Density functional theory calculations of the optical rotation and electronic circular dichroism: The absolute configuration of the highly flexible trans-isocytoxazone revised

Article abstract of DOI:10.1021/jo901175s

(Chemical Equation Presented) Ab initio calculations of the optical rotation (OR) and electronic circular dichroism (ECD) for a series of trans-diastereomers of the natural cytokine modulator cytoxazone 1-4 have been performed by density functional theory

Full text of DOI:10.1021/jo901175s

pubs.acs.org/joc
Density Functional Theory Calculations of the Optical Rotation and
Electronic Circular Dichroism: The Absolute Configuration of the Highly
Flexible trans-Isocytoxazone Revised
ꢀ
Marcin Kwit,* Maria D. Rozwadowska, Jacek Gawronski, and Agnieszka Grajewska
ꢀ
Department of Chemistry, Adam Mickiewicz University, 60-780 Poznan, Poland
marcin.kwit@amu.edu.pl
Received June 3, 2009
Ab initio calculations of the optical rotation (OR) and electronic circular dichroism (ECD) for a
series of trans-diastereomers of the natural cytokine modulator cytoxazone 1-4 have been performed
by density functional theory (DFT). The calculation of OR and ECD curves provides, after critical
assessment, a reliable method for the assignment of absolute configuration of these conformationally
flexible molecules. The effects of the level of theory used for calculations, changes of conformer
equilibrium, and the solvent influence on the geometry and values of calculated OR data are
discussed, leading to the conclusion that the most frequently used B3LYP/6-31G(d) method is not
adequate for prediction of the absolute configuration of this type of highly flexible molecules. The
absolute configurations of levorotatory trans-isocytoxazone 2 and analogues 1, 3, and 4 have been
established as (-)-(4S,5S)-trans-1-4; i.e., it is in opposition to the previously published configura-
tion (-)-(4R,5R)-trans-2.
Introduction
(ECD) and optical rotation (OR) at the sodium D line ([R]D)
are the two most common experimental data that character-
ize an optically active compound. Application of ECD to
conformational and configurational studies relies on a cor-
relation between the main CD parameter;the sign of the
Cotton effect at a given wavelength and the molecular
structure. In principle, absolute configuration (AC) of a
chiral molecule can be deduced directly from its OR and/or
its ECD spectrum using semiempirical correlations.4 In
practice, experimental investigations should be supported
by advanced theoretical calculations of chiroptical phenom-
ena, especially in the cases where simple empirical rules for
various types of chromophores do not provide correct
stereochemical predictions for a broad spectrum of investigated
Chirality is a decisive factor in numerous aspects of
functioning of living organisms.1 As a consequence, chirality
plays an important role in the pharmaceutical industry, and
the development of new methods of the determination of
absolute configuration of chiral molecules is still of interest
for chemists.2
Currently, there are two different approaches for the
determination of absolute structure of chiral molecules.
X-ray crystallography is successful if a single crystal is
available for molecules containing at least one heavy atom
(e.g., sulfur).3 On the other hand, electronic circular dichroism
*To whom correspondence should be addressed. Tel: (+48) 61 8291367.
Fax: (+48) 61 8291505.
(1) Berg, J. M.; Tymoczko, J. L.; Stryer L. Biochemistry; J. Freemann and
Co.: New York, 2002.
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2007. (b) Atkinson, R. A. Stereoselective synthesis; Wiley: New York, 1995.
(3) (a) Ladd M. F. C.; Palmer, R. A. Structure Determination by X-ray
Crystallography, 2nd ed.; Plenum Press: New York, 1985. (b) Harada, N.
Chirality 2008, 20, 691–723.
(4) (a) Djerassi, C. Optical Rotatory Dispersion, Applications to Organic
Chemistry; McGraw-Hill: New York, 1960. (b) Lightner, D. A.; Gurst, J. E.
Organic Conformational Analysis and Stereochemistry from Circular Dichro-
ism Spectroscopy; Wiley-VCH: New York, 2000. (c) Circular Dichroism,
Principles and Applications, 2nd ed.; Berova, N., Nakanishi, K., Woody,
R. W., Eds.; Wiley-VCH: New York, 2000. (d) Snatzke, G. Angew. Chem., Int.
Ed. 1979, 18, 363–377. (e) Schellman, J. A. Chem. Rev. 1975, 75, 323.
(f) Moscowitz, A. Tetrahedron 1961, 13, 48–56.
DOI: 10.1021/jo901175s
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Published on Web 10/09/2009
J. Org. Chem. 2009, 74, 8051–8063 8051
2009 American Chemical Society

Kwit et al.
JOCArticle
molecules.5 Rapid development of new theoretical methods
and dramatic increase of computational power observed
during the past decade led to the use of advanced calculations
not only for model, simple compounds but also for real
molecules, products of asymmetric syntheses, or isolated
from natural sources.6 Experimental/theoretical approach
emerges now as a general and convenient method for the
determination of absolute stereochemistry, where the selec-
tion of a proper method of calculation, which is case
sensitive, is based on the literature data and above all on
the compromise between the accuracy and the computa-
tional costs.7 In the recent years additional methodology
based on comparison between experimental and calculated
vibrational circular dichroism spectra became highly popu-
lar.8 The main advantage of this method is based on doing
the calculations for the electronic ground state, which re-
quires less computational power that calculations involving
electronically excited states.
It is well-known that the conformation of a molecule has a
substantial influence on its physical and chemical proper-
ties.9 Thus, apart from suitability of the computational
method used for calculation of chiroptical properties, reli-
able conformational analysis is of critical importance for
arriving at computational results close to the experimental
ones. It has been shown that even minor changes in molecule
conformation can result in a change of sign and/or magni-
tude of the calculated CD and or OR,10 especially in the cases
of simple nonpolar compounds.11 For generation of all
possible conformers of the molecule in question, the Monte
Carlo search or systematical conformational search with the
use of common force field methods is the most frequently
used solution. In the latter case, the number of possible
conformers grows rapidly with the increase of variables such
as the number of torsion angles or other structural para-
meters taken into consideration.12 While conformational
analysis could be neglected for rigid molecules,13 computa-
tional conformation analysis of flexible molecules should be
done with the highest available accuracy.
Among the computational methods available for stereo-
chemical investigations, those based on the density functional
theory (DFT)14 are most popular. The most widely used
B3LYP hybrid functional,15 in conjunction with a rather small
6-31G(d) basis set, during the past decade became “the Swiss
army knife” for solving many structural and stereochemical
problems. There are many spectacular examples of the use of
this combination of functional/basis set for the determination
of structure and/or AC for complex molecular systems, con-
taining up to 100 carbon atoms.16 Critics of this approach
maintain that correct results obtained with the use the B3LYP/
6-31G(d) method are due to mutual cancelation of the func-
tional and basis set errors and suggest that other density
functionals or higher correlated methods like coupled cluster17,18
and/or enhanced basis sets, especially those including diffuse
p-functions at hydrogen atoms, that sometimes have a
marked effect on the calculated OR values,19 are used.
There are at least three frequently used algorithms for
calculations of chiroptical properties of flexible molecules.
These are in the order of increasing of computational cost:
(a) conformational search at the MM level/geometry opti-
mization and calculation of spectroscopic properties at the
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Asymmetry 2000, 11, 2443–2448. (c) Stephens, P. J.; Devlin, F. J.; Cheese-
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search at the MM level/geometry optimization at the
B3LYP/6-31G(d) level/calculation of spectroscopic proper-
ties at a higher level (e.g., B3LYP/aug-cc-pVDZ method);21
and (c) conformational search at the MM level/geometry
optimization at the B3LYP/6-31G(d) level/geometry reopti-
mization at a higher (e.g., B3LYP/6-311++G(d,p)) level/
calculation of spectroscopic properties at a higher level
(e.g., B3LYP/aug-cc-pVDZ or higher) for reoptimized geo-
metries.22 It should be noted, however, that there is no
guarantee that any of the combinations mentioned above
will provide results that are in full agreement with the
experimental data. Additionally, calculations according to
different algorithms give inconsistent results for the same
molecule.23 One should bear in mind, however, that even for
rigid molecules the acclaimed power of OR calculations
deteriorates if the experimental values are small.24
obtained for either highly polar (e.g., methanol) or nonpolar
(e.g., cyclohexane) solvents.
Cytoxazone ((-)-(4R,5R)-cis-5-hydroxymethyl-4-(4-met-
hoxyphenyl)-1,3-oxazolidin-2-one), an immunosuppressant
agent produced by Streptomyces sp., is a cytokine modula-
tor, whose absolute configuration was assigned by Osada
et al.30 on the basis of X-ray single-crystal diffraction study.
Syntheses of cis- and trans isomers of cytoxazone have been
performed using chemical as well as chemoenzymatic meth-
ods.31 In 2003, Hamersac et al.32 published the racemic
synthesis of structural isomers of cytoxazone, trans- and
cis-isocytoxazones, as a mixture of diastereoisomers sepa-
rated by chiral-phase HPLC.
Most of the calculations are done for isolated molecules in
the gas phase, bringing up the problem of possible contribu-
tions of different types of intermolecular (solvent) interac-
tions to the relative energies of conformational isomers.25
This problem is usually settled by the use of various simpli-
fied models of solvent-solute interactions for single-point
energy calculations and for calculations of chiroptical prop-
erties.25,26 However, the inclusion of factor γ, based on the
simplest classical Lorentz approximation, to the calculated
ORs values leads to substantial deterioration of the agree-
ment with the experiment,27 and for this reason, the interac-
tions between the molecule and the solvent are often
neglected. This approach may be justified in that the results
of the gas-phase calculations reproduce well the experimen-
tal data measured in solvents of different polarity. On the
other hand, some authors favor the use of the polarizable
continuum model (PCM) of solvent for OR28 and excited
state29 calculations. However, the agreement with the experi-
mental data in these cases is highly dependent on the solvent.
Usually a better reproduction of the experimental data is
The biological and spectroscopic properties of cis- and
trans-cytoxazones and cis- and trans-isocytoxazones and
analogues (1-4, Chart 1) have been the subject of relatively
few studies.30,31 Very recently, one of us reported the synth-
esis of (-)-(4S,5S)-3, the structural analogue of trans-iso-
cytoxazone (2),33 having a methylthio substituent at the para
position of the benzene ring and reported a new synthetic
path to (4S,5S)-2.34 The substrate for the synthesis was
enantiomerically pure (+)-thiomicamine ((+)-(1S,2S)-2-
amino-1-(4-methylmercaptophenyl)-1,3-propandiol); there-
fore, chirality of 3 reflects the chirality of thiomicamine,
which was further confirmed by X-ray crystallography of the
single crystal of 3.33
CHART 1. Structures of trans-Oxazolidinones 1-4 and Definition
of Torsion Angles ω1-ω5 Determining the Conformations of trans-
Isocytoxazones
(21) (a) Giorgio, E.; Vigilone, R. G.; Rosini, C. Tetrahedron: Asymmetry
2004, 15, 1979–1986. (b) Giorgio, E.; Maddau, L.; Spanu, E.; Evidente, A.;
Rosini, C. J. Org. Chem. 2005, 70, 7–13. (c) McCann, D. M.; Stephens, P. J.
J. Org. Chem. 2006, 71, 6074–6098. (d) Mennucci, B.; Claps, M.; Evidente,
A.; Rosini, C. J. Org. Chem. 2007, 72, 6680–6691. (e) Petrovic, A. G.;
_
Polavarapu, P. L.; Drabowicz, J.; yyzwa, P.; Mikozajczyk, M.; Wieczorek,
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W.; Balinska, A. J. Org. Chem. 2008, 73, 3120–3129. (f) Stephens, P. J.;
Devlin, F. J.; Schurch, S.; Hulliger, J. Theor. Chem. Acc. 2008, 119, 19–28.
€
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(22) (a) Pedersen, T. B.; Koch, H.; Boman, L.; Sanchez De Meras,
A. M. J. Chem. Phys. Let. 2004, 393, 319–326. (b) Zhao, S.; Zhou, Z.; Wang,
W.; Ma, H. Int. J. Quantum Chem. 2007, 107, 1015–1026. (c) Neto,
A. C.; Jorge, F. E. Chirality 2007, 19, 67–73. (d) Wiberg, K. B.; Wilson, S.
M.; Wang, Y.; Vaccaro, P. H.; Cheesemann, J. R.; Luderer, M. R. J. Org.
Chem. 2007, 72, 6206–6214. (e) Taniguchi, T.; Monde, K.; Nakanishi, K.;
Berova, N. Org. Biomol. Chem. 2008, 6, 4399–4405.
(23) Cheeseman, J. R.; Frisch, M. J.; Devlin, F. J.; Stephens, P. J. J. Phys.
Chem. A 2000, 104, 1039–1046.
(24) Stephens, P. J.; McCann, D. M.; Cheeseman, J. R.; Frisch, M. J.
Chirality 2005, 17, S52–S64.
(25) Pecul, M.; Ruud, K. In Solvent Effects on Natural Optical Activity in
Continuum Solvation Models in Chemical Physics: From Theory to Applica-
tions; Mennucci, B., Cammi, R., Eds.; Wiley-VCH: Weinheim, 2008.
(26) (a) Mukhopadhyay, P.; Zuber, G.; Wipf, P.; Beratan, D. N. Angew.
Chem., Int. Ed. 2007, 46, 6450–6452. (b) Kongsted, J.; Ruud, K. Chem. Phys.
Lett. 2008, 451, 226–232. (c) Wilson, S. M.; Wiberg, K. B.; Murphy, M. J.;
Vaccaro, P. H. Chirality 2008, 20, 357–369.
(27) Stephens, P. J.; Devlin, F. J.; Cheeseman, J. R.; Frisch, M. J. J. Phys.
Chem. A 2001, 105, 5356.
(28) (a) Marchesan, D.; Coriani, S.; Forzato, C.; Nitti, P.; Pitacco, G.;
Ruud, K. J. Phys. Chem. A 2005, 109, 1449–1453. (b) Mennucci, B.; Tomasi,
J.; Cammi, R.; Cheeseman, J. R.; Frisch, M.; Devlin, F. J.; Gabriel, S.;
Stephens, P. J. J. Phys. Chem. A 2002, 106, 6102–6113.
(29) Scalmani, G.; Frisch, M. J.; Mennucci, B.; Tomasi, J.; Cammi, R.;
Barone, V. J. Chem. Phys. 2006, 124, 094107.
(30) Kakeya, H.; Morishita, M.; Kochino, H.; Morita, T.; Kobayashi, K.;
Osada, H. J. Org. Chem. 1999, 64, 1052.
(31) Review: Grajewska, A., Rozwadowska, M. D. Tetrahedron: Asym-
metry 2007, 18, 803-813 and references cited therein.
(32) Hamersak, Z.; Sepac, D.; Ziher, D.; Sunjic, V. Synthesis 2003, 3, 375.
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Chiroptical properties of trans- and cis-cytoxazones as
well as cis- and trans-isocytoxazones, including 2, were
recently the subject of interest of Giorgio et al.35 These
authors correlated the ORs measured at several wavelengths
with those calculated at the B3LYP/6-31G(d) level for
structures optimized at the same level. In this way, the
(4S,5S) absolute configuration has been postulated for the
trans dextrorotatory enantiomer 2, [R]D +70 (c 0.4,
methanol). This assignment remains in conflict with the data
obtained for all trans-oxazolidinones 1-4, with known
(4S,5S) absolute stereochemistry, for which the optical
rotation values measured in methanol at the sodium D line
are negative. To clarify the discrepancy, we performed
extensive computational study on the stereochemistry of
(4S,5S)-1-4, according to the algorithms (a)-(c) described
above, where the algorithm (a) is a reproduction of the
previously reported methodology.35 Additionally, we report
here a new synthetic path to (4S,5S)-4 from 5, the nitro
analogue of thiomicamine.
The aim of the present paper is to show the limitations and
possible drawbacks of simple calculation algorithm (a) men-
tioned above, which led to incorrect assignment of the
absolute configuration previously reported for 2.35 Our
computational analysis is split into two parts. In the first
part of our work, we used hybrid functional B3LYP36
and arbitraly chose three basis sets, 6-31G(d), 6-311++G-
(2d,2p), which provides an acceptable compromise between
the accuracy and the computational costs, as well as aug-cc-
pVTZ as a reference method for calculation of OR.23 In
order to determine which factor most influenced the final
results, we performed the so-called “cross check calcula-
tions” which means the use of a more demanding method for
prediction of OR for “worse” geometry (optimized at a low-
level of theory) and vice versa. For the purpose keeping the
analysis as simple as possible, we limit our discussion to the
[R]D values only (with the exception of the most important
case of compound 2). This type of calculation has been done
for isolated molecules in the gas phase.
basis set. Due to possible importance of intramolecular
London dispersion interaction for such conformational pro-
blem, for all reoptimized at the different level of theory
structures, single-point energies at the PCM/MP2/6-311++G-
(2d,2p) level were calculated. Additionally, for all investi-
gated compounds we measured in acetonitrile and calculated
the ECD spectra at the PCM/B3LYP/6-311++G(2d,2p)
and PCM/B2LYP/6-311++G(2d,2p)40 levels for all stable
geometries optimized at all of the PCM/DFT/6-311++G-
(2d,2p) levels. The solvent effect on optical rotation was
studied for the case of acetonitrile by calculating specific
optical rotations at the PCM/B3LYP/6-311++G(2d,2p)
level for all reoptimized structures.
Results and Discussion
Synthesis. The synthesis of isocytoxazones 1 and 3 has
been published previously.33 The new synthetic route to the
enantiomerically pure trans-isocytoxazone 2 is described in
the preceding paper in this series,34 and here we present the
synthesis of trans-nitro analogue 4. (4S,5S)-5-Hydroxy-
methyl-4-(4-nitrophenyl)oxazolidinone 4 and its regioi-
somer have recently been prepared from (1S,2S)-2-amino-
1-(4-nitrophenyl)-1,3-propanediol (5) by K2CO3-catalyzed
cyclization of the N-Cbz derivative of 5,41 but no specific
rotation of compound 4 has been given.
In the case of the enantiomeric (4R,5R)-oxazolidinone ent-
4, however, both negative [R]D -4.8 (c 1.1, ethanol)42 and the
positive [R]D +1.48 (c 1, methanol)43 signs of the specific
rotation have been reported. Since the sign of the rotation of
the (4S,5S)-enantiomer 4 was important for our study, to
solve the above discrepancy, the synthesis of this compound
was undertaken, using once again the commercially available
amino diol 5 as the substrate (Scheme 1). In the first step of
the synthesis, N-Boc derivative 6 was prepared. To avoid the
formation of the isomeric oxazolidinone, the primary hydro-
xy group in 6 was O-sililated, and the N-Boc, O-TBDMS
derivative 7 was cyclized to oxazolidinone 8. After removal
of the O-silyl blocking group, the target (4S,5S)-5-hydro-
xymethyl-4-(4-nitrophenyl)oxazolidin-2-one 4 was obtained
in 60% overall yield. It showed the mp 142-142.5 °C (ethyl
acetate) [lit.41 mp 137-138 °C (ethyl acetate)], [R]D -21.8
(c 2.07; c 1.01, methanol), and spectral data corresponding to
those described in the literature.41-43
Because all investigated molecules are highly polar and
thus sparingly soluble in nonpolar solvents, like hexane or
cyclohexane, and all measurements were done in polar
solvents like methanol and acetonitrile, in the second part
of the work we employed computational methodology that
better fit the experimental conditions. Based on the results of
conformational search and geometry optimizations at the
B3LYP/6-31G(d) level, all stable conformers were reopti-
mized with the use of the IEFPCM model of solvent
(acetonitrile) and four density functionals B3LYP,36a
PBE0,37 and BHandHLYP38 differing in the amount of
Hartree-Fock exchange as well as pure density functional
BP86,39 all of them in conjuction with the 6-311++G(2d,2p)
Structure. Whereas structures of trans-oxazolidinones
1-4 are deceptively simple, their conformations are not.
There are at least four torsion angles for which expected
bariers of rotation are low. In the case of 2, the rotational
barriers established for torsion angles ω1, ω2, ω4, and ω5 (for
definition, see Chart 1) are low and do not exceed 8 kcal
mol-1 (see Figure A in the Supporting Information). Sur-
prisingly, the lowest rotational barier was found for torsion
angle ω2, whereas the highest is associated with the rotation
of the CH2OH group. Such low rotational barriers result in
large number of local energy minima in PES and small
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3865–3868. (b) Perdew, J. P.; Burke, K.; Ernzerhof, M. Phys. Rev. Lett. 1997,
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(40) Grimme, S. J. Chem. Phys. 2006, 124, 034108.
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Heterocycl. Compd. 2006, 42, 506–511.
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10207.
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Phys. Rev. A 1988, 38, 3098–3100.
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8054 J. Org. Chem. Vol. 74, No. 21, 2009

Kwit et al.
JOCArticle
SCHEME 1. Synthesis of the Nitro Analogue of trans-4
energy differences between stable conformers, the order of
which may be highly dependent on the level of theory used
for the calculations.
seither at the B3LYP/6-31G(d), B3LYP/6-311++G(2d,2p)
or PCM/DFT/6-311++G(2d,2p) levels of theory to confirm
that the conformers are stable; (ix) single-point energy cal-
culations at the MP2/6-311++G(2d,2p) or PCM/MP2/
6-311++G(2d,2p) levels for stable conformers reoptimized at
the B3LYP/6-311++G(2d,2p) and PCM/DFT/6-311++G-
(2d,2p) levels of theory; (x) for the conformers having relative
energies ranging from 0.0 to 2.0 kcal mol-1, percentage
populations on the basis of both ΔE and ΔG values, using
Boltzmann statistics and T=298 K.
The results of our DFT calculations at various levels of
theory for molecules 1-4 are shown in Figure 1 and collected
in Tables A-I in the Supporting Information (see also Figures
A1, B1, C1, and D1, Supporting Information). Figure 2
shows calculated structures of the ΔG-lowest energy con-
formers of 1-4, found at the B3LYP/6-31G(d), B3LYP/6-
311++G(2d,2p) and PCM/DFT/6-311++G(2d,2p) levels
(see also Figure A12, Supporting Information). Note, that
for easier comparison of the results, obtained at different
levels of theory, conformers are numbered according to their
appearance in the conformational search at the MM level,
not in the order of increasing energies.
For the present study, we chose molecules having four
different substituents in the phenyl group;either neutral
(hydrogen), electron-donating (methoxy- and thiomethoxy-),
or electron-withdrawing (nitro-);in order to determine the
significance of the electronic effects on the conformational
equilibriums. The structures and spectroscopic properties of
these molecules were calculated by the DFT methods.
Our computational studies were performed as follows: (i)
full conformational searches with the use CONFLEX44
software and MM3 force field for 1-4, which allowed con-
struction of the PES for these molecules; (ii) full structure
optimizations at the B3LYP/6-31G(d)45 level for all confor-
mers ranging from 0.0 to 15 kcal mol-1 in their relative
energies; (iii) full structure reoptimizations at the B3LYP/6-
311++G(2d,2p) level for all structures optimized at the
B3LYP/6-31G(d) level, regardless of their relative energies;
(iv) calculation of “gas phase” optical rotations (at various
levels) for all conformers structurally optimized at both
B3LYP/6-31G(d) and B3LYP/6-311++G(2d,2p) levels;
(v) full structure reoptimizations using PCM solvent model
of acetonitrile and B3LYP, BHandHLYP, PBE0, and BP86
density functionals in conjunction with the 6-311++G-
(2d,2p) basis set were performed for all the structures
optimized in the gas phase at the B3LYP/6-31G(d) level,
regardless their relative energies; (vi) calculation of optical
rotations at PCM/B3LYP/6-311++G(2d,2p) level for all
conformers structurally optimized at PCM/DFT/6-311++G-
(2d,2p) levels; (vii) oscillator and rotatory strengths for
thermally accessible conformers of 1-4 at the PCM/B3LYP/
6-311++G(2d,2p) and PCM/B2LYP/6-311++G(2d,2p) levels;
(viii) for all optimized structures, frequency calculation-
It is clearly seen that all of the calculated at B3LYP/6-
31G(d) level lowest energy conformers of 1-4 are similar,
regardless of the substituent at the C4 position in the phenyl
ring. A common feature of the lowest energy conformers is
the presence of the hydrogen bonding of the hydroxy group
with the nitrogen atom. The distances N H(O) are in the
3 3 3
˚
range 2.39-2.45 A, and due to the less electron-donating
character of the oxazolidinone nitrogen atom these interac-
tion are rather weak. In the case of 2 and 3, the two lowest
energy conformers differ only in relative orientation of the
OMe or SMe groups. It should be noted that the lowest
energy conformer of 2, previously calculated by Giorgio
et al.,35 is virtually the same as the lowest energy conformer
of 2 found by our computation. The low energy structures
reoptimized at the B3LYP/6-311++G(2d,2p) level are the
same in terms of ΔE values. However, in the case of 2, taking
into consideration the ΔG values, conformer 42 is of the
lowest energy. This may be due to the stabilization of the
structure by dipole-dipole interactions in parallel arrange-
ments of the NH and CO bonds (see Figure 2 and Figure
A12, Supporting Information). According to our calcula-
tions, there are 17 stable low-energy conformers of 2 found at
the B3LYP/6-31G(d) level, contrary to only 10 low energy
conformers found in the previous study35 and 21 stable
structures ranging in relative free energies from 0.0 to
2.0 kcal mol-1 found at the B3LYP/6-311++G(2d,2p) level
(44) CAChe WS Pro 4.5, Fujitsu Ltd.
(45) Gaussian 03, Revision C.02 : Frisch, M. J.; Trucks, G. W.; Schlegel,
H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.,
Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.;
Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda,
R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski,
V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.;
Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian, Inc., Wallingford, CT, 2004.
J. Org. Chem. Vol. 74, No. 21, 2009 8055

Kwit et al.
JOCArticle
FIGURE 1. Relative energies (ΔEDFT, ΔGDFT, and ΔEMP2 in kcal mol-1) and percentage populations of stable conformers of 1-4 calculated
at various levels of theory.
8056 J. Org. Chem. Vol. 74, No. 21, 2009

Kwit et al.
JOCArticle
FIGURE 2. Structures of the ΔG lowest energy conformers of 1-4 calculated at the different levels of theory. Arrows indicate possible
attractive interactions and distances between the hydrogen and the polar atoms.
of calculation. For other isocytoxazones the number of
stable conformers found at both the B3LYP/6-31G(d) and
the B3LYP/6-311++G(2d,2p) levels is, respectively, 12 and
11 for 1, 18 and 20 for 3, and 14 and 10 for 4.
method in a general sense, save for small changes in the bond
lenghts and values of torsion angles within conformers of the
same numbers optimized with other methods. It should be
noted that even small changes in molecular structure may
significantly affect its chiroptical properties. Since there is no
possibility to confront the conformational equilibria of 1-4
with the experiment, the choice of the best method of
geometry/energy determination has been done indirectly by
comparising the calculated ECD and/or OR with the experi-
mental data.
The structures of the low-energy conformers of 1-4
calculated at the B3LYP/6-311++G(2d,2p) level can be
described by the values of torsion angles ω1-ω5 due to the
rotation around the C-C or C-heteroatom bonds, i.e., by
conformation of the five-membered ring and its substituents
(for definition see Chart 1). Specifically, torsion angle ω3
defines the mutual orientation of the 4-substituted benzene
ring and the hydroxymethylene group and also characterizes
the conformation of the five-member ring. The tabulated
sequences of the torsion angles are deposited in Supporting
Information. Torsion angle ω1 adopts only two extreme
The solvent effect aproximated by PCM model in con-
junction with DFT methods changes the situation. First, the
number of stable conformers is reduced in all cases and the
relative energies become smaller. Second, the stabilizing
effect of hydrogen bonding between the hydroxy group
and the nitrogen atom appears negligible at these levels of
theory, and the most important structure determining factor
are the dipole-dipole interacions between the NH and CO
bonds. In the majority of cases, the ΔG lowest energy
conformers are stabilized by these dipole-dipole interac-
tion. Third, the relative energies calculated at the PCM/
MP2/6-311++G(2d,2p) level are similar to those calculated
at PCM/DFT/6-311++G(2d,2p) levels, which indicates
that the intramolecular London dispersion interaction are
less important than expected. The respective structures
reoptimized at the PCM/DFT/6-311++G(2d,2p) levels are
similar to those obtained with the use of B3LYP/6-311++G(2d,2p)
J. Org. Chem. Vol. 74, No. 21, 2009 8057

Kwit et al.
JOCArticle
values, either ca. 0° or 180°. Any deviation from these values
results in a significant increase of energy. The same is true for
the nitro group, which lies in the plane of the benzene ring.
Torsion angle ω2 is in all cases negative and corresponds to
two conformations only, sp or g-, sp conformation pre-
ferred. Formally ac torsion angle ω3 can adopt selected
discrete values, for simplicity grouped according to their
magnitude. Torsion angles ω3 ranging from -96° to -91°
belong to the first group and correspond to a pseudodiequa-
torial arrangement of the benzene ring and the hydroxy-
methyl substituents. In the case of the second group, ω3
ranges from -129° to -139°, and this corresponds to a
pseudodiaxial arrangement of the substituents. The third
group is exceptional. Calculated values of torsion angles ω3
are about 105°, and the conformation of the five-membered
ring is slightly distorted from planarity. In our opinion, such
structures are close to the possible transition state in the
pseudorotation of the five-member ring. Due to their rather
high relative energies, conformers belonging to this group do
not affect much the conformational equilibriums. Torsion
angles ω4 and ω5 can adopt either ap, g- or g+ conforma-
tions. The general rule is that in any conformer found by
calculation, there is no more than one g+ torsion angle ω4
and ω5; however, no such restrictions apply to other torison
angles. Thus, the presence of three ap or g- torsion angles
within an individual conformer is possible. In the majority of
cases, the five-membered ring adopts an envelope conforma-
tion, where atoms (Ph)C-O-C(dO)-N are nearly coplanar
and the second stereogenic center (at the nonbenzylic carbon
atom) lies out of plane. In the case of the lowest energy
conformers of 1-4 (ΔE scale), torsion angles ω1-ω5 are in
the arrangement sp (or ap), sp-, ac-, g+, and g-, respec-
tively, and the five-membered ring adopts an envelope con-
formation. In the case of 2, the ΔG lowest energy conformer
is characterized by the ap, sp-, ac-, g-, ap arrangement of the
torsion angles ω1-ω5 and again the five-membered ring
adopts an envelope conformation. In the cases of the lowest
energy conformers of 1-4 (both ΔE and ΔG scales) both the
benzene ring and the hydroxymethyl substituent adopt a
pseudodiequatorial conformation
cussion is restricted to the most important representative
of this group, trans-isocytoxazone 2 (see Table A2, Sup-
porting Information). For comparison, we collected in
Table D (Supporting Information) sequences of the tor-
sion angles ω1-ω5, calculated at both the B3LYP/6-31G-
(d) and B3LYP/6-311++G(2d,2p) levels for individual
conformers of 2 (see also Tables E-G, Supporting
Information).
At the first glance, there is no substantial difference
between the geometries obtained with the use of either
B3LYP/6-31G(d), B3LYP/6-311++G(2d,2p) or PCM/
DFT/6-311++G(2d,2p) methods. The values of torsion
angles ω1-ω5 obtained at the B3LYP/6-311++G(2d,2p)
level are slightly (2-9°) smaller than the respective values
obtained at the B3LYP/6-31G(d) level. The most significant
change is observed in the case of angle ω2, which is calculated
smaller at the higher calculation level. This is apparently due
to a weak interaction between the oxygen atom and one of
the hydrogen atom in the ortho position, being overesti-
mated in calculations at a lower level of theory. The aver-
˚
age distance between these O and H atoms is about 2.65 A.
Another clearly visible change is flattening of the five-mem-
bered ring with the increase of calculation level; however, the
overall conformation remains the same as found by calcula-
tions at the B3LYP/6-31G(d) level. The flattening of the five-
membered ring is correlated with a longer distance between
the (O)H and N atoms, calculated at the higher level.
A further observation is that if one neglects the ω1 angle,
all of the ΔE-based lowest energy conformers of 1-4 and
next to the lowest energy conformers in the cases of 2 and 3
form one family described by sp-, ac-, g+, g- values of the
torsion angles ω2-ω5 having the same envelope conforma-
tion of the five-membered ring, with the substituents in
pseudodiequatorial positions. Although this analysis seems
purely statistical, it can help to correlate structural para-
meters of the isocytoxazone molecules with the signs and
magnitudes of the calculated optical rotations.
Optical Rotation. Optical rotations for 1-4 calculated at
various levels of theory and measured in acetonitrile and
methanol solutions at the sodium D line are collected in
Table 1 and Tables A1-A4 and Tables I1-I25 in the
Supporting Information.
Due to the similarities found in the results of conforma-
tional searches for 1-4, a more detailed structural dis-
TABLE 1. Optical Rotations Measured in Acetonitrile and Methanol Solutions and Calculated at Various Levels of Theory for trans-Isocytoxazones 1-4
[R]D/method
compd
[R]D expa
Ab
Bc
Cd
De
Ef
Fg
Gh
Hi
Ij
1
-77 (-58)
ΔEDFT
ΔGDFT
ΔEMP2
ΔEDFT
ΔGDFT
ΔEMP2
ΔEDFT
ΔGDFT
ΔEMP2
ΔEDFT
ΔGDFT
ΔEMP2
+90
+81
+22
+32
+27
+13
-12
-12
-8
-51
-63
-45
-43
-41
-43
-2
-11
-13
-64
-60
-59
-78
-107
-72
-60
-58
-62
-52
-48
-57
-61
-57
-57
-82
-78
-73
-55
-51
-57
-36
-32
-39
-47
-36
-36
-71
-91
-66
-52
-45
-53
-21
-6
-89
-81
-83
-88
-93
-82
-80
-93
-82
-65
-64
-66
2
3
4
-87 (-94)
-81 (-77)
-53 (-24)
+35
+11
-7
-18
-28
-54
-55
-67
+44
+19
-16
-15
-18
-26
-28
-26
+68
+51
+26
+30
+28
+27
-2
+4
+4
-2
-22
aIn acetonitrile solution (optical rotations measured in methanol are shown in parentheses). bB3LYP/6-31G(d)//B3LYP/6-31G(d). cB3LYP/6-
d
e
f
311++G(2d,2p)//B3LYP/6-31G(d). B3LYP/6-31G(d)//B3LYP/6-311G++(2d,2p). B3LYP/6-311G++(2d,2p)//B3LYP/6-311G++(2d,2p). B3LYP/
aug-cc-pVTZ//B3LYP/6-311G++(2d,2p). gPCM/B3LYP/6-311++G(2d,2p)//PCM/B3LYP/6-311++G(2d,2p). hPCM/B3LYP/6-311++G(2d,2p)//
PCM/BHandHLYP/6-311++G(2d,2p). iPCM/B3LYP/6-311++G(2d,2p)//PCM/PBE0/6-311++G(2d,2p). jPCM/B3LYP/6-311++G(2d,2p)//PCM/
BP86/6-311++G(2d,2p).
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Kwit et al.
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It is evident that calculated OR are highly dependent on
the method and algorithm used. The use of the B3LYP/6-
31G(d) method for both geometry and OR (method A,
Table 1 and Tables A1-A4 in Supporting Information)
results in incorrect prediction of AC. Boltzmann-averaged
absolute values of OR obtained by this methodology are in
most cases higher than the experimental ones. The use of a
“better” method for OR calculation, with “worse” geometry
calculated at the B3LYP/6-31G(d) level, is by far the most
frequently used algorithm for calculation of chiroptical
properties. This approach has improved the results in the
cases of 2 and 3 (correct sign of OR), but in the cases of 1 and
4 the signs are still incorrect (method B, Table 1 and Tables
A1-A4 in Supporting Information). Further improvement
of the results was achieved for 1-3 with the use methods
D and E, where the calculations of OR were performed at
higher levels of theory (B3LYP in conjunction with 6-311++G -
(2d,2p) or aug-cc-pVTZ basis sets) for “better” geometries
(optimized at the B3LYP/6-311++G(2d,2p) level). trans-
Nitro-substituted isocytoxazone 4 is of special interest,
due to its measured low optical rotation. None of the
methods mentioned previously was able to reproduce well
the experimental OR. In this case, a better agreement with
the experiment was obtained with the use of the ΔE-based
Boltzmann averaged values, calculated according to
methods D and E. In these cases, the calculated values
were corrected in sign but much lower than the experi-
mental OR value.
Method C (a “worse” method of OR calculation using
“better” geometries, Table 1 and Tables A1-A4 in Support-
ing Information) is a cross-check calculation showing the
importance of proper determination of both the structures
and populations of conformers for the correctness of OR
calculation. Although in the cases of 1 and 4 the signs of the
calculated average optical rotations are still incorrect, in all
investigated cases (method A to E) the values of averaged
optical rotations are gradually changing from positive to
negative values and asymptotically better reproduce the
experiment.
Detailed inspection of the relationship between the struc-
tures of individual conformers of 2 and calculated optical
rotations (method E, Table 1 and Tables A1-A4 in the
Supporting Information) allows the structural parameters
that significantly influence the calculated OR to be indicated.
For example, conformers 20 and 21 differ only in the relative
orientation of the methoxy group; calculated optical rotation
values, although of the same negative signs, differ in magni-
tude by ∼20°. The most significant effect of rotation of the
methoxy group on the OR is visible in the cases of confor-
mers 1 and 9, where the difference of calculated ORs is over
80°. Flipping the five-membered ring does not influence the
calculated OR (see, for example, conformers 13 and 25 or 15
and 22), other parameters being equal. Contrary to this,
rotation of the hydroxy group changes the sign of OR from a
negative (conformer 47) to a positive (conformer 57) value. It
seems important to note that rotation of a relatively small
but polar group, like a hydroxy or methylthio group (in the
case of 3), can have a significant effect on the calculated OR
value. Calculations of OR for rotamers of ethane and other
simple hydrocarbon molecules show that the C-C bond
rotation changes the signs and values of ORs by hundreds of
degrees.19b,46 The same phenomenon has been observed in
the case of simple amino acids, like alanine and proline,
where the rotations of either carboxylic, amino, or hydroxy
groups significantly influenced the sign and magnitude of
calculated OR.10 Wiberg et al. proposed that this phenom-
enon is due to the change of electron density upon confor-
mational interconversion, which strongly affects the
magnetic properties of the molecule.19b
Solvent Effect. In order to obtain a better approximation
of the experimental data we performed calculations of OR
taking into account the environment surrounding the real
molecules. This is of special importance in the case of 4, due
to the incorrect prediction of the sign as well as the magni-
tude of optical rotations by calculations in the gas phase, so
for this reason we start our discussion from this example.
Preliminary computations limited to single-point relative
energies and optical rotations in the presence of the solvent
dielectric constant improved the results for 4 significantly.
We employed the well-known PCM model25,27,29 of the
solvent molecules for single-point energy calculations in
either polar (acetonitrile and methanol) or nonpolar
(chloroform) environment (the results are summarized in
Table H in the Supporting Information). It is evident that
the presence of solvent molecules may change the relative
energies of conformers. For example, relative energies cal-
culated for the nonpolar chloroform dielectric constant are
similar to those calculated for the gas phase. An increase of
solvent polarity makes the differences in calculated relative
energies of conformers smaller due to the decrease of stabi-
lization interaction between the (O)H and N atoms that
determines the structure in the gas phase, as mentioned
previously.
In the case of 4, solvent effect is visible not only in the
calculated conformer energies but also in the calculated
optical rotations. For the majority of low energy conformers
of 4, the magnitude of OR calculated with the use of PCM for
methanol was doubled. After Boltzmann averaging the
calculated net optical rotation was found close to the mea-
sured value (Table H, Supporting Information).
FIGURE 3. Optical rotations for 2 measured in acetonitrile (solid
black line) and (ΔG-based Boltzmann evaraged) calculated at the
PCM/B3LYP/6-311++G(2d,2p) level for structures optimized at
the PCM/DFT/6-311++G(2d,2p) levels. Experimental data taken
from ref 35.
(46) (a) Wiberg, K. B.; Wang, Y.; Vaccaro, P. H.; Cheeseman, J. R.;
Luderer, M. R. J. Phys. Chem. A 2005, 109, 3405–3410. (b) Wiberg, K. B.;
Vaccaro, P. H.; Cheeseman, J. J. Am. Chem. Soc. 2003, 125, 1888–1896.
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In this approach, it is presumed that the geometry of the
investigated molecules is not affected by the presence of
solvent and is the same as in the gas phase. According to
the results obtained by full structure optimization using
PCM model and different density functionals this asumption
is not longer true. For this reason, we calculated OR at the
PCM/B3LYP/6-311++G(2d,2p) level for all structures
optimized with the use of the PCM solvent model, in con-
junctionwith differentDFT methods(methodsF-I, Table1,
and Tables I1-I20, Supporting Information). Results ob-
tained with this approach are consistent, regardless of the
algorithm and method of Boltzmann averaging used; all OR
calculated according to different approaches are qualita-
tively the same. However, in the cases of 1-3 the use of the
PCM/BP86/6-311++G(2d,2p) method for geometry opti-
mization, together with OR calculations at the PCM/
B3LYP/6-311++G(2d,2p) level, gives the best results,
whereas in the case of 4 this approach is the second best
(after the PCM/B3LYP/6-311++G(2d,2p) method); the OR
was ∼20% overestimated in comparison with the experi-
mental data.
Finally, we calculated OR for 2 taking into account the
solvent effect aproximated by the PCM model for acetoni-
trile and compared the theoretical results with the experi-
mental OR data taken at four different wavelengths
(Figure 3 and Tables I21-I24, Supporting Information).
The comparison clearly shows that the previously proposed
absolute configuration for 2 is incorrect35 and is in fact
4R,5R.
It is clearly seen that increasing the level of calculation for
both the structure and ORs results in a better approximation
of the experimental data. For polar compounds, approxima-
tion of solvent environment appears mandatory for obtain-
ing results well approximating the experimental data.
FIGURE 4. UV (left panels) and CD (right panels) spectra of 1-4, experimental (solid lines) and calculated at the PCM/B3LYP/6-
311++G(2d,2p) level (for geometries optimized at the PCM/PBE0/6-311++G(2d,2p) level), ΔG-based and Boltzmann-averaged (dashed lines).
All calculated spectra were wavelength corrected to match the experimental UV spectra.
8060 J. Org. Chem. Vol. 74, No. 21, 2009

Kwit et al.
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Electronic Circular Dichroism. In order to fully character-
ize the chiroptical properties of isocytoxazones 1-4, we
performed measurements and calculations of their ECD
spectra using the PCM/TD-B3LYP/6-311++G(2d,2p)
and PCM/TD-B2LYP/6-311++G(2d,2p) methods for the
geometries optimized at the B3LYP/6-311++G(2d,2p) and
PCM/DFT/6-311++G(2d,2p) levels. The best calculation
results and the experimental spectra are shown in Figure 4
(see also the Supporting Information). All calculated spectra
were wavelength corrected to match the experimental UV
λmax values. The experimental UV bands used for wave-
length correction were the long wavelength absorption max-
ima in the cases of 3 and 4 or the short wavelength absorption
maximum in the cases of 1 and 2. As we mentioned pre-
viously, the best working method for geometry/energy cal-
culation can be evaluated indirectly by comparing the
theoretical and experimental CD/OR data. In the cases of
1-4, the use of the PCM/B3LYP/6-311++G(2d,2p) method
for ECD calculation with the geometries optimized at
the PCM/PBE0/6-311++G(2d,2p) level appears to be the
best combination. It is worth noting that while the TD-
B2LYP approach usually outperforms other TD-DFT
approaches,18,40 in the case of trans-izocytoxazones 1-4, it
gives acceptable but no better results than these due to
B3LYP hybrid functional (see Figures A-E in the Support-
ing Information for comparison), regardless of the method
used for geometry optimization.
Similar to the OR calculations, the best agreement be-
tween the calculated and the experimental data has been
obtained in the most important case of 2, whereas in the cases
of 3 and 4 the agreement was good, except that the calculated
electronic transition energies were red-shifted. Generally,
molecules containing sulfur atom(s) constitute difficult cases
for ECD calculations with the use of B3LYP functional.47 In
the case of 1, the Boltzmann-averaged calculated ECD
spectrum differs from the measured one. This may be due
to the fact that the absorption bands are in the region that is
not well-reproduced by TD-DFT computations with the use
of B3LYP functional and the basic chromophore is achiral
but only perturbed by a chiral, saturated substituent.
We analyzed the CD spectrum of 2 in a more detailed way.
In Figure 5 are shown the calculated UV and ECD for the
ΔG-based lowest energy conformer of 2 (optimized at the
PCM/PBE0/6-311++G(2d,2p) level).
The measured and calculated UV and ECD spectra of 2
consist of three absorption bands. The lowest energy positive
Cotton effect (Δε = +0.3) is observed at 276 nm, and it
corresponds to the 1Lb band in the UV spectrum at 273 nm
(ε 1400). In the theoretical spectra this band appears at
around 250 nm, and the electronic transition involves both
HOMO and LUMO orbitals (Figure 5).
FIGURE 5. UV and ECD spectra calculated at the PCM/B3LYP/
6-311++G(2d,2p) level for the ΔG-based lowest energy conformer
of 2 (optimized at the PCM/PBE0/6-311++G(2d,2p) level). Ver-
tical bars represent the oscillator and the rotatory strengths, respec-
tively.
band at 228 nm (ε 11800). Note that for all low energy
conformers of 2, the net calculated rotatory strengths for this
spectral region are negative, which means that the sign of
rotatory strength for this electronic transition is conforma-
tion-independent. The high energy region of the UV and
ECD spectra of 2 is difficult to interpret due to many
contributing electronic transitions. The experimental nega-
tive high-energy Cotton effect (Δε = -5.8) is observed at
197 nm and corresponds to the UV absorption band at 196
nm (ε 43500). The respective band for the conformer-aver-
aged theoretical spectra appears at around 200 nm for ECD
and at about 195 nm for UV. Detailed inspection of calcu-
lated ECD leads to the conclusion that low energy transitions
are overestimated by ca. 20 nm, whereas higher energy
electronic transitions are underestimated by about 10 nm.
Conclusions
In this work, we demonstrate that the previously deter-
mined AC for 2, based on DFT calculations at a low level of
theory, is inccorect. Additionally, we show which factors
need to be taken into consideration for reliable theoretical
prediction of absolute configuration of molecules having
flexible structures. First is the method of conformational
search. In our procedure (method (a) mentioned in the
Introduction), the systematic conformational search gener-
ated a much larger set of conformers compared to that
generated by the Monte Carlo search.35 This step is in fact
the most important;omitting a number of starting struc-
tures of flexible molecules may lead to incorrect predictions
According to the theoretical predictions, the second low
energy negative Cotton effect consists of two electronic
transitions with calculated maxima at 227 and 225 nm. The
negative rotatory strengths are contributed by the HOMO f
LUMO+1 transition, calculated at 227 nm, and the HOMO
f LUMO+2 (major contribution) transition calculated at
225 nm. The corresponding experimental negative Cotton
effect (Δε=-1.6) is found at 230 nm and is linked to a UV
(47) Gawronski, J.; Kwit, M.; Skowronek, P. Org. Biomol. Chem. 2009, 7,
1562–1572.
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Kwit et al.
JOCArticle
of molecular properties, regardless the level of calculations in
the next steps. The second factor is the choice of adequate
DFT method (functional) for calculation of chiroptical
properties. While for OR calculations B3LYP seems to
be the most frequently used DFT method, the ECD calcula-
tions are performed with the use of various functionals
(for example, B2LYP or B2PLYP),18,40,47 sometimes work-
ing better than the B3LYP functional. In light of our results,
proper selection of the DFT method for ECD calculation is
indeed case sensitive. The third factor that may affect the
final result is the basis set error. This is clearly seen in the case
of OR calculations, where addition of diffuse functions,
especially for hydrogen atoms, is mandatory for proper
calculation of magnetic polarizability tensor. Whereas a
small basis set, such as 6-31G(d) in conjunction with the
B3LYP functional, is routinely used for calculation of
molecular structures, it is desirable to perform optimization
of molecular geometry at a higher level of theory. Errors in
B3LYP/6-31G(d) equilibrium geometries may indeed con-
tribute significantly to deviations of calculated ORs. It
should be noted that ECD is less sensitive to possible errors
of structure calculation. In our calculations, we neglected the
vibrational effect. This effect;not in the strict sense;may
be visualized by comparison of the OR values calculated for
the same conformer structure optimized at different levels of
theory, where the conformers differ slightly by the magni-
tudes of torsion angles. Vibrational effects have been shown
to contribute significantly to the optical rotations and to a
smaller extent to ECD, their evaluation currently being
limited to relatively small molecules.48
Although routinely solvent effects on OR are ignored we
have shown that in the cases of 1-4 change of the environ-
ment to polar, simulated by polarizable continuum model
(PCM), significantly affected both the molecular geometries
and/or energies as well as optical rotations. A conclusion is
that the electrostatic contribution to the solvent effects is of
great importance even though the PCM is of limited accu-
racy.
For flexible molecules any compromise in the choice of
computation method may lead to incorrect prediction of
absolute stereochemistry. The use of “cheap and quick”
methods of calculation in practice may turn out to be
expensive and should be limited to the molecules that are
rigid. In any case, the results of computational experiment
should be carefully evaluated and interpreted.
and limited to those within the 15 kcal mol-1 energy window
were further fully optimized at the DFT/B3LYP/6-31G(d) level
as implemented in the Gaussian03 package.45 This reduced
significantly the number of conformers. Then all stable con-
formers, regardless their relative energies, were reoptimized at
the B3LYP/6-311++G(2d,2p), PCM/B3LYP/6-311++G(2d,2p),
PCM/BHandHLYP/6-311++G(2d,2p), PCM/PBE0/6-311+
+G(2d,2p), and PCM/BP86/6-311++G(2d,2p) levels. These
conformers were the real minima (no imaginary frequencies
have been found). Free energy values have been calculated
and used to obtain the Boltzmann population of conformers
at 298.15 K. Only the results for conformers that differ from
the most stable one by less than 2 kcal mol-1 have been taken
into account for further calculations, following a generally
accepted protocol.13a,49
Optical rotation calculations have been carried out by means
of time-dependent DFT methods, using the hybrid B3LYP
functional and three different basis sets 6-31G(d), 6-311þþG-
(2d,2p), and aug-cc-pVTZ for conformers optimized at the low
and at higher levels of theory (for selected cases, additional OR
calculation at the B3LYP/aug-cc-pVDZ level for geometries
optimized at the B3LYP/6-311þþG(2d,2p) level was per-
formed; however, these results were not further discussed due
to their similarity to the results obtained with the B3LYP/6-
311þþG(2d,2p) method). For all conformers reoptimized with
the use of PCM solvent model the optical rotations were
calculated at the PCM/B3LYP/6-311þþG(2d,2p) level. Lon-
don orbitals (which ensure the origin independency of the
results) have been used. Additionally, PCM/TD-DFT/
B3LYP/6-311þþG(2d,2p) and PCM/TD-DFT/B2LYP/6-
311þþG(2d,2p) calculations of ECD of 1-4 were performed
for all structures reoptimized at higher levels of theory. Rotatory
strengths were calculated using both length and velocity repre-
sentations. In the present study, the differences between the
length and velocity of the calculated values of rotatory strengths
were quite small, and for this reason only the velocity represen-
tations were further used (see also the Supporting Information).
The CD spectra were simulated by overlapping Gaussian func-
tions for each transition according to the procedure previously
described.9e
(1S,2S)-(þ)-2-tert-Butoxycarbonylamino-1-(4-nitrophenyl)-
1,3-propanediol (6). Amino diol 5 (1.7 g, 8 mmol) and (BOC)2O
(3.27 g, 15 mmol) were placed in an agate mortar and ground
from time to time, while the progress of the reaction was
monitored by TLC. After 17 h at room temperature, the mixture
was dissolved in ethyl ether, transferred into separatory funnel,
and washed with 1% HCl. The ethereal solution was dried and
concentrated to give crude product, which was crystallized from
ethyl acetate to give pure 6 (2.24 g, 89.7%): mp 116-117.5 °C;
[R]D þ19.5 (c 1.1, methanol), [R]D þ55.2 (c 1.01, DCM), [R]D
þ57.4 (c 0.1, DCM) [lit.50 mp 112 - 114 °C; [R]D þ74.1 (c 0.1,
DCM); lit.51 for ent-6 mp 113-114 °C, [R]D -22.0 (c 1,
Experimental Section
Computational Details. Preliminary conformer distribution
search was performed by the CAChe WS Pro package44 using
the MM3 molecular mechanics force field. The systematic
search of all possible conformers has been performed using
molecular mechanics method taking into account the degrees of
freedom of the molecule (i.e., different positions, axial or
equatorial, of both the phenyl and the hydroxymethyl groups
and the rotation around the single bond of the hydroxymethyl,
phenyl, and other groups). In particular, we took into account
various conformations of the five-membered ring. The real
minimum energy conformers found by molecular mechanics
1
methanol)]; IR (KBr) cm-1: 3431, 3378, 3243, 1714, 1605; H
NMR (CDCl3) δ: 8.2 (m, 2H), 7.57 (m, 2H), 5.20 (m, 2H), 3.86
(m, 4H), 2.59 (s, 1H), 1.31 (s, 9H); 13C NMR (CDCl3) δ 156.2,
148.8, 147.3, 126.9, 123.4, 80.3, 73.2, 63.7, 56.6, 28.1; ESI MS m/
z 335 [(M þ Na)þ]. Anal. Calcd for C14H20N2O6 (312.13): C,
53.84; H, 6.45; N, 8.97. Found: C, 53.70; H, 6.70; N, 8.84.
(1S,2S)-(þ)-2-tert-Butoxycarbonylamino-3-tert-butyldimeth-
ylsilyl-1-(4-nitrophenyl)-1,3-propanediol (7). To a solution of
compound 6 (0.624 g, 2 mmol) and imidazole (0.334 g, 4.9 mmol)
in DCM (4 mL) was added TBDMSCl (0.33g, 2.2 mmol), and the
(49) Stephens, P. J.; Devlin, F. J.; Cheeseman, J. R.; Frisch, M. J.;
Bortolini, O.; Besse, P. Chirality 2003, 15, S57.
(50) Yuan, J.-L.; Dai, H.-F.; Chen, F.-E. OPPI Briefs 2004, 36, 164–166.
(51) Testa, M. L.; Ciriminna, R.; Hajji, C.; Garcia, E. Z.; Ciclosi, M.;
Arques, J. S.; Pagliaro, M. Adv. Synth. Catal. 2004, 346, 655–660.
(48) (a) Pedersen, T. B.; Kongsted, J.; Crawford, D. T.; Ruud, K.
J. Chem. Phys. 2009, 130, 034310. (b) Lin, N.; Santoro, F.; Zhao, X.; Rizzo,
A.; Barone, V. J. Phys. Chem. A 2008, 112, 12401–12411. (c) Grimme, S.;
Furche, F.; Ahlrichs, R. Chem. Phys. Lett. 2002, 361, 321–328.
8062 J. Org. Chem. Vol. 74, No. 21, 2009

Kwit et al.
JOCArticle
mixture was stirred for 17 h at room temperature. The solution
was washed with water and 20% NH4Cl, and the organic fraction
was dried and concentrated at reduced pressure to afford oily 7 in
quantitative yield, which crystallized on standing and was used in
the next step of the synthesis without further purification. An
analytical sample was digested with hexane to give crystalline 7:
mp 95.5-97.5 °C; [R]D þ14.2 (c 1, methanol); IR (KBr) 3446,
1696, 1606,1600cm-1; 1H NMR(DMSO-d6) δ8.19 (d, J=9.0Hz,
2H), 7.57 (d, J=9.0 Hz, 2H), 6.26 (d, J=9.0 Hz, 1H, disappears
on treatment with D2O), 5.65 (d, J=5 Hz, 1H, disappears on
treatment with D2O), 4.90 (s, 1H), 3.75-3. 70 (m, 2H), 3.56-3.43
C16H24N2O5Si (352.46): C, 54.52; H, 6.86; N, 7.95. Found: C,
54.35; H, 7.32; N, 7.93.
(4S,5S)-(-)-4-Hydroxymethyl-5-(4-nitrophenyl)oxazolin-2-
one (4). To a stirred solution of compound 8 (0.6 g, 1.7 mmol) in
THF (10 mL) was added Et3N 3HF (0.99 g, 6.1 mmol) at room
3
temperature. The reaction mixture was stirred at this tempera-
ture for 20 h and then basified with 5% NaOH, and THF was
evaporated at reduced pressure. The aqueous phase was
extracted with EtOAc, and the organic solution was washed
with H2O and NH4Cl, dried, and concentrated to give TLC-pure
oxazolidinone 4 (0.36 g, 88.7%): mp 142-142.5 °C (ethyl
acetate) [lit.41 mp 137-138 °C (ethyl acetate)]; [R]D -21.8
(c 2.07, methanol), [R]D -21.7 (c 1.01, methanol); HPLC
(m, 1H), 1.23 (s, 7H), 1.05 (s, 2H), 0.88 (s, 9H), 0.06 (s, 6H); 13
C
NMR (DMSO-d6) δ 155.1, 151.7, 146.4, 127.4, 122.9, 77.7, 69.9,
62.3, 57.5, 28.0, 25.8, 17.9, -5.3; ESI MS m/z 449 [(M þ Na)þ].
Anal. Calcd for C20H34N2O6Si (426.22): C, 56.31; H, 8.03; N,
6.57. Found: C, 56.30; H, 7.99; N, 6.60.
(hexane/2-propanol 65:35, 0.5 mL/min, λ = 262.6, tR
=
17.9 min); IR (KBr) 3385, 3268, 1762, 1746, 1694, 1607, 1603
cm-1; 1H NMR (DMSO-d6) δ 8.32-8.29 (m, 2H), 7.99 (s, 1H,
disappears on treatment with D2O), 7.68-7.63 (m 2H), 5.51 (d,
J=4.0 Hz, 1H), 5.24 (t, J=5.3 Hz, 1H, disappears on treatment
with D2O), 3.56 (m, 3H); 13C NMR (DMSO-d6) δ 157.7, 147.5,
147.3, 126.7, 124.0, 77.4, 62.4, 61.0; ESI MS m/z 261 [M þ Na)þ].
Anal. Calcd for C10H10N2O5 (238.2): C, 50.42; H, 4.23; N, 11.76.
Found: C, 50.39; H, 4.35; N, 11.83.
(4S,5S)-(-)-4-tert-Butyldimethylsilyloxymethyl-5-(4-nitroph-
enyl)oxazolin-2-one (8). Compound 7 (1.1 g, 2.58 mmol) in THF
(10 mL) was treated with NaH (0.206 g, 5.16 mmol, 60%
dispersion in mineral oil) at 0 °C under argon atmosphere.
The mixture was stirred at room temperature for 2 h and then
left overnight (19 h) in the refrigerator. To the mixture were
added methanol (5 mL) and 20% NH4Cl (5 mL), and the
organic solvents were evaporated under reduced pressure. The
aqueous phase was extracted with ethyl ether, and then the
organic extracts were dried and concentrated to give yellow oil,
which was purified by column chromatography [silica gel (1:15),
hexane ethyl acetate (80:20)] to supply pure oxazolidinone 8
(0.69 g, 76%) as an oil. It solidified on standing, and as such was
used in the next step of the synthesis. An analytical, crystalline
sample was obtained by digestion of the solid with hexane: mp
78.5-81 °C; [R]D -41.7 (c 1, methanol); IR (KBr) 3385, 3344,
Acknowledgment. This work was supported by Grant No.
N N204 056335 from the Ministry of Science and Higher
Education (MK). All calculations were performed at the
ꢀ
Poznan Supercomputing Center.
Supporting Information Available: All calculated at B3LYP/
6-311þþG(2d,2p) level structures of 1-4, all CD and UV spectra
calculated at different levels for individual conformers of 1-4,
absolute energies of individual conformers of 1-4, values of
optical rotations calculated at various levels for all optimized
structures, Cartesian coordinates for all calculated structures,
and copies of 1H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
3246, 1777, 1749, 1718, 1608 cm-1
8.30-8.25 (m, 2H), 7.59-7.56 (m, 2H), 6.29 (s, 1H), 5.49 (d,
J=3.7 Hz, 1H), 3.85-3.74 (m, 3H), 0.93 (s, 9H), 0.12 (s, 6H); 13
;
1H NMR (CDCl3) δ
C
NMR (CDCl3) δ 158.6, 148.0, 146.1, 126.1, 124.1, 78.8, 64.4,
61.3, 25.7, 18.2; ESI MS m/z 375 [(M þ Na)þ]. Anal. Calcd for
J. Org. Chem. Vol. 74, No. 21, 2009 8063