333
Research Article
Received: 26 August 2008 Revised: 30 November 2008 Accepted: 3 December 2008 Published online in Wiley Interscience: 10 February 2009
(www.interscience.com) DOI 10.1002/mrc.2396
The application of empirical methods of 13C
NMR chemical shift prediction as a filter for
determining possible relative stereochemistry
Mikhail E. Elyashberg,a Kirill A. Blinova and Antony J. Williamsb∗
The reliable determination of stereocenters contained within chemical structures usually requires utilization of NMR data,
chemical derivatization, molecular modeling, quantum-mechanical (QM) calculations and, if available, X-ray analysis. In this
article, we show that the number of stereoisomers which need to be thoroughly verified, can be significantly reduced by the
application of NMR chemical shift calculation to the full stereoisomer set of possibilities using a fragmental approach based on
HOSE codes. The applicability of this suggestedmethod is illustrated using experimental data published for a series of complex
chemical structures. Copyright c© 2009 John Wiley & Sons, Ltd.
Keywords: NMR; 1H; 13C; chemical shift prediction; stereochemistry
Introduction
A number of different methods of NMR chemical shift prediction
have been applied to the process of molecular structure
elucidation and validation. Empirical methods are attractive since
they are fast enough and fully automatic. The fastest NMR spectra
calculations are provided using an incremental approach and offer
a computational speed of 6000–10 000 chemical shifts per second
on a normal desktop computer (ca 2007) and provides an average
chemical shift deviation for carbon NMR of 1.8 ppm.[1,2] Spectral
prediction utilizing artificial neural networks provides similar
speed and accuracy performance.[1,2] The third most popular
empirical method is slower and is based on the application of a
database containing the reference structures with assigned 13C
or 1H chemical shifts. The target and reference structures are
described by means of HOSE codes[3] and this allows prediction
of the chemical shift of an atom from the target structure using
the chemical shifts of the reference structures as the basis. In
the ACD/NMR predictor,[4] the prediction algorithms use a library
containing 185 000 structures with NMR chemical shifts assigned
to carbon and hydrogen atoms. If information regarding the
relative stereochemistry of a given atom ai and its environment
is known then these data are also coded into the reference
structures. To predict the chemical shift of an atom ai in the
target structure, its HOSE code is compared with the codes of the
corresponding atoms in the reference structures. As a result of
statistical processing of the chemical shifts assigned to all ‘atom-
twins’ detected in the reference structures, the chemical shift of
an atom from the target structure is predicted. A strategy based
on combining all mentioned methods was suggested.[5,6] It allows
selection of the most probable structure from the output file of an
expert system developed for the molecular structure elucidation.
At the same time a series of articles have been published
espousing the value of ab initio quantum-mechanical (QM)
approaches for NMR chemical shift calculations (for instance,[7 – 12])
and most frequently the GIAO option of the DFT method[13]
has been employed for the calculation of 1H and 13C chemical
shifts. It was shown that DFT-based methods can be applied for
the selection of a preferred structural hypothesis by means of
comparing the predicted chemical shifts with those determined
experimentally. This approach was also an efficient tool for
evaluating the different conformers of flexible molecules as well
as the elucidation of the most probable stereoisomers.[14 – 17]
In our previous report[18] we have shown that empirical
methods of NMR chemical shift prediction can be successfully
used at the selection stage of structural hypotheses which
are verified further with application of molecular geometry
optimization and QM chemical shift prediction. In this regard
we hypothesize that empirical methods can help in preliminary
selection of a set of the most probable stereoisomers for their
subsequent verification by additional experimental techniques
and QM chemical shift predictions. This may be possible since
the stereocenters of structures included into the ACD/CNMR
database and the stereochemistry is taken into account by the
NMR chemical shift prediction algorithms. The incremental and
neural nets based algorithms of chemical shift prediction also use
the stereochemistry information related to the atoms included
into 3–6-membered cycles.[2] It was interesting to know whether
this information can be useful for stereochemistry determination.
We have tested our hypothesis using a series of examples.
We have used examples from recent literature (2007–2008) for
novel structures for which relative stereochemistry was reported.
These structures are deliberately absent from the ACD/CNMR
database. The application of empirical methods of 13C NMR
chemical shift prediction is shown to allow the selection of a
∗ Correspondence to: Antony J. Williams, ChemZoo Inc., 904 Tamaras Circle,
Wake Forest, North Carolina 27587, USA.
E-mail: antony.williams@chemspider.com
a Advanced Chemistry Development, MoscowDepartment, 6 Akademik Bakulev
Street, Moscow 117513, Russian Federation
b ChemZoo Inc., 904 Tamaras Circle, Wake Forest, North Carolina 27587, USA
Magn. Reson. Chem. 2009, 47, 333–341 www.soci.org Copyright c© 2009 John Wiley & Sons, Ltd.

334
M. E. Elyashberg, K. A. Blinov and A. J. Williams
set of the most probable stereoisomers and always includes the
genuine stereoconfiguration.
Results and Discussion
Fattorusso et al.[15] utilized DFT chemical shift computation to
confirm the most probable stereoisomer of artarborol, 1, a
rare nor-caryophyllane derivative, isolated by the authors[15] and
structurally characterized by both 1D and 2D NMR spectroscopic
methods.
1
2
3
4
5
6
7
8
9
O
10
11
12
HO
13
CH3
14
CH3
15
CH3
16
H
17
H
18
H
19
1
To select the most probable stereoisomer the authors[15] carried
out a series of investigations. Structure 1 contains five stereogenic
carbons (numbered 1–5 on structure 1) with four of them at
junctions between the 9-membered ring and the small ring cycles,
while both cis- and trans- junctions of rings adjacent to the
9-membered core are possible in natural caryophyllanes.
A combination of 2D ROESY experiments with Mosher’s
modified method[19] was used to assess the absolute configuration
of C-2 (R) and allowed the authors[15] to reduce the total number
of possible stereoisomers to the following four (Fig. 1):
Further selection was made by analyzing the scalar coupling
constants and additional spatial couplings across the entire
molecule for which all candidate structures were subjected
to a conformational search. As a result, structures B and D
were rejected at the first step, structure C was then excluded
and finally stereoconfiguration A was assigned to artarborol.
To support this stereochemical assignment each conformation
of the stereoisomers A and C were fully optimized by the
authors[15] and the NMR chemical shifts were calculated using
the GIAO option of the MPW1PW91/6-31G(d,p) DFT method.[20] A
Boltzmann-weighted average of the 13C NMR chemical shifts for
all carbon atoms in the low-energy conformers was calculated for
each configuration, using the ab initio standard free energies
as weighting factors.[21] The total processing time for each
molecule was approximately 60 h (PC Pentium IV). A comparison of
calculated chemical shifts with those determined experimentally
for structures A and C showed that deviations were smaller for
structure A thereby confirming the validity of the solution.
Selection of the most probable stereoisomer was attained
as a result of a comprehensive experimental and theoretical
investigation of the compound and its conceivable 3D models.
We investigated what results would be obtained if the problem is
solved using 1D and 2D NMR spectra and the empirical chemical
shift prediction methods implemented into the expert system
Structure Elucidator.[5,6,22]
To perform this analysis structure 1 was input into the system
and all carbon and hydrogen atoms were supplied with chemical
shifts in accordance with the author’s assignment. Then all 25 = 32
streoisomers were generated by the program and depicted using
conventional designations for stereobonds. 1H and 13C chemical
shifts were calculated for the complete stereoisomer set using
the fragment-based approach within the Structure Elucidator
program. In addition, 13C NMR chemical shifts were calculated
using both neural net (N) and incremental (I) approaches.
The average deviations of the predicted chemical shifts relative
to the experimental shifts (dA = fragmental approach, dN = NN
approach and dI = incremental approach) were calculated for
each of 32 stereoisomers and all stereoisomers were ranked
in ascending order of the 13C deviation values. Since the
chemical shifts are insensitive to the absolute configuration
of a stereoisomer and its inverse partner, the reduced ranked
stereoisomer set was finally represented as a sequence of 16
stereoisomer pairs, each pair having equal deviations. Figure 2
shows the first 8 out of 16 ‘unique’ stereoisomers ranked in
ascending order of the average deviations calculated for 13C NMR
spectrum. The remaining stereoisomers are characterized by 13C
average deviations dA(13C) falling in the range between 2.49 and
2.90 ppm.
Figure 2 shows that the correct stereoisomer was distinguished
both by its 13C and 1H average deviations. Our experiences in
the field of computer-aided structure elucidation have shown[22]
that the dA(1H) deviation is a less reliable criterion compared with
dC and it is usually only used for additional confirmation of the
most probable structural isomer.[5,6,22] The difference between the
deviations dA(13C) found for the second and first ranked structures
is not large (0.2 ppm), but this value is frequently observed in
1
2
3
4
5
6
7
8
9
O
10
11
12
HO
13
CH314
CH315
CH316
H
17
H
18
H
19
1
2
3
4
5
6
7
8
9
O
10
11
12
HO
13
CH314
CH315
CH316
H
17
H
18
H
19
1
2
3
4
5
6
7
8
9
O
10
11
12
HO
13
CH314
CH315
CH316
H
17
H
18
H
19
1
2
3
4
5
6
7
8
9
O
10
11
12
HO
13
CH314
CH315
CH316
H
17
H
18
H
19
A B C D
Figure 1. The four candidate stereoisomer structures of artarborol.
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335
The application of empirical NMR prediction to determine stereochemistry
O
HO
CH3
CH3
CH3H
H
H
H
H
H
H
H
H
H
H
dA(13C): 1.773 V(11.01)
dI(13C): 2.791
dN(13C): 2.738
dA(1H): 0.289 V(11.01)
1 (ID:29) A
O
HO
CH3
CH3
CH3H
H
H
H
H
H
H
H
H
H
H
dA(13C): 1.959 V(11.01)
dI(13C): 2.893
dN(13C): 2.817
dA(1H): 0.313 V(11.01)
2 (ID:4)
O
HO
CH3
CH3
CH3H
H
H
H
H
H
H
H
H
H
H
dA(13C): 1.969 V(11.01)
dI(13C): 2.893
dN(13C): 2.817
dA(1H): 0.312 V(11.01)
3 (ID:13)
O
HO
CH3
CH3
CH3H
H
H
H
H
H
H
H
H
H
H
dA(13C): 1.982 V(11.01)
dI(13C): 2.893
dN(13C): 2.817
dA(1H): 0.313 V(11.01)
4 (ID:24)
O
HO
CH3
CH3
CH3H
H
H
H
H
H
H
H
H
H
H
dA(13C): 1.998 V(11.01)
dI(13C): 2.791
dN(13C): 2.738
dA(1H): 0.293 V(11.01)
5 (ID:8) D
O
HO
CH3
CH3
CH3H
H
H
H
H
H
H
H
H
H
H
dA(13C): 2.092 V(11.01)
dI(13C): 2.791
dN(13C): 2.738
dA(1H): 0.293 V(11.01)
6 (ID:20) C
O
HO
CH3
CH3
CH3H
H
H
H
H
H
H
H
H
H
H
dA(13C): 2.358 V(11.01)
dI(13C): 3.643
dN(13C): 3.306
dA(1H): 0.313 V(11.01)
7 (ID:12)
O
HO
CH3
CH3
CH3H
H
H
H
H
H
H
H
H
H
H
dA(13C): 2.364 V(11.01)
dI(13C): 2.893
dN(13C): 2.817
dA(1H): 0.309 V(11.01)
8 (ID:33)
Figure 2. The first 8 out of 16 stereoisomers ranked in ascending order of the average deviation dA(13C).
the structure elucidation process when the ‘best structure’ is
selected.[22] It is worthy to note that in the stereoisomers 3, 4,
6 and 9, atoms H-17 and H-19 are situated on opposite sides
of the macrocycle and are unlikely to be close enough in space
to show a ROESY coupling. Since the authors[15] made the final
choice between structures A and C on the basis of comparison
of differences between experimental and calculated 13C chemical
shifts of all carbon atoms, we also compared these values (Fig. 3).
Figure 3 shows that the main difference between the chemical
shifts calculated for structures A and C is observed for atoms 6 and
7. For structure A the calculated values are markedly closer to the
experimental values. The maximum prediction errors are shown
for atoms 3 and 5 at the junction between the macrocycle and the
4-membered ring. Stereoisomer ranking with dN (13C) and dI (13C)
values in general supported the priority of stereoisomers A–D;
these fell into the first four stereoisomers for which all dN (13C)
values and all dI (13C) values proved to be equal (see Supporting
Informations, Figure 1S).
The approach described here looks attractive due to its
simplicity and high speed: the 13C and 1H chemical shift
calculations for all 32 isomers took about 2 minutes on a
Pentium IV, 2.8 GHz processor compared to 60 h per prediction
as reported by the authors of the original paper. It could be
useful for the preliminary assessment of a full stereoisomer
set and rejection of deliberately improbable structures when
the analyzed molecule is relatively rigid. The reliability of such
-10
-8
-6
-4
-2
0
2
4
6
3 5 7 9 11 13
Atom number
Ch
em
ica
l s
hi
ft
di
ffe
re
nc
e,
p
pm
A C
1
Figure 3. A comparison of the 13C chemical shift deviations calculated for
the carbon atoms contained in stereoisomers A and C.
conclusions can be heuristically evaluated by visual comparison
of the reference structures used for chemical shift prediction
with the target structure. For instance, a series of structures
containing the ring framework of artarborol were shown by the
program when examining the chemical shift prediction protocol.
Magn. Reson. Chem. 2009, 47, 333–341 Copyright c© 2009 John Wiley & Sons, Ltd. www.interscience.wiley.com/journal/mrc

336
M. E. Elyashberg, K. A. Blinov and A. J. Williams
It should be emphasized that the artarborol molecule (a new
compound) was absent from the library of structures included
within the ACD/NMR prediction program. Reference structure 2
is the most similar structure to the artarborol structure under
investigation:
40.1029.45
24.4551.50
44.2543.75
27.60
63.65
59.80
34.6039.50
O
CH3
16.90
66.40
HH
CH3
21.55
CH3
29.85
HO
H
2
We demonstrated that removing structure 2 from the database
did not influence the results, the deviation characteristic for
the best stereoisomer was only slightly increased from 1.773
to 1.799 ppm.
The described approach was also applied to two new
ketopelenolides 3 and 4 which were separated and scrutinized
by the same research group.[23] The stereochemistry shown in
structures 3 and 4 was determined by authors[23] as a result
of conformational analysis and QM based 13C chemical shift
calculation of the most probable stereoisomers. The calculations
were performed in groups of four for each structure (C1–C4 for
structure 3 and D1–D4 for structure 4, Fig. 4). It has been shown
that C1 corresponds to stereoisomer 3 and D1 to stereoisomer 4.
HO
CH3
O
H3C
O
O
CH3
H
H
H
H
H
3
H3C
H3C
O
O
O
O
CH3
CH3H
H
H
H
4
Structure Elucidator was used to generate all possible stereoiso-
mers for structures 3 and 4 (in both cases N = 64) and to perform
NMR chemical shift calculations for all stereoisomers using empir-
ical methods. 13C chemical shift prediction using the fragmental
method placed stereoisomer C2 in first position in the ranked file
and the genuine stereoisomer C1 at the second position with a dif-
ference between deviations of 0.01 ppm. At the same time ranking
stereoisomers using dN(13C) values brought stereoisomers C1–C4
to the 1–4 positions with equal dN(13C) and dI(13C) values for all
of the stereoisomers (see Supporting Informations, Figure 2S). For
structure 4 the stereoisomers were ranked by dA(13C) values in the
following order: first – D1, second – D2, third – D3, fifth – D4 (see
Supporting Informations, Figure 3S). The correct stereoisomer was
placed in first position and the other most probable stereoisomers
HO HOCH3
O
H3C
O
O
CH3
H
H
H
H
H
C1
CH3
O
H3C H3C
O
O
CH3
H
H
H
H
H
C2
OH CH3
O
O
O
CH3
H3C
H
H
H
H
H
C3
OH CH3
O
O
O
CH3
H
H
H
H
H
C4
O
O
H3C H3C H3C
O
O
CH3
CH3H
H
H
H
H
D1
O
O
O
O
CH3
CH3H
H
H
H
H
D2
O
O
O
O
CH3
CH3H
H
H
H
H
D3
O
O
H3C
O
O
CH3
CH3H
H
H
H
H
D4
Figure 4. The most probable stereoisomers of structures 3 and 4 selected for detailed theoretical analysis in the work.[23]
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337
The application of empirical NMR prediction to determine stereochemistry
selected in[23] were distinguished by the program as also deserving
attention.
For preliminary evaluation of the generality of the described
approach we repeated the work using the structures of natural
products belonging to a number of different classes, i.e. steroids,
alkaloids, terpenes, cembranoids, etc. A set of such structures
whose relative stereochemistry was recently described in a series
of publications was chosen (Table 1).
All selected structures were supplied with assigned experi-
mental 1H and 13C NMR chemical shifts. Three similar structures
borrowed from earlier publications (of 2003 and 2004) were tem-
porarily removed from the database during our research. For each
Table 1. Examples of structures for which sets of preferable stereoisomers were selected using empirical methods of 13C NMR chemical shift
prediction. The R and S designations shown in the structures correspond to the stereochemistry at the particular stereocenter
Example No. Structure Nds, Number of stereoisomers
Sr, position of correct
stereoisomer Reference
1
R
R
R
R
R
RS
S
S
R
R
HO
CH3
OH
O
CH3
H3C
H3C
H3C
OH
OH
O
CH3
H
H
H
1024 1 [24]
2
R
R
S
S
S
S E
HO
OH
H3C
H3C
E
E
CH3
E
E E
CH3
O
OC H
O
CH3
H
H
H
256 1 [25]
3
R
R
S
S
S
R
N
N
O
O
H
H
H
H
H
H
32 1 [26]
4
O
R
S
R
O R
S
O
O
H3C
H3C
CH3
H3C
OH
O
O
CH2
H
H
H
32 1 [27]
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338
M. E. Elyashberg, K. A. Blinov and A. J. Williams
Table 1. (Continued)
Example No. Structure Nds, Number of stereoisomers
Sr, position of correct
stereoisomer Reference
5
CH3
H3C
CH3
H3C
H3C
H3C
CH3
S
S
S
R
S
S
S
CH2
OO
O
O
O
O
HO
H
H
H
H
H
H
64 1 [28]
6
S
S
S S
S
R
HO
OH
OH
OH
OH
O
O
O
O
O
H
H
H
H
H
H
32 3 [29]
7
S
S R
S
N
S
R R
S
H3C
O
O
CH3
HO CH3
H H
H
H
H
H
128 3 [30]
8
R
R
S
R
R
R
S
S
O
HO
HO
OH
CH3
CH3
R
H3C
R
O O
R
*
CH3
OH
CH3
H
H
H H
H
H
H 2048 3 [31]
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339
The application of empirical NMR prediction to determine stereochemistry
Table 1. (Continued)
Example No. Structure Nds, Number of stereoisomers
Sr, position of correct
stereoisomer Reference
9
R
R
S
S
S
S R
S
R R
R
H3C
H3C
H3C
HO
O
O
O
O
CH3
CH3
O
O
O
CH3
CH3
O
CH3
O
CH3
O
CH3
HH
H
H H
H
H
H
H
1024 3 [32]
10
CH3
CH3
H3C
H3C
H3C
H3C
H3C
CH3
CH2
R
R
S
S
R
RS
E
E
SS
O
O
O
O
O
O
O
O
O
O
OH
OH
H
H
H
H
H
H
H
512 3 [28]
11
R
S
R
S
R S
N
S N
H3C
H3C
H3C
H3C
H3C
C
H
H
H 64 3 [33]
12
O
S R S
R
CH3
OHH2C
S
RO
H3C
H3C
O
O
O
CH2
H
H
H
H
32 4 [27]
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340
M. E. Elyashberg, K. A. Blinov and A. J. Williams
Table 1. (Continued)
Example No. Structure Nds, Number of stereoisomers
Sr, position of correct
stereoisomer Reference
13
SS
S
S
S Z
Z
S
O
R
R
S
CH2
O
CH3
O
O
H3C
H3C
H3C
H3C
O
O
CH3
O
CH3
O
OH
O
O H
H
H
H
H
H
H
256 8 [34]
14
R
R
S
R
R
R
S
R SH3C
HO
HO
HO
CH3
OH
CH3
O
OH
HH
H
H
H
256 12 [35]
molecule a full set of N possible stereoisomers was generated
and the 13C NMR chemical shifts of Nds differing stereoisomers
(Nds = N/2, N = 2n, n – number of stereocenters) were calculated
by all three mentioned algorithms. A stereoisomer file was ranked
in the same way as in the artarborol case – in descending order
of dA(13C) values and the position of the correct stereoisomer,
as determined in the corresponding article, was detected in the
ranked file. The result of each computational experiment was char-
acterized by an Sr value where Sr is the number of stereoisomers
for which the deviations dA(13C) are less than or equal to the de-
viation calculated for the right stereoisomer. For instance, Sr = 1
means that the right stereoisomer was ranked the first in the file
with deviation dA1(13C), and dA1(13C) < dA2(13C), where dA2(13C)
is the deviation calculated for the stereoisomer ranked in second
position. The notation Sr = 4 means that the correct stereoisomer
is among the first four stereoisomers in the ranked file.
Table 1 shows that our suggested approach can indeed be
used for selecting a set of the most probable stereoisomers from
all possible members of the family. Even for rather complex
structures the preferable stereoisomer was ranked early in the set.
Stereoisomer ranking usingdN(13C) is not as effective asdA(13C) but
nevertheless in this case the right stereoisomer most frequently
fell into the set of the first 8 ranked stereoisomers. Consequently,
the neural net approach can be used for preliminary ranking the
stereoisomer file for subsequent spectrum prediction based on
fragmental method as is common in Structure Elucidator system.[6]
When NOESY/ROESY data were available from the corresponding
articles, application of these data to structures presented in top
sets (Sr = 3–12) allowed us to conclude that the right stereoisomer
is the preferred one algorithmically also. Examples of the several
top ranked sets of stereoisomers are presented in the Supporting
Informations.
Computational Details
All calculations were performed using ACD/NMR predictor version
11.01. A personal computer equipped with a 2.8 GHz Intel
processor and 2Gb of RAM and running the Windows 2000
operating system was used. All computer programs are an
integral part of the Structure Elucidator expert system. Other
than supplying a set of structures, stereoisomer generation and
NMR chemical shift calculation requires no intervention from the
chemist and are performed fully automatically.
Conclusions
The possibility of applying empirical methods of 13C NMR chemical
shift prediction for selection of a set of the most probable
stereoisomers related to a given chemical structure has been
shown for a series of examples. Application of this approach
to the elucidation of the preferred stereoisomer of artarborol
has been considered in more detail. We selected the most
probable stereoisomer of artarborol using a simple and fast
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341
The application of empirical NMR prediction to determine stereochemistry
empirical method of chemical shift prediction based on HOSE
codes. We suggest that it is worth employing this approach for
the preliminary evaluation of all possible stereoisomers generated
by the expert system Structure Elucidator. We expect that this
approach will show general utility when the analyzed structure
is relatively rigid and the reference structures used for chemical
shift prediction contain large common fragments with stereo
assignments. This approach can markedly reduce the number of
stereoisomers that should be thoroughly investigated on the basis
of NOE correlations, coupling constant values and QM calculations
to finally establish the preferable stereoisomer. The method can be
enhanced by utilizing the methodology suggested in our work[36]
and vice versa; if a starting stereoisomer fed as input to the genetic
algorithm for prediction is close to the right one the genetic
algorithm will complete the calculations in a shorter time.
To continue to develop an optimal strategy and deduce further
practical recommendations it is necessary to investigate a larger set
of diverse structures. In this way we can further refine our methods
of NMR chemical shift prediction and make them more sensitive
to relative stereochemistry. For this aim a statistically relevant
collection of material must be accumulated and generalized. This
work is in progress, and results will be presented in our next
publication.
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Magn. Reson. Chem. 2009, 47, 333–341 Copyright c© 2009 John Wiley & Sons, Ltd. www.interscience.wiley.com/journal/mrc