We report the determination of the absolute configuration (AC) of the iridoid natural product oruwacin by comparison of the optical rotations, [alpha] D, of its two enantiomers, calculated using time-dependent density functional theory (TDDFT), to the experimental [alpha] D value, +193. Conformational analysis of oruwacin using density functional theory (DFT) identifies eight conformations which are significantly populated at room temperature. [alpha] D values of these eight conformations are calculated using TDDFT at the B3LYP/aug-cc-pVDZ//B3LYP/6-31G* level, leading to the conformationally averaged [alpha] D values of -193 for the (1 R,5 S,8 S,9 S,10 S)-enantiomer and +193 for the (1 S,5 R,8 R,9 R,10 R)-enantiomer. Comparison of the calculated [alpha] D values to the value of the natural product proves that naturally occurring oruwacin has the AC 1 S,5 R,8 R,9 R,10 R. This AC is opposite to that assigned by Adesogan by comparison of the [alpha] D of oruwacin to that of the iridoid plumericin. Our results show that the assignment of the AC of a natural product by comparison of its [alpha] D to that of a chemically related molecule can be unreliable and should not be assumed to be definitive.

The Absolute Configuration (AC) of the chiral chromium complex, tricarbonyl-η6-N-pivaloyl-tetrahydroquinoline-chromium(0) has been determined using Vibrational Circular Dichroism (VCD) spectroscopy. Comparison of the VCD spectrum predicted using the Stephens equation for vibrational rotational strengths, implemented using Density Functional Theory (DFT), to the experimental VCD spectrum shows that the AC is S-(+).

The absolute configurations (ACs) of the iridoid natural products, plumericin (1) and isoplumericin (2), have been re-investigated using vibrational circular dichroism (VCD) spectroscopy, electronic circular dichroism (ECD) spectroscopy, and optical rotatory dispersion (ORD). Comparison of DFT calculations of the VCD spectra of 1 and 2 to the experimental VCD spectra of the natural products, (+)-1 and (+)-2, leads unambiguously to the AC (1R,5S,8S,9S,10S)-(+) for both 1 and 2. In contrast, comparison of time-dependent DFT (TDDFT) calculations of the ECD spectra of 1 and 2 to the experimental spectra of (+)<-1 and (+)-2 does not permit definitive assignment of their ACs. On the other hand, TDDFT calculations of the ORD of (1R,5S,8S,9S,10S)-1 and -2 over the range of 365-589 nm are in excellent agreement with the experimental data of (+)-1 and (+)-2, confirming the ACs derived from the VCD spectra. Thus, the ACs initially proposed by Albers-Schonberg and Schmid are shown to be correct, and the opposite ACs recently derived from the ECD spectra of 1 and 2 by Elsasser et al. are shown to be incorrect. As a result, the ACs of other iridoid natural products obtained by chemical correlation with 1 and 2 are not in need of revision.

The chiral oxadiazol-3-one 2 has recently been shown to exhibit myocardial calcium entry channel blocking activity, substantially higher than that of diltiazem. To determine the enantioselectivity of this activity, the enantiomers of 2 have been resolved using chiral chromatography. The absolute configuration (AC) of 2 has been determined by comparison of density functional theory (DFT) calculations of its vibrational circular dichroism (VCD) spectrum, electronic circular dichroism (ECD) spectrum, and optical rotation (OR) to experimental VCD, ECD, and OR data. All three chiroptical properties yield identical ACs; the AC of 2 is unambiguously determined to be S(+)/R(-).

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The Absolute configuration (AC) of the chiral alkane D 3 -anti-trans-anti-trans-anti-trans-perhydrotriphenylene (PHTP), 1 , is determined by comparison of density functional theory (DFT) calculations of its vibrational circular dichroism (VCD) and optical rotation (OR) to the experimental VCD and OR of (+)− 1 , obtained in high enantiomeric excess using chiral gas chromatography. Conformational analysis of 1 demonstrates that the all-chair (CCCC) conformation is the lowest in energy and that other conformations are too high in energy to be significantly populated at room temperature. The B3PW91/TZ2P calculated IR spectrum of the CCCC conformation of 1 is in excellent agreement with the experimental IR spectrum, confirming the conformational analysis and demonstrating the excellent accuracy of the B3PW91 functional and the TZ2P basis set. The B3PW91/TZ2P calculated VCD spectrum of the CCCC conformation of S- 1 is in excellent agreement with the experimental VCD spectrum of (+)− 1 , unambiguously defining the AC of 1 to be S(+)/R(−). The B3LYP/aug-cc-pVDZ calculated OR of S- 1 over the range 589–365 nm has the same sign and dispersion as the experimental OR of (+)− 1 , further supporting the AC S(+)/R(−). Our results confirm the AC proposed earlier by Farina and Audisio. This study provides a further demonstration of the excellent accuracy of VCD spectra predicted using Stephens’ equation for vibrational rotational strengths together with the ab initio DFT methodology, and further documents the utility of VCD spectroscopy in determining the ACs of chiral molecules.

The determination of the absolute configurations (ACs) of chiral molecules using the chiroptical techniques of optical rotation (OR), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) has been revolutionized by the development of density functional theory (DFT) methods for the prediction of these properties. Here, we demonstrate the significance of these advances for the stereochemical characterization of natural products. Time-dependent DFT (TDDFT) calculations of the specific rotations, [alpha](D), of four cytotoxic natural products, quadrone (1), suberosenone (2), suberosanone (3), and suberosenol A acetate (4), are used to assign their ACs. TDDFT calculations of the ECD of 1 are used to assign its AC. The VCD spectrum of 1 is reported and also used, together with DFT calculations, to assign its AC. The ACs of 1 derived from its [alpha](D), ECD, and VCD are identical and in agreement with the AC previously determined via total synthesis. The previously undetermined ACs of 2-4, derived from their [alpha](D) values, have absolute configurations of their tricyclic cores identical to that of 1. Further studies of the ACs of these molecules using ECD and, especially, VCD are recommended to establish more definitively this finding. Our studies of the OR, ECD, and VCD of quadrone are the first to utilize DFT calculations of all three properties for the determination of the AC of a chiral natural product molecule.

We demonstrate that derivatization of the OH group of endo-borneol, 1, leads to conformational rigidification. Conformational analysis (CA) of 1 and its methyl, acetate, tert-butyl, and trimethylsilyl derivatives, 2-5, is carried out using ab initio density functional theory (DFT). The number of thermally accessible stable conformations is reduced from 3 in 1, to 2 in 2, and to 1 in 3-5. Comparison of IR and vibrational circular dichroism (VCD) spectra of 1 and 3-5, calculated using DFT, to experimental spectra unambiguously confirms the DFT CA. The determination of absolute configurations (ACs) of chiral molecules via analysis of chiroptical spectra using DFT methods increases in complexity and decreases in reliability as the number of populated conformations increases. Our results for endo-borneol support the conclusion that, in the case of chiral alcohols, derivatization can lead to substantial rigidification and, as a result, significantly facilitate the determination of ACs.

[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.

The vibrational circular dichroism (VCD) spectra of the acetate derivative, 3, of 2-(1-hydroxyethyl)-chromen-4-one, 1, and the acetate derivative, 4, of 6-bromo-2-(1-hydroxyethyl)-chromen-4-one, 2, in the C=O stretching region are reported. Density functional theory (DFT) predictions of the VCD spectra of the C=O stretching modes of (R)-3 and (R)-4 are in excellent agreement with the experimental spectra for (+)-3 and (+)-4, demonstrating that the absolute configurations of both molecules are (R)-(+)1(S)- Since acetylation of (+)-1 and (+)-2 yields (+)-3 and (+)-4, this in turn leads to (R)-(+)1(S)-(-) for both 1 and 2. The absolute configurations of (-)-1 and (-)-2 were previously determined using X-ray crystallography to be R and S, respectively. Our results lead to the conclusion that the previously reported absolute configuration of 1 is incorrect.This work is the first to apply the 'conformational rigidification via chemical derivatisation' methodology to the determination of absolute configuration using VCD spectroscopy and illustrates its utility in determining the absolute configurations of chiral alcohols and, by extension, other classes of chiral molecules containing flexible functional groups. (c) 2005 Elsevier Ltd. All rights reserved.

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)-(−).

The infrared (IR) and vibrational circular dichroism (VCD) spectra of S-2,2'-dimethyl-biphenyl-6,6'-dicarboxylic acid, S-1, in CDCl(3) solution are concentration-dependent, showing that oligomerization occurs with increasing concentration. DFT calculations support the conclusion that the oligomer formed is the cyclic tetramer (S-1)(4), in which S-1 monomers are linked by hydrogen(H)-bonded (COOH)(2) moieties. Due to the existence of two inequivalent tautomeric conformations of each (COOH)(2) moiety, six inequivalent conformations of (S-1)(4) are possible. B3LYP/6-31G* DFT calculations predict that the conformation "aaab", possessing three equivalent (COOH)(2) conformations, a, and one tautomeric conformation, b, has the lowest free energy. B3LYP/6-31G* IR and VCD spectra vary substantially with conformation. The B3LYP/6-31G* IR and VCD spectra of the C=O stretch modes of "aaab" are in excellent agreement with the experimental spectra, while those of all other conformations exhibit poor agreement, confirming the prediction that the "aaab" conformation is the predominant conformation. Comparison of the calculated IR and VCD spectra of the six conformations to the experimental spectra in the range 1100-1600 cm(-1) further supports this conclusion. The study is the first to use VCD spectroscopy to determine the structure of a supramolecular species.

Optically pure enantiomers of the chiral tetrahydroxythiepane derivative 3,6-dihydroxy-4,5-O-isopropylidene-thiepane (3) are obtained using a novel protocol in which a library of all possible stereoisomers of 3 is synthesized, followed by two-step stereoselective chromatography, using, first, conventional achiral and, then, chiral stationary phases. Configurational and conformational analysis of 3 are carried out using Vibrational Circular Dichroism (VCD) spectroscopy in conjunction with ab initio DFT calculations. The absolute configuration of 3 is shown to be 3R,4S,5R,6R-(+)/3S,4R,5S,6S-(-).

The technique of time-dependent density functional theory (TDDFT) has very recently been applied to the calculation of both transparent spectral region optical rotations and electronic circular dichroism (CD). Here, we report the concerted application of the new methodologies to the determination of the absolute configuration (AC) of [3(2)](1,4)barrelenophanedicarbonitrile, 1, the first optically active barrelenophane. 1 is conformationally flexible: the two three-carbon bridges of 1 can each exhibit two conformations, leading to three inequivalent conformations of 1: a, b, and c. Conformational structures and energies are predicted using DFT at the B3LYP/6-31G* level. Comparison of the calculated structures to structures obtained via X-ray crystallography of (+)-1 shows that (remarkably) all three conformations a-c are simultaneously present in crystalline (+)-1. The sodium D line specific rotations, [alpha]D, and CD spectra of a-c are calculated using TDDFT at the B3LYP/aug-cc-pVDZ level. Comparison of the conformationally averaged specific rotation and CID spectrum to the experimental data of Matsuda-Sentou and Shinmyozu leads to the AC 9S,12S(+)/9R,12R(-). The same AC is obtained both from [alpha](D) and from the CD, strongly supporting its reliability.

CC2 and CCSD coupled-cluster calculations of the sodium D line specific rotations of 13 chiral organic molecules are compared to HF and DFT/B3LYP calculations and to experiment. For 12 of the molecules, whose [α]D values are in the range 0–200, CCSD and B3LYP [α]D values are in very similar agreement with experiment: average deviations are 19.8 and 19.4, respectively. CC2 and HF values are less accurate: average deviations are 24.7 and 32.2, respectively. For one molecule, norbornenone, the CCSD [α]D value (741) is very different from the B3LYP value (1216) and in much worse agreement with experiment (1146).

Ab initio Density Functional Theory (DFT) calculations of transparent spectral region, discrete frequency specific rotations were used to assign the absolute configurations (ACs) of: 1, 2H-naphtho[1,8-bc]thiophene 1-oxide; 2, m-F-phenyl glycidic acid methyl ester; 3, o-Br-phenyl glycidic acid methyl ester; 4, p-CH(3)-phenyl glycidic acid methyl ester; 5, 2-(1-hydroxyethyl)-chromen-4-one; and 6, 6-Br-2-(1-hydroxyethyl)-chromen-4-one. The ACs of 5 and 6 were previously determined via X-ray crystallography to be: 5, R(-)/S(+); 6, R(+)/S(-). The ACs obtained using [alpha](D) are the same for both 5 and 6: R(+)/S(-). We conclude that the previously reported AC of 5 is incorrect.

We reexamined the absolute configuration (AC) of the chiral sulfoxide 1-thiochromanone S-oxide (1) using vibrational circular dichroism (VCD) spectroscopy. The VCD spectrum of 1 was analyzed using density functional theory (DFT). DFT predicts two stable conformations of 1, separated by <1 kcal/mole. Their VCD spectra were calculated using the DFT/GIAO methodology. The VCD spectrum predicted for the equilibrium mixture of the two conformations of (S)-1 is in excellent agreement with the experimental spectrum of (+)-1. The AC of 1 is therefore definitively R(-)/S(+).

We report ab initio calculations of the frequency-dependent electric dipole-magnetic dipole polarizabilities, beta(nu), at the sodium D line frequency and, thence, of the specific rotations, [alpha](D), of 2,7,8-trioxabicyclo[3.2.1]octane, 1, and its 1-methyl derivative, 2, using the Density Functional Theory (DFT) and Hartree-Fock/Self-Consistent Field (HF/SCF) methodologies. Gauge-invariant (including) atomic orbitals (GIAOs) are used to ensure origin-independent [alpha](D) values. Using large basis sets which include diffuse functions DFT [alpha](D) values are in good agreement with experimental values (175.8 degrees and 139.2 degrees for (1S,5R)-1 and -2, respectively); errors are in the range 25-35 degrees. HF/SCF [alpha](D) values, in contrast, are much less accurate; errors are in the range 75-95 degrees. The use of small basis sets which do not include diffuse functions substantially lowers the accuracy of predicted [alpha](D) values, as does the use of the static limit approximation: beta(nu) approximately beta(o). The use of magnetic-field-independent atomic orbitals, FIAOs, instead of GIAOs, leads to origin-dependent, and therefore nonphysical, [alpha](D) values. We also report DFT calculations of [alpha](D) for the 1-phenyl derivative of 1, 3. DFT calculations find two stable conformations, differing in the orientation of the phenyl group, of very similar energy, and separated by low barriers. Values of [alpha](D) predicted using two different algorithms for averaging over phenyl group orientations are in good agreement with experiment. In principle, the absolute configuration (AC) of a chiral molecule can be assigned by comparison of the optical rotation predicted ab initio to the experimental value. Our results demonstrate the critical importance of the choice of ab initio methodology in obtaining reliable optical rotations and, hence, ACs, and show that, at the present time, DFT constitutes the method of choice.

The chiral monosubstituted derivatives of spiropentane, spiropentylcarboxylic acid methyl ester, 1, and spiropentyl acetate, 2, have been synthesized in optically active form. Configurational and conformational analysis of 1 and 2 has been carried out using infrared (IR) and vibrational circular dichroism (VCD) spectroscopies. Analysis of the experimental IR and VCD spectra has been carried out using ab initio density functional theory (DFT). For both 1 and 2, DFT predicts two populated conformations. Comparison to experiment of the conformationally averaged IR and VCD spectra of 1 and 2, predicted using DFT, provides unequivocal evidence of the predicted conformations and yields the absolute configurations R(-)/S(+) for 1 and R(+)/S(-) for 2. These absolute configurations are consistent with the R(-)/S(+) absolute configuration of spiropentylcarboxylic acid, assigned previously via X-ray crystallography of its alpha-phenylethylammonium salt.

A new theory of solvent effects on the optical rotations of chiral molecules is presented. The frequency-dependent electric dipole−magnetic dipole polarizability, βαβ(ν), is calculated using density functional theory (DFT). Solvent effects are included using the polarizable continuum model (PCM). DFT/PCM calculations of sodium D line specific rotations, [α]D, have been carried out for seven conformationally rigid chiral organic molecules (fenchone, camphor, α-pinene, β-pinene, camphorquinone, verbenone, and methyloxirane) for a diverse set of seven solvents (cyclohexane, carbon tetrachloride, benzene, chloroform, acetone, methanol, and acetonitrile). The predicted variation in [α]D for the solvents cyclohexane, acetone, methanol, and acetonitrile are in excellent agreement with experiment for all seven molecules. For the solvents carbon tetrachloride, benzene, and chloroform, agreement is much poorer. Since only electrostatic solute−solvent interactions are included in the PCM, our results lead to the con...