circumstances, namely, with molecules for which the sign and order of magnitude of [alpha](D) are determined by the lowest-energy valence-shell transitions (referred to as class (a) molecules), a small basis set calculation of chiroptical properties provides reliable results, and that such a treatment can be employed for absolute configurational assignment of larger oligomers, for which the increased flexibility renders the analysis as formidable task. Actually, as the aforementioned two molecules belong to class (a) systems, a TDDFT/B3LYP/6-31G* calculation of the ECD and ORD spectra gives rise to a more than satisfactory simulation of these data, assuming the reported absolute configurations.

Flexible biphenyl chromophore as a circular dichroism probe for assignment of the absolute configuration of carboxylic acids.

A general and nonempirical approach to determine the absolute configuration (AC) of 2-substituted chiral carboxylic acids by circular dichroism (CD) spectroscopy has been developed. In this protocol, the chiral acids are converted to the corresponding biphenyl amides, in which a flexible biphenyl probe gives rise to a Cotton effect at 250 nm (A band) in the CD spectrum, the sign of which is related to the acid AC. Two different mechanisms of transfer of chirality from the acid stereogenic center to the biphenyl moiety are operative in amides derived from 2-alkyl- and 2-aryl-substituted acids, respectively.

Fenchone, camphor, 2-methylenefenchone and 2-methylenecamphor: a vibrational circular dichroism study.

We report and discuss the infrared (IR) vibrational circular dichroism (VCD) spectra of the enantiomeric pairs of the olefin derivatives of fenchone (1,3,3-trimethyl-2-methylenebicyclo[2.2.1]heptane) and camphor (1,7,7-trimethyl-2-methylenebicyclo[2.

Enantioselective nonsteroidal aromatase inhibitors identified through a multidisciplinary medicinal chemistry approach.

To identify enantioselective nonsteroidal aromatase inhibitors, a multidisciplinary medicinal chemistry approach was pursued. First, our earlier CoMFA model [Bioorg. Med.

Determination of the absolute configuration of flexible molecules by ab initio ORD calculations: a case study with cytoxazones and isocytoxazones.

Ab initio calculations of the optical rotatory power of the natural cytokine modulator cytoxazone 1 and its trans-diastereomer 2, as well as the structural isomers cis-3 and trans-4 isocytoxazones, have been performed at four different wavelengths (589, 546, 435, and 405 nm) by Density Functional Theory. The calculation of ORD curves provides a reliable method for the assignment of absolute configuration of these conformationally flexible molecules. The absolute configurations of isocytoxazones has been established as (+)-(4R,5S)-cis-3 and (+)-(4S,5S)-trans-4.

Theoretical simulation of the electronic circular dichroism spectrum of calicheamicin.

The aglycon, or so-called 'warhead' portion, of several potent 10-membered ring enediyne antitumor antibiotics contain dienonecarbamate and enediyne chromophores in an unusual bicyclic ring structure in which these two subunits are essentially orthogonal to each other. The circular dichroism (CD) spectra of the calicheamicin, esperamicin, and shisijimicin A families, all of which contain this bicyclic ring system, exhibit a characteristic negative exciton coupled CD at about 310 and 270 nm. This signature CD feature suggested the absolute stereochemical relationship between these chromophores as originally assigned and which was later confirmed by stereospecific total synthesis.

Non-empirical assignment of the absolute configuration of (-)-naringenin, by coupling the exciton analysis of the circular dichroism spectrum and the ab initio calculation of the optical rotatory power.

The non-empirical assignment of the absolute configuration of (-)-naringenin, the aglycone of (-)-naringin, a flavanone glycoside abundant in the albedo of immature grapefruits and showing several interesting biological properties, has been approached by two different methods: (a) the exciton analysis of the circular dichroism (CD) spectrum and (b) the ab initio calculation of the optical rotatory power. Both the methods indicate the configurational correlation (-)/(S), as empirically suggested by Gaffield. A comparison of advantages and limitations of the two methods of analysis is also presented.

Ab initio calculation of optical rotatory dispersion (ORD) curves: a simple and reliable approach to the assignment of the molecular absolute configuration.

In this paper, both Hartree-Fock (HF) and density functional theory (DFT) methods have been used to make ab initio calculations of the optical rotatory power of selected molecules at several wavelengths; that is, part of the optical rotatory dispersion (ORD) curve has been predicted. This approach constitutes a new, simple, and reliable method to assign the molecular absolute configuration, at least for rigid molecules such as those studied in the present work. In fact, in this way, it is possible to overcome the difficulties connected to some relevant cases, in particular that of (-)-beta-pinene, for which even a very high-level (DFT/B3LYP/6-311++G(2d,2p)) calculation affords the wrong sign of the optical rotation at 633 nm.

Structural determinations by circular dichroism spectra analysis using coupled oscillator methods: an update of the applications of the DeVoe polarizability model.

The exciton (coupled oscillator) model for optical activity is a very useful and powerful method which allows to analyze a circular dichroism (CD) spectrum in a nonempirical way, arriving at a safe assignment of the absolute configuration of organic and inorganic compounds. Usually in this model only the exciton coupling of two electrically allowed transitions (oscillators) is taken into account. This approach has the important advantage of an easy application but, sometimes, it may lead to wrong results.

A general and nonempirical approach to the determination of the absolute configuration of 1-aryl-1,2-diols.

We describe herein a simple, general, and reliable nonempirical approach, based on the exciton coupling method, to assign the absolute configuration of the benzylic stereogenic center of 1-aryl-1,2-diols. According to this method, it is only necessary to prepare the 4-biphenylboronic esters of the diols and to record their CD spectra in the 230-300 nm range, i.e.