Determining the absolute configuration of benzopyrenomycin by optical rotation, electronic circular dichroism, and population analysis of different conformations via DFT methods and experiments

Article abstract of DOI:10.1016/j.tet.2013.01.082

In this work, we have studied the absolute configuration of benzopyrenomycin using different density functional theory (DFT) methods, such as optical rotation (OR), electronic circular dichroism (ECD), and conformation distribution analysis for three kinds of Mosher esters at different levels, e.g., B3LYP/6-31G(d), B3LYP/6-311+G(d), and B3LYP/6-311++G(2d,p) in the gas phase and in solution, respectively. Careful investigations for different chiral Mosher esters using DFT theory exhibited the application conditions for certain chiral molecules in absolute configuration determination. Benzopyrenomycin possesses a unique benzo[a]pyrene-type skeleton and shows strong cytotoxicity against various tumor-cell lines.

Full text of DOI:10.1016/j.tet.2013.01.082

Tetrahedron xxx (2013) 1e8
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Determining the absolute configuration of benzopyrenomycin by
optical rotation, electronic circular dichroism, and population
analysis of different conformations via DFT methods and
experiments
,
b
,
,
b
,
,
Qing-Ming Li a 1, Jie Ren a 1, Bei-Dou Zhou b, Bing Bai b, Xin-Chun Liu c
,
*
Meng-Liang Wen d, Hua-Jie Zhu a
,b,
*
a College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002,
PR China
b State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academic of Sciences,
132# Lanhei Road, Kunming 650204, PR China
c Graduate School of CAS, Beijing 100049, PR China
d Key Laboratory of Medicinal Chemistry for Natural Resources, Ministry of Education, Yunnan University, Kunming, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 June 2012
Received in revised form 17 January 2013
Accepted 28 January 2013
Available online xxx
In this work, we have studied the absolute configuration of benzopyrenomycin using different density
functional theory (DFT) methods, such as optical rotation (OR), electronic circular dichroism (ECD), and
conformation distribution analysis for three kinds of Mosher esters at different levels, e.g., B3LYP/6-31G(d),
B3LYP/6-311þG(d), and B3LYP/6-311þþG(2d,p) in the gas phase and in solution, respectively. Careful
investigations for different chiral Mosher esters using DFT theory exhibited the application conditions for
certain chiral molecules in absolute configuration determination. Benzopyrenomycin possesses a unique
benzo[a]pyrene-type skeleton and shows strong cytotoxicity against various tumor-cell lines.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Absolute configuration assignment
DFT computation
Optical rotation
Electronic circular dichroism
Conformational analysis
1. Introduction
calculated with the experimental results, good agreements were
recorded between the computational and experimental data.3 After
It remains a challenge to determine the absolute configuration
of complex compounds by both experimental and theoretical
approaches. One potential solution is to use empirical methods
such as the widely used Mosher method,1 and optical rotation (OR)
where the OR of an unknown chiral compound is compared with
that of a structurally similar chiral compound. However, the
wrongly assigned absolute configuration of oruwacin 1 has been
predicted by comparing its OR with that of 2.2 Here we use density
functional theory (DFT) method with different options (geometry
optimizations, solvent model) to determine the absolute configu-
ration of benzopyrenomycin (3). Additionally, we synthesized an-
alog (4A) of 4 (including 4) and compared 4A’s OR and ECD
combination of all evidences together, we demonstrated that
the absolute configuration of 3 has been wrongly predicted as
(2R,3S) by the empirical Mosher method and correlation of exper-
imental OR.4a
As the first example from nature, benzopyrenomycin (3) has
a unique benzo[a]pyrene-type skeleton4b and shows strong cyto-
toxic activity against various tumor-cell lines. For instance, benzo-
pyrenomycin exhibited GI50 of 3.2 mg/mL and 4.2 mg/mL for L-929
and K562 cell lines, respectively. The absolute configuration of
benzopyrenomycin (3) was reported by Hertweck et al., which is
the same as that of rubiginone A2 (4) (2R,3S), based on their similar
molecular structures and close OR values (þ38ꢀ for 3 and þ50ꢀ for 4
in chloroform).4a,5 Meanwhile, Hosokawa et al. concluded that the
absolute configuration of 3 was the same as that of 4 based on the
1H NMR shift differences of the synthesized (R)- or (S)-Mosher ester
of 5 whose structure was eventually converted to 3.6a However,
when using Mosher ester to determine the absolute configuration
* Corresponding authors. Fax: þ86 312 5994812; e-mail addresses: zhuhuajie@
hotmail.com, hjzhu@mail.kib.ac.cn (H.-J. Zhu).
1
These authors contributed equally to this work.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.082
Please cite this article in press as: Li, Q.-M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.01.082

2
Q.-M. Li et al. / Tetrahedron xxx (2013) 1e8
O
O
O
O
12
11
O
H
11
O
8
H3C
OMe
HO
H
O
H
5
10
H
12
H
H O
4
O
O
H
1
O
H
OMe
(1R,5S,8S,9S,10S)-2,
iso plumericin
3
(1R,5S,8S,9S,10S)-1, oruwacin
Exp.: [ ]D
Calcd.: [ ]D
+ 198
+ 195
Exp.: [ ]D +193
Calcd.: [ ]D -193
OMe
1
R
1
O
14
O
O
12a
O
12
O
11
2
10
3b
3a
10
11
6
9
OH
S
OH
3
10a
10b
OH
5a
4
8
4
6a
6
7
5
MeO
O
O
MeO
O
Bezopyrenomycin, 3
Rubiginone A2, 4
4A
Exp. [ ]D +75 in CHCl3
[ ] : +38 in CHCl
[ ] : +50 in CHCl
Exp.
Exp.
D
3
D
3
of 5 analogs, wrong predictions could be made because these chiral
molecules have a bulky group.6b As a result, the absolute configu-
ration of 3 might be wrongly determined, due to the incorrect
distribution of the major and minor conformations predicted by
Mosher method. Moreover, the synthetic results did not provide
sufficient evidences to support the conclusion that (þ)-3 should
have (2R,3S) configuration.7 In the present work, we have carefully
investigated the ORs and ECDs of 3 and 4 using eight DFT methods
(see the following Computational section for details) via Gaussian
03 package,8 and compared our results with the current OR com-
putational methods that are reliable for rigid compounds.2,9,10
the low level to the high level. In our study, all geometries with
relative energy at 0e2.5 kcal/mol were selected for OR computa-
tions at the B3LYP/6-311þþG(2d,p) level in the gas phase (method
1). Sequentially, we used single point energy (SPE) data that were
computed at the B3LYP/aug-cc-pVDZ level in CHCl3 via PCM model
in the OR computation (method 2). All B3LYP/6-31G(d)-optimized
geometries were re-optimized at the B3LYP/6-31þG(d,p) level in
the gas phase. The OR values were obtained at the B3LYP/6-
311þþG(2d,p) level (method 3), and SPE at the B3LYP/aug-cc-
pVDZ level in CHCl3 via PCM model was then used in the OR com-
putation again (method 4). To simulate the solvent effect on ge-
ometries, we performed the optimizations at the B3LYP/6-311þG(d)
level in chloroform using PCM model for all conformers. ORs were
then computed at the B3LYP/6-311þþG(2d,p) level in the gas phase
(method 5), followed by the OR calculations at the same level in
CHCl3 using PCM model (method 6). Furthermore, we investigated
the effect of different optimization methods by computing all the
geometries at the B3LYP/6-311þþG(2d,p) level in the gas phase, and
calculating their OR values at the B3LYP/6-311þþG(2d,p) level
(method 7). The SPE data were then used for OR computations
(method 8). In our recent study, it was found that the use of total
electronic energy (TEE), zero-point energy (ZPE, vibrational cor-
rection), and free Gibbs energy (GFE) in OR computations for small
OR compounds gave good agreements in OR prediction.11b Consid-
ering other results that ZPE (vibrational correction) is important for
chiral compounds with small OR values,11c thus, TEE, ZPE, and GFE
are also considered in OR computations.
2. Results and discussion
2.1. Computational methods
The methods used here are according to previous reports.9,10
First, conformational studies were performed using Amber and
MMFF94S force field, respectively. We selected those geometries
with relative energy from 0 to 5.5 kcal/mol using Amber force field
for the optimizations at the B3LYP/6-31G(d) level. If the confor-
mations obtained via MMFF94S force field were more than 300,
only the first 100 geometries with lower energy were used in the
computations at the B3LYP/6-31G(d) level. We made sure that all
the conformations with very low energy were selected.
2.1.2. Circular dichroism (CD) computation. The major conforma-
tions obtained at the B3LYP/6-311þþG(2d,p) level were used in CD
computation at the B3LYP/6-311þþG(2d,p) level. Boltzmann sta-
tistics were used for final CD simulations. A total of 100 excited
states were computed.
2.1.3. Conformational analysis. All B3LYP/6-31G(d)-optimized ge-
ometries of 6, 7, and 8 at the relative energy of 0e1.5 kcal/mol were
re-optimized at the B3LYP/6-311þG(d) and B3LYP/6-311þþG(2d,p)
levels, respectively. TEE and GFE data were used to study the con-
formations with lowest energy for both major and minor confor-
mations of 6 that were predicted by Mosher approach. It was found
that TEE could also give good prediction for 6. On the other hand, it
2.1.1. OR computation. The literature results showed that OR sign
obtained at the lower level may differ from those predicted at higher
basis sets.11a Thus, we computed the ORs using eight methods, from
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Q.-M. Li et al. / Tetrahedron xxx (2013) 1e8
3
is impossible at the present to compute frequency to obtain the GFE
and ZPE data for one more thousand of conformations of big mol-
ecule of Mosher esters of 7 and 8 at B3LYP/6-311þG(d) or B3LYP/6-
311þþG(2d,p) level. Thus, the TEE data were used for further
conformation analyses for Mosher esters of 7 and 8. The distribu-
tion of geometries with different energy at the B3LYP/6-31G(d)
level can be found in Supplementary data.
have S configuration. The recorded OR for (2R,3S)-4 was þ46, this is
closer to the reported OR magnitude of þ50 for (2R,3S)-4.4aed The
data are almost the same as the OR of þ47.4e On the other hand, if it
is (2R,3R) configuration, its OR should be ꢁ106 in chloroform that
had been found in Yoshihama’s reports.4e The predicted OR for
(2R,3S)-4 is from þ14 to þ87, mostly in the range of þ33 to þ73. The
predictions agree well with the experimental results. Therefore, the
theoretical methods used here are reliable. In contrast, the pre-
dicted OR for (2R,3S)-3 was in the range of ꢁ12 to ꢁ86, mostly, from
ꢁ29 to ꢁ50. The OR sign is opposite to the experimental result
(þ50). Since the relative configuration of (þ)-3 was well estab-
lished as (2R,3S) or (2S,3R), the negative OR value from ꢁ29 to ꢁ50
calculated for (2R,3S)-3 hints that the obtained (þ)-3 should be
absolute configuration of (2S,3R).
2.2. Computational results for OR
The results are listed in Table 1.7 In all the methods, we found
that (2R,3S)-3 has negative OR values between ꢁ28ꢀ and ꢁ86ꢀ,
mostly ranging from ꢁ28ꢀ to ꢁ50ꢀ, using the TEE. The OR values
based on vibrational corrections (ZPE) are also negative and most of
them are in the range of ꢁ16ꢀ to ꢁ32ꢀ. A þ9.5 of OR was recorded
when free energy was used for B3LYP/6-31G(d)-optimized geom-
etries in method 1. However, other two ORs were ꢁ14 to ꢁ28, re-
spectively, at the higher levels. It looks that the free energy data
recorded at the B3LYP/6-31G(d) level was not the best in OR
computations. Meanwhile, the predicted OR values for (2R,3S)-4 are
mostly in the range of þ2.1ꢀ to þ104ꢀ using TEE, ZPE, and GFE data,
mostly from þ32ꢀ to þ87ꢀ. The results are in good agreement with
the experimental results. Relatively, to use the SPE in solutions
predicted lower OR values such as the data in method 8.
2.3. Computational results for ECD
Evidences from OR support that (þ)-3 should have (2S,3R)
mentioned above. Another independent evidence, such as ECD
should be also important and valid. No experimental ECD was found.
Thus, it is impossible to compare the ECD of (2R,3S)-3 with the ex-
perimental results when we can compare the predicted ECD of
(2R,3S)-4 with the experimental ECD. However, if one method can
predict the absolute configuration for (2R,3S)-4 well via comparing
its ECD to the experimental results, in this case, it is possible to
compare the predicted ECD for (2R,3S)-3 to the computed (2R,3S)-4
to see their differences. This is similar with the results happened in
OR computations, the signs for the computed ORs of (2R,3S)-3 and
(2R,3S)-4 are reversed. Therefore, the absolute configuration of
(2R,3S)-3 was used in ECD computations first, and the same absolute
configuration of (2R,3S)-4 was computed too using TEE, ZPE, and
GFE data, respectively, in ECD simulations.2,10 Both ECDs looked like
that compounds 3 and 4 had reversed stereo-structures using all
three energy data in simulations (Fig. 1(a)e(c)). Especially, that the
ECD simulated using GFE had large differences between 3 and 4. The
ECD spectra indicate that the two compounds have different abso-
lute configurations at C-2 and C-3. This independent evidence
supports the conclusion from OR data.
Due to that (2R,3S)-4 was not obtained at the first time as
mentioned above, only an analog of 4, (2R,3S)-4A was obtained.3
After that, (2R,3S)-4B was obtained. Thus, we study (2R,3S)-4B.
The ECD was computed at the B3LYP/6-311þþG(2d,p)//B3LYP/6-
311þþG(2d,p) level. The ECD of (2R,3S)-4B simulated using GFE
was close to the experimental results (Fig. 1(d)). After UV correc-
tions, the simulated ECD is much close to the experimental ECD
(Fig. 1(e)). Also, the computed ECD of (2R,3S)-4B is also the same as
the ECD computed for (2R,3S)-4 using all of TEE, ZPE, and GFE data
(Fig. 1(f)e(h)). After (2R,3S)-4 was obtained recently, it was used for
ECD determination again. Its ECD is the same as that of (2R,3S)-4B,
and also almost the same as that of (2R,3S)-4A (Fig. 1(i)). Obviously,
it indicates that 4A, 4B, and 4 have the same absolute configuration.
It suggested that the methods used here are reliable for the pre-
dictions of ECD for 4 and 4A and 4B.
Table 1
Computed OR values using different methods
(2R,3S)-3
(2R,3S)-4
[
a
]
þ38
þ50
D exp
Method 1a
Method 2b
Method 3c
Method 4b
Method 5d
Method 6e
Method 7f
Method 8b
ꢁ50.4/ꢁ16.2g/þ9.5h
þ48.7/þ47.7g/þ87.2h
þ18.7
ꢁ44.1
ꢁ27.8/ꢁ26.8g/ꢁ28.4h
þ33.4/þ72.6g/þ104.7h
þ34.1
ꢁ40.5
ꢁ28.9
þ32.4
ꢁ86.1
þ2.12
ꢁ49.2/ꢁ28.6g/ꢁ14.0h (CHCl3)
ꢁ12.2
þ38.4/þ61.4g/þ87.8h
þ13.5
a
B3LYP/6-311þþG(2d,p)//B3LYP/6-31G(d), total electronic energetics are used in
OR computations.
b
Single point energy at the B3LYP/aug-cc-pVDZ level in chloroform via PCM
model was used in OR computations.
c
B3LYP/6-311þþG(2d,p)//B3LYP/6-31þG(d,p).
d
B3LYP/6-311þþG(2d,p)//PCM(CHCl3)/B3LYP/6-311þG(d).
e
PCM(CHCl3)/B3LYP/6-311þþG(2d,p)//PCM(CHCl3)/B3LYP/6-311þG(d).
f
B3LYP/6-311þþG(2d,p)//B3LYP/6-311þþG(2d,p).
g
Vibration corrections are performed in OR computations.
h
Free energy data were used in OR computations.
To determine the correct or not of the methods used here for OR
predictions of 3 and 4, the best way is to synthesize 3 or 4 using
standard methods. However, to synthesize 3 is a huge job. Thus, we
decided to synthesize 4 via a commercially available (2R,5R)-
(þ)-dihydrocarvone (6). Unfortunately, it failed to obtain 4 in this
route after we firstly synthesized 4A as a model in study.3 Com-
pound (2R,3S)-4A had the OR of þ75 in chloroform, and (2R,3S)-4B
had þ79. Both had good agreement in ORs although 4A had no eOH
on C-7. At the same time, (2R,3S)-4B just had no Me on eOH group
of C-7 compared to (2R,3S)-4, both had the same skeleton. There-
fore, it can be used as a standard sample to test the theoretical
methods used here. The ORs for (2R,3S)-4B mostly were from þ31
to þ119 in the gas phase using methods 1, 3, 5, and 7, respectively.
The computed OR sign for (þ)-(2R,3S)-4B agreed well with exper-
imental results.3 Very recently, 4 was obtained using the same
methods that we used in syntheses of 4A and 4B (Scheme 1).3
Furthermore, in its ROESY experiments, the NOE between the H-3
and the eMe on C-2 was observed, it hints that the H-3 and eMe
locate at the same side. Since C-2 has R configuration, C-3 should
Based on the calculated ECD and OR results and the fact that the
relative configuration of 3 was well established, we propose that the
absolute configuration of (þ)-3 is (2S,3R), namely, (þ)-(2S,3R)-3.
2.4. Computational results for conformation analysis
The difficulty is to understand why the Mosher method pre-
dicted a wrong result in absolute configuration determination for
an intermediate 5 in total synthesis. Indeed, Mosher approach is
a type of NMR method that has been used to determine the abso-
lute configurations of secondary alcohols or amines. It has a very
strict range used in absolute configuration determinations. It was
introduced by Raban and Mislow,12 and further developed by
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4
Q.-M. Li et al. / Tetrahedron xxx (2013) 1e8
O
Br
O
O
O
Ref. 3
O
O
AcO
OMOM
ο
(1) toluene
,90 C
(2) MeOH/H2O
reflux
HO
O
7 (total 32%)
(2R,5R)-6
8 (40%)
O
O
O
O
(1) Ag
2O/MeI
CH3
CN,reflux
OH
h / O2
OMOM
EtOAc, rt
(2) 3N HCl
EtOH,reflux
O
O
HO
O
4, Rubiginone A
2
(52%)
9 (84%)
Scheme 1. The synthetic route to (2R,3S)-rubiginone A2.
1
2
O
O
O
O
O
O
O
12
10
7
3a
4
9
8
11
6
3
OH
OH
OH
6a
5a
5
O
OH
MeO
O
Rubiginone A2, 4
(2R,3S)-4B[Ref. 3]
Exp. [ ]D: +79
(2R,3S)-4A[Ref.3]
Exp. [ ]D: +75
[Ref. 4]
[ ] : +50 in CHCl
Exp.
3
D
Or: +46 in our exp.
Calcd.[ ]D: +14 to +87
Calcd. [ ]D: +31 to +119
Calcd. [ ]D: +55 to +91
Lewis,13 Trost,14 Rigura,15 and other chemists.6b In the existing
protocol, predicting the absolute configuration requires the fol-
lowing two conditions: (1) atoms H1, C1, O1, C2, O2, C3, and C4
should be in the same plane (MTPA plane) as illustrated below, e.g.,
10 in Fig. 2; (2) H1 and O2 must be at the same side (direction) of
the major conformer so that the phenyl ring has proper effect on
the electronic current induced proton resonance. If the populations
of the major and minor conformations were not properly assigned,
wrong prediction of the absolute configuration could be made by
the Mosher (NMR) method.
To examine the existence of MTPA plane and the correct pop-
ulation of the major and minor conformations, both of which are
required to predict the absolute configuration of chiral compounds
correctly using NMR (Mosher) methods, we applied the computa-
tional methods to 10 first, whose conformational searches were
carried out.7 Total electronic energy and free energy data were used
in conformational analyses for Mosher esters 10a-1, 10a-2, 10b-1,
and 10b-2. It was found that major isomer was 10b-1 for (S)-ester
predicted using total energy, which agreed with the Mosher’s
prediction. However, it changed to 10b-2 predicted by the relative
energy data when B3LYP/6-31G(d)- and B3LYP/6-311þþG(2d,p)-
optimized geometries were used (Fig. 3). The wrong prediction
looks similar to that the wrong OR value of 3 using GFE data ob-
tained at the B3LYP/6-31G(d) level. Indeed, to compute the GFE for
all the Mosher esters of 11 and 12 is an extremely difficult task since
their stable conformations are more than one thousand obtained at
the B3LYP/6-31G(d) and B3LYP/6-311þG(d) levels. Indeed, to use
TEE can also give good agreements at the B3LYP/6-311þþG(2d,p)//
B3LYP/6-311þG(d) level.11b Similar results that we recently re-
ported in chiral catalysts conformation analyses had the same
predictions using total energy data.16 Thus, TEE data were used in
conformation analysis for other Mosher esters of 11 and 12.
The computational results showed that the MTPA plane was
present. The predicted major conformations of 10 were 10a-2 for
(R)-Mosher ester at the B3LYP/6-31G(d) level. The predicted major
one changed to 10a-1 using B3LYP theory at the basis sets of 6-
311þG(d) and 6-31þþG(2d,p) levels, respectively. Mosher method
can be used to predict the absolute configuration of secondary al-
iphatic alcohols, e.g., 10. Thus, the major conformation of 10 must
be 10a-1 (Fig. 3).17a Moreover, the ratio of the major (10a-1) to
minor (10a-2) computed for (R)-Mosher ester 10 was 5.9:4.1 and
7.0:3.0 at the 6-311þG(d) and 6-31þþG(2d,p) levels, respectively.
Though compound 10 is different from cyclohexanol, the ratio of
the major to minor conformation is almost the same as the ex-
perimental results using the band profile analysis of the IR ad-
sorptions (in CCl4) on the (R)-MTPA esters of several cyclohexanols,
where the (R)-Mosher’s conformation of the MTPA moiety is much
more preferable (7:3) than the one with CF3 groups anti to the ester
carbonyl.17b This observation lays the foundation for using the
current Mosher method to derive the absolute configuration of
secondary alcohols.
The same methods were used for the conformation searches for
(R)- and (S)-Mosher ester of (2R,3S)-11. In total 726 geometries
were computed at the B3LYP/6-31G(d) level. The conformations
with relative energy of 0e1.5 kcal/mol were re-optimized at
the B3LYP/6-311þG(d) level. Given the high cost and long time
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Q.-M. Li et al. / Tetrahedron xxx (2013) 1e8
5
Fig. 1. Comparisons of the computed ECD spectra for (2R,3S)-3 and (2R,3S)-4 simulated using TEE (a), ZPE (b), and GFE (c). Comparisons of computed ECD for (2R,3S)-4B and its
experimental ECD without UV corrections (d) and with UV corrections (e). Comparisons of the computed CD spectra for (2R,3S)-4 and (2R,3S)-4B using TEE (f), ZPE (g), and GFE (h).
The experimental ECD for (2R,3S)-4, (2R,3S)-4A, and (2R,3S)-4B (i).
O3(Ph)
current from phenyl ring on the proton resonance, as well as their
differences.
(R)-MTPA
(OMe)
(S)-MTPA
OMe
Ph
The conformers with the lowest energy and second lowest
energy for (R)-Mosher ester were 11a-1 and 11a-2, at the B3LYP/
6-31G(d) level, respectively. However, to correctly use Mosher
methods, it requires 11a-1 being the minor isomer. Thus, the pre-
diction does not agree with that the Mosher method predictions.
The above two changed to 11a-2 (54%) and 11a-1 (46%) at the
B3LYP/6-311þG(d) level, respectively. This does not match
the prediction of Mosher method yet. The major and minor con-
formations for (S)-Mosher esters of 7 were 11b-1 and 11b-2, re-
spectively, at the B3LYP/6-311þG(d) level, which do not meet the
requirements of Mosher method. In the actual experiments per-
R2
O1
O
C3
C1
C2
CF3
R1
C4
H H1 OO2
MTPA plane
R1
10: R1=Me, R2=Et
R2
Fig. 2. Mosher ester MTPA plane and its predominate conformations.
formed for 11, the observed Dd sign caused by the effect of p-cloud
of phenyl ring on the other 1H shifts reversed, indicating that the
predicted configuration was incorrect. The C-3 in 3 displays (R)
configuration, which agrees well with the prediction using OR
values. The population difference between (R)-11a-1 and (R)-11a-2
at the B3LYP/6-311þG(d) level is 8%. The population between (R)-
10a-1 and (R)-10a-2 is 18%. The distribution differences between
(S)-11b-1 and (S)-11b-2 (16%) are also less than one, such as 41%
between (R)-10b-1 and (R)-10b-2. The small population differences
indicate that the electronic effect recorded by NMR is small, which
requirement for such a big molecule, we did not apply the
method at the B3LYP/6-311þþG(2d,p) level at present time. All the
predicted major and minor conformations are illustrated below
(Fig. 4).
If Mosher method could be modified to determine the absolute
configuration of 11, the correct major conformation should be 11a-1
for (R)-Mosher ester, and the major one for (S)-Mosher ester should
be 11b-1. Consequently, NMR can record the effect of electronic
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6
Q.-M. Li et al. / Tetrahedron xxx (2013) 1e8
H
H
O
O
OMe
CF3
H
O
Et
Et
H
CF3
OMe
Et
O
CF3
OMe
Et
O
O
Me
Me
O
Me
O
Me
F3C
MeO
(R)-Mosher 10a-1
(R)-Mosher 10a-2
(S)-Mosher 10b-1
(S)-Mosher 10b-2
major
minor
major
minor
Mosher Prediction
ΔE1/(%)
ΔE2/(%)
ΔE3/(%)
0.443 (32%)
0.518 (29%)
0.650 (25%)
Calcd.
0.279 (38%) *
0.000 (59%)
0.000 (70%)
0.000(62%)
0.211(41%)
0.488(30%)
0.000 (68%)
0.000 (71%)
0.000 (75%)
Yes
Yes
Yes
Agreement
Yes
ΔG1 (%): 0.193 (42%)
ΔG2 (%): 0.000 (68%)
ΔG3 (%): 0.000 (69%)
0.000 (58%)
0.442 (32%)
0.468 (31%)
Yes
0.236 (40%)
0.000 (84%)
0.711 (23%)
No
0.000(60%)
0.975 (16%)
0.000 (77%)
No
Agreement
Yes
* Data in italic did not agree with the predicteion as the computed. ΔE: relative energy, ΔG: relative free energy.
ΔE1 and ΔG1: Energy at the B3LYP/6-31G(d) level; ΔE2and ΔG2: at the B3LYP/6-311+G(d) level;
ΔE3 and ΔG3: B3LY/6-311++G(2d,p)
Fig. 3. Predicted major and minor conformers for Mosher esters 10 by Mosher and DFT computations.
2'
5'
O
4'
3'
1'
N
O
17
Me
O
O
16
15
1
13
Me
12
12a
11
14
MeO
2
10
3
3b
Ph
10a
5b
5a
OMe
CF3
9
10b
6
O
O
3a
4
8
7
6a
5
MeO
O
11, (R) or (S)-Mosher ester
Ar= big aromatic ring residue, R= C2*-containing residue
H
H
O
O
OMe
CF3
H
O
R
R
H
CF3
OMe
R
O
OMe
R
CF3
O
O
Ar
Ar
O
Ar
O
Ar
F3C
MeO
(R)-Mosher 11a-2
(S)-Mosher 11b-2
(R)-Mosher 11a-1
(S)-Mosher 11b-1
major
minor
major
minor
Mosher Prediction
ΔE /(%)
ΔE2/(%)
0.000/(67%)
0.000/ (54%)
0.0904/(46%)
0.000/(58%)
0.504 (30%)
0.0847 (46%)
0.000 /(54%)
0.200 /(42%)
Calcd.
1
No
No
No
No
Agreement
ΔE1: obtained at the B3LYP/6-31G(d) level. ΔΕ2: Β3LYP/6-311+G(d)
Fig. 4. Differences of energy between two pairs of conformers for (R)- and (S)-Mosher esters 11.
is supported by the very small Dd data (generally less than
0.01 ppm) except for CH3-13.
The relative energy (DE) between 12a-1 and 12a-2 at the B3LYP/
6-31G(d) level is close to zero, which also occurs to 12b-1 and 12b-
2. This difference increases to about 0.24 kcal/mol at the
6-311þG(d) and 6-311þþG(2d,p) basis sets. The predicted major
and minor conformations are those that the Mosher ester required.
Compound 7 has a very long side chain and a bulky aromatic
ring, and its Dd may not obey the empirical rule, as pointed out by
Likewise, the correct major conformation is 12a-2 for (R)-Mosher
ester, and 12b-2 for (S)-Mosher ester. Thus, the stable conformations
of (R)- and (S)-Mosher ester (12) of (2R,3S)-4 were searched using all
three methods. Their relative energy data and populations are listed
together with the corresponding geometries (Fig. 5).
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Q.-M. Li et al. / Tetrahedron xxx (2013) 1e8
7
O
R=
O
MeO
H
O
H
H
O
O
O
OMe
H
H
O
O
H
OMe
O
O
H
OMe
O
O
O
O
R
R
R
R
H
MeO
(R)-Mosher 12a-1
(R)-Mosher 12a-2
(S)-Mosher 12b-1
(S)-Mosher 12b-2
Mosher Prediction
minor
major
minor
major
Calcd. E1/(%)
E2/(%)
0.0144 (49.5%)
0.245 (39.8%)
0.243 (39.9%)
0.000 (50.5%)
0.000 (60.2%)
0.000/(60.1%)
0.0107 (49.6%)
0.268 (38.9%)
0.265 (39.0%)
0.000 (50.4%)
0.000 (61.1%)
0.000 (61.0%)
E3(%)
Yes
Yes
Agreement
Yes
Yes
Fig. 5. Predicted major and minor conformers for Mosher esters of 4 (12a and 12b) by Mosher and DFT computations.
+45
+5.0
H
*RO H
O
*RO
O
H
-23.5
-16.5
OH
H
-0.5
-6.0
H
+42.5
OH
H
H
H
H
-41.5
-15.5
0
H
H
+48.5
H
10
H
H
H
H
OH
OH
13
14
R*= (R)- or (S)-Mosher ester moiety, the number labelled near
Δδ
atom is the
value.
Fig. 6. Two pairs of stable conformations’ OR, relative energy, and the contribution to the total OR.
Kakisawa.6b For example, the Dd values of sipholenol-A (13) and
episipholenol-A (14)18 have exhibited random changes.
We point out that the OR values of 3 and 4 are determined by
two parts: the two stereogenic centers and the helical structure. It
is well known that helical structures generally produce large OR
values. Thus, the direction of OR value (positive or negative) de-
pends on the OR magnitude of most stable helical conformation. As
expected, the two helical geometries that are the most and second
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8
Q.-M. Li et al. / Tetrahedron xxx (2013) 1e8
R. G. Science 1979, 206, 1309e1311; (e) Kimura, K.; Kanou, Fu.; Koshino, H.;
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most stable conformations have shown opposite OR directions. For
example, two pairs of B3LYP/6-311þþG(2d,p)-optimized helical
conformations have almost the same absolute OR values but op-
posite directions for 3, and they make over 70% contribution to the
total OR. Similarly, four conformations have made about 80% con-
tributions to the total OR of 4. The results are summarized in Fig. 6.
J. Antibiot. 1990, 43, 967e976.
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3. Conclusion
Empirical methods mentioned in the text have played important
roles in determinations of absolute configurations. However, their
use conditions block their more widely uses. In contrast, quantum
methods have more widely use ranges than the empirical methods.
With the development of supercomputers, quantum methods in-
cluding other mathematic methods should be encouraged in as-
signment of absolute configuration for chiral compounds.
Acknowledgements
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Supplementary data
Material of computed OR, ECD, and experimental results for
all compounds. Supplementary data associated with this article
can be found in the online version, at http://dx.doi.org/10.1016/
j.tet.2013.01.082.
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Please cite this article in press as: Li, Q.-M.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.01.082