Determination of absolute configuration using vibrational circular dichroism spectroscopy: the chiral sulfoxide 1-thiochroman S-oxide

We have determined the absolute configuration of the chiral sulfoxide 1-thiochroman S-oxide 1 using vibrational circular dichroism (VCD) spectroscopy. The VCD spectrum of a CCl₄ solution of 1 was analyzed using density functional theory (DFT), which predicts three stable conformations of 1, separated by <1 kcal/mol. The VCD spectrum predicted using the DFT/GIAO methodology for the equilibrium mixture of the three conformations of (S)-1 is in excellent agreement with the experimental spectrum of (+)-1. The absolute configuration of 1 is therefore (R)-(−)/(S)-(+). (+)-1 and (−)-1 of high enantiomeric excess (e.e.) were synthesized in high yields via asymmetric oxidation of 1-thiochroman 2 using Ti(iso-PrO)₄/(R,R)-1,2-diphenylethane-1,2-diol/H₂O/tert-butyl hydroperoxide and Ti(iso-PrO)₄/l-diethyl tartrate/H₂O/cumene hydroperoxide, respectively.     

Determination of molecular stereochemistry using vibrational circular dichroism spectroscopy: absolute configuration and solution conformation of 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic acid lactone

The determination of the absolute configuration of chiral molecules is an important aspect of molecular stereochemistry. Vibrational circular dichroism (VCD) is the extension of electronic CD into the infrared region where fundamental vibrational transitions occur. VCD has a number of advantages over all previous methods of absolute configuration assignment. The absolute configuration and predominant solution-state conformation in CDCl(3) of the chiral lactone, 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic acid lactone, 1, obtained by the comparison of measured and calculated VCD spectra, are reported. It is found that (-)-1 corresponds to the absolute configuration (1S,3S,5R)-1.     

Direct observation of odd-even effect for chiral alkyl alcohols in solution using vibrational circular dichroism spectroscopy

The odd-even effect of chiral alkyl alcohols, (S)-CH(3)CHOHC(n)()H(2)(n)()(+1) (n = 2-8), in solution state has been observed spectroscopically for the first time. The vibrational circular dichroism (VCD) bands at 1148 cm(-)(1) exhibit a clear odd-even effect. The observed VCD bands of (R)-(-)-2-hexanol correspond well to those predicted (population weighted). Density functional theory calculations indicate that the most prevalent conformations in solution are the all-trans forms. The odd-even effect of the VCD bands is ascribed to the alternating terminal methyl motions in the alkyl chains relative to fixed motions near the chiral center in the trans conformations. The conformational sensitivity of VCD for the chiral alcohols in the solution state may be useful for the design of liquid crystals and ligands in the future.     

Determination of absolute configuration using vibrational circular dichroism spectroscopy: phenyl glycidic acid derivatives obtained via asymmetric epoxidation using oxone and a keto bile acid

The (+)-enantiomers of the o-Br, m-F and p-CH₃ derivatives of trans phenyl glycidic acid have been obtained from the corresponding trans cinnamic acid derivatives using Oxone and the tri-keto bile acid dehydrocholic acid. Vibrational circular dichroism (VCD) spectroscopy of their methyl esters has been used to determine their absolute configurations. In each case, the absolute configurations of both methyl ester and parent acid were shown to be (2S,3R)-(+)/(2R,3S)-(−).     

Intermolecular association of tetrahydrofuran-2-carboxylic acid in solution: a vibrational circular dichroism study

Carboxylic acids are known for their strong intermolecular associations. With chiral carboxylic acids, this behavior can be studied using vibrational circular dichroism (VCD). Tetrahydrofuran-2-carboxylic acid 1, a chiral building block for beta-lactam antibiotics, is studied by emphasizing the effect of the dimerization. Experimental results indicate that for solutions of 1 in CDCl3 and CS2, a complex equilibrium exists between the monomers and dimers. B3LYP/aug-cc-pVTZ calculations are performed on both monomer and dimer structures. To simulate IR and VCD spectra, populations for monomer and dimers were approximated using a semiquantitative model. A good agreement between experimental and simulated spectra is obtained by taking into account both the monomeric and the dimeric structures, weighted using the experimentally determined populations.     

Conformational manifold of alpha-aminoisobutyric acid (Aib) containing alanine-based tripeptides in aqueous solution explored by vibrational spectroscopy, electronic circular dichroism spectroscopy, and molecular dynamics simulations

Replacement of the alpha-proton of an alanine residue to generate alpha-aminoisobutyric acid (Aib) in alanine-based oligopeptides favors the formation of a 3(10) helix when the length of the oligopeptide is about four to six residues. This research was aimed at experimentally identifying the structural impact of an individual Aib residue in an alanine context of short peptides in water and Aib's influence on the conformation of nearest-neighbor residues. The amide I band profile of the IR, isotropic and anisotropic Raman, and vibrational circular dichroism (VCD) spectra of Ac-Ala-Ala-Aib-OMe, Ac-Ala-Aib-Ala-OMe, and Ac-Aib-Ala-Ala-OMe were measured and analyzed in terms of different structural models by utilizing an algorithm that exploits the excitonic coupling between amide I' modes. The conformational search was guided by the respective 1H NMR and electronic circular dichroism spectra of the respective peptides, which were also recorded. From these analyses, all peptides adopted multiple conformations. Aib predominantly sampled the right-handed and left-handed 3(10)-helix region and to a minor extent the bridge region between the polyproline (PPII) and the helical regions of the Ramachandran plot. Generally, alanine showed the anticipated PPII propensity, but its conformational equilibrium was shifted towards helical conformations in Ac-Aib-Ala-Ala-OMe, indicating that Aib can induce helical conformations of neighboring residues positioned towards the C-terminal direction of the peptide. An energy landscape exploration by molecular dynamics simulations corroborated the results of the spectroscopic studies. They also revealed the dynamics and pathways of potential conformational transitions of the corresponding Aib residues.     

Lactic acid in solution: investigations of lactic acid self-aggregation and hydrogen bonding interactions with water and methanol using vibrational absorption and vibrational circular dichroism spectroscopies

The infrared vibrational absorption (VA) and vibrational circular dichroism (VCD) spectral features of L-(+)-lactic acid (LA) in CDCl3 solution are concentration dependent, showing evidence of oligomerization with increasing concentrations. To understand the observed spectra, geometry optimizations, vibrational frequencies, and VA and VCD intensities were evaluated for (LA)n with n=1-4 using density functional theory calculations at the B3LYP6-311++G(d,p), B3LYP/cc-pVTZ, and in some cases, B3LYP/aug-cc-pVTZ levels of theory. Comparisons with the experimental spectra indicate that the lowest energy LA dimer (AA), formed by two C Double Bond O...HO hydrogen bonds, is one of the dominating species in solution at room temperature. Possible contributions from the LA trimer and tetramer are also discussed. To model the VA and VCD spectra of LA in water and in methanol, both implicit polarizable continuum model and explicit hydrogen bonding considerations were used. For explicit hydrogen bonding, geometry optimizations of the AA-(water)n and AA-(methanol)n complexes, with n=2,4,6, were performed, and the corresponding VA and VCD spectra were simulated. Comparisons of the calculated and experimental VA and VCD spectra in the range of 1000-1800 cm(-1) show that AA-(water)n with n=6 best reproduces the experimental spectra in water. On the other hand, AA-(methanol)n with n=2 reproduces well the experimental results taken in methanol solution. In addition, we found evidence of chirality transfer, i.e., some vibrational bands of the achiral water subunits gain VCD strength upon complexation with the chiral LA solute. The study is the first to use VCD spectroscopy to probe the structures of LA aggregates and hydrogen bonding solvation clusters in the solution phase.     

Determination of absolute configuration using vibrational circular dichroism spectroscopy: the chiral sulfoxide 1-(2-methylnaphthyl) methyl sulfoxide

We report the determination of the absolute configuration (AC) of the chiral sulfoxide, 1-(2-methylnaphthyl) methyl sulfoxide, 1, using vibrational circular dichroism (VCD) spectroscopy. The VCD of 1 has been measured in the mid-IR spectral region in CCl(4) solution. Analysis employs the ab initio DFT/GIAO methodology. DFT calculations predict two stable conformations of 1, E and Z, Z being lower in energy than E by <1 kcal/mol. In both conformations the S-O bond is rotated from coplanarity with the naphthyl moiety by 30-40 degrees. The predicted unpolarized absorption ("IR") spectrum of the equilibrium mixture of the two conformations permits assignment of the experimental IR spectrum in the mid-IR spectral region. The presence of both E and Z conformations is clearly evident. The VCD spectrum predicted for S-1 is in excellent agreement with the experimental spectrum of (-)-1, unambiguously defining the AC of 1 as R(+)/S(-).     

Investigation of guanosine-quartet assemblies by vibrational and electronic circular dichroism spectroscopy, a novel approach for studying supramolecular entities

The self-assembly of guanosine-5'-hydrazide G-1 in D(2)O, in the presence and absence of sodium cations, has been investigated by chiroptical techniques: electronic (ECD) and the newly introduced vibrational (VCD) circular dichroism spectroscopy. Using a combination of ECD and VCD with other methods such as IR, electron microscopy, and electrospray ionization mass spectrometry (ESI-MS) it was found that G-1 produces long-range chiral aggregates consisting of G-quartets, (G-1)(4), subsequently stacked into columns, [(G-1)(4)](n), induced by binding of metal cations between the (G-1)(4) species. This process, accompanied by gelation of the sample, is highly efficient in the presence of an excess of sodium cations, leading to aggregates with strong quartet-quartet interaction. Thermally induced conformational changes and conformational stability of guanosine-5'-hydrazide assemblies were studied by chiroptical techniques and the melting temperature of the hydrogels formed was obtained. The temperature-dependent experiments indicate that the long-range supramolecular aggregates are dissociated by increasing temperature into less ordered species, monomers, or other intermediates in equilibrium, as indicated by MS experiments.     

Investigating cyclic sotolon,maple furanone and their dimers in solution using optical rotation,electronic circular dichroism and vibrational circular dichroism

The experimental optical rotation (OR), electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra of (R)-3-hydroxy-4,5-dimethylfuran-2(5H)-one (sotolon, 1) and (R)-5-ethyl-3-hydroxy-4-methylfuran-2(5H)-one (maple furanone, 2) taken in chloroform were compared to their spectra calculated with time-dependent density functional theory (TDDFT). Sotolon was shown to exist as a dimer in chloroform while maple furanone remains a monomer. Transition state barriers for the enol/keto tautomerization of sotolon were calculated and found to be high. The VCD method offers promise to ultimately distinguish between the presence of monomers or dimers.     

Fliplike motion in the thalidomide dimer: Conformational analysis of (R)-thalidomide using vibrational circular dichroism spectroscopy

The dynamic fliplike motion in the (R)-thalidomide dimer has been reported for the first time. The vibrational circular dichroism (VCD) spectrum of (R)-thalidomide in DMSO-d6 indicates the characteristic nu(CO) bands with opposite signs and reflects the structural property of the equatorial configuration of the phthalimide ring. On the other hand, the VCD spectrum of (R)-thalidomide in CDCl3 exhibits a different pattern of nu(CO) bands and suggests the fliplike motion in dimer forms. This novel insight for the dimer forms would be helpful for the understanding of the structure-activity relationship for thalidomide.     

Determination of molecular structure using vibrational circular dichroism spectroscopy: the keto-lactone product of Baeyer-Villiger oxidation of (+)-(1R,5S)-bicyclo[3.3.1]nonane-2,7-dione

[reaction: see text] The Baeyer-Villiger oxidation of (+)-(1R,5S)-bicyclo[3.3.1]nonane-2,7-dione, 1, can lead to four keto-lactone products, 2a-d. A single isomer is obtained experimentally. We have used IR and VCD spectroscopies to identify the structure of this product. DFT calculations of the IR and VCD spectra of 2a-d show unambiguously that the experimental product is (+)-(1R,6R)-2a, and not the expected product 2b. NMR studies, including comparison of DFT and experimental 1H and 13C spectra, support this conclusion. This work provides the first example of the use of VCD spectroscopy to discriminate between structural isomers of a chiral molecule. The specific rotation of (+)-(1R,6R)-2a, predicted using TDDFT methods, is negative demonstrating that absolute configurations determined from TDDFT calculations of specific rotations are not 100% reliable.     

Determination of the absolute configurations using electronic and vibrational circular dichroism measurements and quantum chemical calculations

The stereochemistry of products obtained via a chemical reaction may not always be obvious from the reaction scheme utilized. The identification of convenient methods to determine the stereochemistry in such cases is highly desirable. To identify these methods, we considered a substituted 4-vinyl-1-azabicyclo[3.2.0]hept-3-en-7-one that undergoes spontaneous oxidation in the atmosphere at room temperature, yielding an epoxide with unknown absolute configuration. To determine the absolute configuration of the resulting epoxide, three different approaches have been utilized: (a) experimental NOE measurements; (b) experimental electronic circular dichroism (ECD) spectroscopic measurements and their analysis using corresponding quantum chemical predictions at the B3LYP/aug-cc-pVDZ level; (c) experimental vibrational circular dichroism (VCD) spectroscopic measurements and their analysis using corresponding quantum chemical predictions at the B3LYP/aug-cc-pVDZ level. It was found that the NOE data could not provide enough proof for assigning the absolute configuration, while ECD data could not provide enough discrimination to distinguish between the two possible stereoisomers. On the other hand, VCD spectroscopic analysis provided enough discrimination to distinguish between the two possible stereoisomers, and the absolute configuration could be assigned with confidence.     

Molecular structure of guanine-quartet supramolecular assemblies in a gel-state based on a DFT calculation of infrared and vibrational circular dichroism spectra

The infrared (IR) and vibrational circular dichroism (VCD) spectra of guanosine-5'-hydrazide ( G-1), a powerful hydrogelator, have been measured and analyzed on the basis of ab initio modeling. B3LYP/6-31G** DFT calculations predict that G-1, forming a clear solution in deuterated DMSO, is present in monomeric form in this solvent, whereas strong gelation in a phosphate buffer is due to the formation of a guanine-quartet structure, ( G-1)4, in which the four G-1 are linked by hydrogen-bonded guanine moieties and stabilized by an alkali metal cation. The B3LYP/6-31G** IR and VCD spectra of the nearly planar G-quartet, whose structure is slightly distorted from the C4h symmetry, in which the G-bases interact via four Hoogsteen-type hydrogen bonds and a sodium cation is positioned in the middle of the G-quartet, are in very good agreement with the experimental spectra, indicating that this structure is the predominant structure in the gel state. The geometric parameters are discussed. This study is the first to use IR and VCD spectroscopies coupled with DFT calculations to elucidate the structure of a supramolecular species in a gel state and shows the VCD spectroscopy as a powerful method for investigating the structure of complex supramolecular self-assemblies where the use of other structural methods is limited.     

Determination of the absolute configuration of three as-hydrindacene compounds by vibrational circular dichroism

[Structure: see text]. The absolute configurations of three compounds with a rigid 1,8-disubstituted as-hydrindacene skeleton have been determined using vibrational circular dichroism spectroscopy and quantum chemical calculations. Experimental spectra were compared to B3LYP/6-31G and B3LYP/cc-pVTZ level predicted spectra. Based on the agreement between the predicted and experimental spectra, the stereochemistry could be assigned with high confidence. The results were found to be in agreement with ECD determinations and/or predictions based on the applied asymmetric methods in the synthetic route.     

Sol-gel phase transition of brucine-appended porphyrin gelator: a study by vibrational circular dichroism spectroscopy

A novel approach to study the sol-gel phase transition of a brucine–porphyrin based gelator, which uses vibrational circular dichroism (VCD) spectroscopy, is described. The gelation process leading to highly ordered chiral supramolecular assemblies was investigated in various solvents at the different temperatures and concentrations. The VCD spectra sensitively reveal the specific parts of molecule whose configuration is influenced by a sol-gel phase transition and chiral supramolecular aggregation and therefore indicate the parts of the molecule responsible for the chiral self-assembly formation. Temperature stability of the organogel studied is discussed on the basis of the VCD and IR absorption spectra. The scanning electron microscopy was used to visualize the structure of brucine–porphyrin conjugate in the gel phase.     

Structural transitions in polyriboadenylic acid induced by the changes in pH and temperature: vibrational circular dichroism study in solution and film states

A correlation of the changes in vibrational absorption and vibrational circular dichroism (VCD) spectral features with the structural changes of polyriboadenylic acid (polyA) as a function of pH is reported. Analysis of the solution spectral data as a function of pH led us to establishing the importance of a previously unrecognized absorption band at approximately 1665 cm(-1). The present studies indicate that this absorption band and associated VCD originate from the double-helical structure of polyA. The observed changes in solution-state VCD features are indicative of the pH-dependent transitions among the three acidic forms of polyA (A, B, and "frozen" form). In addition to the solution-state spectral data, pH-dependent absorption and VCD spectra for films of polyA, derived from dilute H2O solutions, are also presented. The pH-dependent changes in the absorption and VCD spectra of films are also correlated to the polyA structural changes.     

Phosphorylation effect on the GSSS peptide conformation in water: infrared, vibrational circular dichroism, and circular dichroism experiments and comparisons with molecular dynamics simulations

The phosphorylation effect on the small peptide conformation in water has not been clearly understood yet, despite the widely acknowledged notion that control of protein activity by phosphorylation works mainly by inducing conformational change. To elucidate the detailed mechanism, we performed infrared (IR) absorption and vibrational and electronic circular dichroism studies of both unphosphorylated and phosphorylated tetrapeptides, GSSS 1 and GSSpS 2. The solution structure of the tetrapeptide is found to be little dependent on the presence of the neutral or negatively charged phosphoryl group, and to be a mixture of extended structures including polyproline II (PII) and beta-sheet conformations. The additional band at 1598 cm(-1) in the amide I IR spectrum of the phosphorylated peptide GSSpS at neutral pD appears to be clear spectroscopic evidence for direct intramolecular hydrogen-bonding interaction between the side chain dianionic phosphoryl group and the backbone amide proton. On the basis of amide I IR band analyses, the authors found that the probability of finding the phosphoryl group strongly H bonded to the backbone proton in GSSpS is about 43% at pD 7.0 and 37 degrees C. Such a H-bonding interaction in GSSpS has the biological standard enthalpy and entropy of -15.1 kJ/mol and -51.2 J/K mol, respectively. Comparisons between the experimentally measured IR and VCD spectra and the numerically simulated ones suggested that the currently available force field parameters need to be properly modified. The results in this paper may shed light on an unknown mechanism of controlling the peptide conformation by phosphorylation.     

Structural transitions in polyribocytidylic acid induced by changes in pH and temperature: vibrational circular dichroism study in solution and film states

Changes in vibrational absorption and vibrational circular dichroism (VCD) spectra of polyribocytidylic acid (polyC) in buffered D(2)O solution as a function of pH and temperature are reported. Analysis of these spectral data led us to establish the absorption band at approximately 1693 cm(-1) and associated negative VCD couplet as diagnostic markers of the double-helical form of polyC. An alternate interpretation suggesting quadruplex formation for polyC is also discussed. In addition to the solution state spectral data, pH-dependent absorption and VCD spectra for polyC films derived from dilute H(2)O solutions are also presented. The pH-dependent changes in the absorption and VCD spectra of polyC films are found to be similar to those observed for polyC in solution.