Determination of the Relative Configuration of Terminal and Spiroepoxides by Computational Methods. Advantages of the Inclusion of Unscaled Data

Article abstract of DOI:10.1021/acs.joc.6b02129

The assignment of the relative configuration of spiroepoxides or related quaternary carbon-containing oxiranes can be troublesome and difficult to achieve. The use of GIAO NMR shift calculations can provide helpful assistance in challenging cases of structural elucidation. In this regard, the DP4 probability is one of the most popular methods to be employed when only one set of experimental data is available, though modest results were obtained when dealing with spiroepoxides. Recently, we introduced an improved probability (DP4+) that includes the use of both scaled and unscaled NMR data computed at higher levels of theory. Here, we report a comprehensive study to explore the scope and limitations of the DP4+ methodology in the stereoassignment of terminal or spiroepoxides bearing a wide variety of molecular complexity and conformational freedom. The excellent levels of correct classification achieved were interpreted on the basis of a constructive compensation of errors upon using both scaled and unscaled proton and carbon data. The advantages of the DP4+ methodology in solving two case studies that could not be unequivocally assigned by NOE experiments are also provided.

Full text of DOI:10.1021/acs.joc.6b02129

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Featured Article
Determination of the relative configuration of terminal and spiroepoxides
by computational methods. Advantages of the inclusion of unscaled data.
María Marta Zanardi, Alejandra Graciela Suárez, and Ariel M. Sarotti
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02129 • Publication Date (Web): 04 Nov 2016
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Determination of the relative configuration of terminal and spiroepoxides by
computational methods. Advantages of the inclusion of unscaled data.
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María M. Zanardi;†,‡ Alejandra G. Suárez† and Ariel M. Sarotti*†
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† Instituto de Química Rosario (CONICET), Facultad de Ciencias Bioquímicas y
Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, Rosario 2000,
Argentina
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‡ Facultad de Química e Ingeniería del Rosario, Pontificia Universidad Católica
Argentina, Av. Pellegrini 3314, Rosario 2000, Argentina.
Abstract
The assignment of the relative configuration of spiroepoxides or related quaternary
carbonꢀcontaining oxiranes can be troublesome and difficult to achieve. The use of
GIAO NMR shift calculations can provide helpful assistance in challenging cases of
structural elucidation. In this regard, the DP4 probability is one of the most popular
methods to be employed when only one set of experimental data is available, though
modest results were obtained when dealing with spiroepoxides. Recently, we introduced
an improved probability (DP4+) that includes the use of both scaled and unscaled NMR
data computed at higher levels of theory. Here, we report a comprehensive study to
explore the scope and limitations of the DP4+ methodology in the stereoassignment of
terminal or spiroepoxides bearing a wide variety of molecular complexity and
conformational freedom. The excellent levels of correct classification achieved were
interpreted on the basis of a constructive compensation of errors upon using both scaled
and unscaled proton and carbon data. The advantages of the DP4+ methodology in
solving two case studies that could not be unequivocally assigned by NOE experiments
are also given.
Introduction
Epoxides are among the most useful functional groups in organic chemistry. Apart from
being present in many biologically active natural products, such as the mitomycins,
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azinomycins and epothilones, they are extremely versatile building block in organic
synthesis.1 Its synthetic utility is due to the strain associated with the threeꢀmembered
heterocycle, which are “springꢀloaded” for reactions with nucleophiles, allowing a wide
array of functionalization strategies to be achieved in high stereo and regioselectivity.
Therefore, the preparation of epoxides has been of considerable interest and many
methods have been developed to date, including the oxygen transfer to alkenes,
intramolecular nucleophilic displacements and additions to carbonyl compounds.1
The determination of the relative configuration of quaternary carbonꢀcontaining
epoxides (such as the case of spiroepoxides) can be often troublesome and difficult to
achieve by using only NMR data, as NOE measurements can lead to ambiguous results
because of the the sp2ꢀlike character of the carbon atoms of the oxirane ring (vide
infra).2 The use of NMR anisotropic interactions, such as residual dipolar couplings
(RDCs) and residual chemical shift anisotropy (RCSAs), represent useful strategies that
could be used in these cases.3 The relative configuration of complex organic molecules
(including those bearing several quaternary carbon atoms) could be efficiently
determined by these methods.3 In this regard, the need of special media to perform the
molecular alignment in anisotropic media represents one of the main limitations of these
methods, though impressive advances have been achieved in the field.3 On the other
hand, NMR calculations with quantumꢀbased methods represents a simple and useful
alternative to determine the relative configuration of epoxides, avoiding chemical
derivatization (inappropriate when low amount of sample is available) or Xꢀray studies
(unfeasible in several cases).4ꢀ6 The structure and stereochemistry of a wide variety of
complex natural products have been assigned or revised on the basis of NMR
calculations with remarkable levels of confidence, emerging as indisputable new tools
in NMR spectroscopy.4ꢀ6 Several strategies have been developed to correlate the
experimental and theoretically computed chemical shifts, including CP3,7 DP4,8 and
ANNꢀPRA9 (artificial neural network pattern recognition analysis).5a In this regard, the
DP4 probability is the most accurate and popular method to determine the correct
stereostructure of an organic molecule when only one set of experimental data is
available (as in the case of isomerically pure compounds). This method was developed
by the Goodman group in 2010, and was used in the structural assignment or revision of
plenty natural and unnatural products,8 many of them verified by total synthesis of the
most likely structure.5a,10 Recently, we introduced a modified probability (DP4+),
demonstrating that the inclusion of unscaled data and the use of higher levels of theory
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for the GIAO NMR calculation procedure resulted in a significant improvement in the
classification performance of the method.11 We showed that the original DP4
probability consistently afforded poor results when dealing with spiroepoxides
(compounds
stereoassignment of these types of compounds. In four cases (compounds
the incorrect isomer was identified in high probability (the worst scenario), whereas in
one of the remaining examples (compound ) the correct isomer was successfully
1
ꢀ
7
, Figure 1), providing further evidence of the challenge involved in the
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1
,
2,
5
and 7)
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assigned in modest confidence (50ꢀ95%). In contrast, our DP4+ probability succeeded
in correctly pointing towards the correct isomer with high probability (>95%) in all
cases.
O
O
H
O
O
O
O
O
O
O
∗
O
O
H
5
R
6 (R)
7 (S)
1
2 (R=H)
3 (R=OMe)
4 (R=CH2OMe)
Figure 1. Seven examples of spiro epoxides used in the evaluation of the DP4+ probability.
The use of DP4+ in the stereoassignment of epoxides was also highlighted by a recent
work of TaglialatelaꢀScafati and coꢀworkers on the structural elucidation of
plakdiepoxide, isolated from the Chinese sponge Plakortis simplex 12
.
Given the importance of alternative and reliable methods to provide assistance in the
stereochemical assignment of spiro or related quaternary carbonꢀcontaining epoxides,
we explored the scope and limitations of DP4+ as a benchmark methodology to be used
whenever the NMR data is not conclusive.
Result and discussion
To accomplish our goals, we selected 24 spiroꢀ or terminal epoxides from the recent
literature (compounds 8-31, Figure 2), including 2 unpublished examples from our own
synthetic work (compounds 21 and 22, Figure 2), with known relative configuration
(established by Xꢀray analysis, chemical synthesis or irrefutable NMR data).13,14 In
addition, we foresaw a wide variety of molecular complexity, functional groups and
conformational freedom in the selected compounds. Following the DP4+ general
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procedure, the chemical shifts were computed at the PCM/mPW1PW91/6ꢀ
31+G**//B3LYP/6ꢀ31G* level of theory using the GIAO method implemented in
Gaussian 09.11
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9
O
O
H
H
H
H
O
H
O
H
O
O
O
O
O
O
OH
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H
O
HO
O
H
H
OHC
O
O
H
O
O
O
H
H
H
H
O
O
9
O
10 (S)
8
12
13
14
11 (R)
2´
∗
O
O
O
OH
H
O
O
H
O
H
O
O
O
H
O
O
O
O
O
AcO
AcO
O
O
H
H
O
O
H
O
H
O
O
OH
O
O
H
O
O
OH
OAc
O
O
15 (S)
16 (R)
19 (S)
20 (R)
21 (R)
22 (S)
17
18
23
OMe
MeO
O
TMS
O
OH
OH
OMe
O
O
O
O
H
N
O
O
N
O
O
O
O
HO
O
OMe
N
O
O
O
Me
Si
28
O
H
CO2H
Et
O
29 (R)
30 (S)
26
25
27
24
31
Ph
Figure 2. 24 selected spiro or terminal epoxides used in this study.
With the shielding tensors in hand we evaluated the DP4+ performance in establishing
the correct configuration at the epoxide stereocenter, using the Excel spreadsheet
provided free of charge at sarottiꢀnmr.weebly.com or as part of the Supporting
Information of the original reference.11 Briefly, the DP4+ probability, is a modified
version of DP4, in which
correct, and is a function of the corresponding probabilities computed using scaled and
unscaled chemical shifts, termed DP4+ and DP4+, respectively. Moreover, each
P(i) is the probability that candidate i (out of m isomers) is
s
u
DP4+ term can be calculated using only 1H data, 13C data or both.
In Figure 3 we show the result of the DP4+ probabilities computed for the 24 examples
shown in Figure 2, along with the corresponding probabilities using only unscaled or
1
scaled shifts (
u
DP4+ and
s
DP4+, respectively), computed from H data, 13C data, or
both. We also included the results obtained for the 7 examples previously reported by us
(compounds 1-7) to provide insightful discussion. Since no strictly defined cutoff limits
are imposed, the probability computed for a given isomer indicates the level of certainty
of the assignment itself. Thus, we have identified three different scenarios depending on
the confidence level of the associated probability: the optimal (indicated in green)
represents a correct assignment made in high probability (>95%), the acceptable
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(indicated in yellow) represents a correct assignment made in lower probability (50ꢀ
95%) and the bad (indicated in red) represents cases in which the correct isomer is
assigned with low probability (<50%).
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Figure 3: Overall performance of the DP4+ probabilities computed for compounds 1ꢀ31.
At first glance, the results provided in Figure 3 indicate the excellent performance of the
DP4+ probability in successfully assigning the right isomer in high certainty. Not only
none of the 31 examples was incorrectly assigned, but also only 2 of them were
correctly classified in modest probability. In the remaining 29 cases the right
configuration of the epoxide was properly identified in >95% confidence. Comparing
the results obtained with uDP4+ and sDP4+ with the corresponding DP4+ values, it is
clear that the combination of both scaled and unscaled NMR shifts affords the highest
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assignment capacity. Interestingly, the performance of
uDP4+ (all data) was higher than
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that found for DP4+ (all data), indicating that the inclusion of unscaled shifts allows a
s
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better differentiation among the candidate structures. This observation emphasizes one
of the major differences with the original DP4 formalism, that neglects any effect
exerted by the unscaled shifts.8 Another important feature is the error compensation
between both scaled and unscaledꢀderived probabilities, meaning that the failure of
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s
DP4+ (for example, compounds 13 and 18) is overcompensated by
uDP4+, or vice
versa (for example, compound 22), affording good overall results.
A different insightful discussion arises when analyzing the type of data employed for
DP4+ analysis, that is, proton and carbon data. Recently, an interesting debate
originated about whether one nucleus is more discriminating than the other, and proton
has been suggested to allow a better differentiation among stereoisomers.15 However, in
our case using only 1H or 13C data alone significantly reduced the performance of DP4+,
as well as their associated
exclusive use of scaled 1H NMR shifts (
sDP4+ and
u
DP4+ probabilities. For instance, with the
s
DP4+, H data), or 13C NMR shifts (
sDP4+, C
data), 8 (26%) or 7 isomers (23%), respectively, were incorrectly assigned, whereas 7
1
(23%) were correctly assigned but in modest confidence. However, using both H and
13C data significantly improved the overall performance (
sDP4+, all data), reducing to 2
(6%) and 6 (19%) the number of bad and modest examples, respectively. Similar
behavior was observed when analyzing the series of unscaled chemical shifts (uDP4+).
13
Interestingly, in this case the results obtained from C NMR data were slightly better
1
results than those obtained from H NMR (3 vs. 8 examples incorrectly assigned,
respectively, and 12 vs. 8 examples correctly assigned in modest confidence,
respectively), suggesting that when dealing with epoxides, carbon data is the most
discriminating one. Nevertheless, the performance of the method significantly improved
upon the inclusion of both types of data in the
u
DP4+ formalism, facilitated by a
13
constructive compensation of errors. This means that a good assignment made by C
1
data often overrides a bad assignment made by H data (for example, compounds 1, 7,
10, 18, 19, 23 and 26), or vice versa (for example, compounds 12 and 27).
This overall compensation of errors is mainly the reason of the nice performance of the
DP4+ method. This is particularly relevant when considering that only 4 examples were
perfectly assigned (>95% probability) simultaneously with all the nine DP4+ꢀderived
probabilities (compounds 16, 20, 24 and 31), whereas in 19 examples (61% of the total)
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at least one of the parameters failed by indicating towards the incorrect isomer in high
certainty.
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To sum up, our DP4+ strategy yielded excellent results in discerning the relative
configuration of spiro or terminal epoxides. In order to obtain high confidence in the
assignments, both 1H and 13C data must be used, along with scaled and unscaled shifts.
To further illustrate the usefulness of this methodology for the organic chemistry
community, two case studies of compounds that could not be unequivocally assigned by
the exclusive use of experimental NMR are also given and thoroughly analyzed.
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Case study 1
As part of our ongoing program aimed at the development of new chiral catalysts from
levoglucosenone (32),16 a biomassꢀderived bicyclic enone,17 we envisaged the
preparation of 1,2ꢀaminoalcohols by aminolysis of the spiroꢀepoxides 21ꢀ22, that in turn
could be obtained upon epoxidation of the carbonyl group of ketone 33 (Figure 4).
O
O
O
O
H2
O
O
O
O
H
O
H
O
epox.
Pd/C
1
2
1
2
+
100%
3
3
O
O
Ha
7
Ha
7
32
33
H
H
H
H
Hb
Hb
21
22
Figure 4: Synthesis of spiroepoxides 21 and 22, with key NOE correlations.
Treatment of 33 with diazomethane in chloroform solution afforded two inseparable
diastereomeric epoxides 21 and 22 in a 54:46 ratio based on 1H NMR integration of the
mixture. With the intention to provide pure sample of one isomer, the Coreyꢀ
Chaycovsky protocol was next employed,18 and the 21/22 ratio increased to 90:10. All
attempts to improve the selectivity of the reaction met with no success. Nevertheless,
1
we could manage to unequivocally assign all the H and 13C resonances of both
compounds in the NMR spectra of the mixture by routine combination of 1D and 2D
experiments. However, the determination of the absolute configuration at Cꢀ2 was
ambiguous on the basis of NOE experiments. While irradiation at the Hꢀ7a and Hꢀ7b
signals of the major compound (21) afforded an increase at the Hꢀ1 and Hꢀ3eq signals,
respectively, the exact same situation was observed upon irradiation at both Hꢀ7 signals
of the minor compound (22), Figure 4. This observation deserves a further comment
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regarding the use of NOE for this kind of compounds. The fact that both isomers
exhibited the same NOE correlations between the same nuclei, raise the question of
which assignment would have been made if only one would have been isolated.
Probably, in any case isomer 21 (with the methylene moiety directed towards the αꢀface
of the molecule, to which are arranged both Hꢀ1 and Hꢀ3eq) should have been identified
as the correct one.
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1
Detailed analysis of the H NMR spectra of the mixture of 21ꢀ22 provided further
evidence to determine the absolute configuration at Cꢀ2. Examination of the signal
corresponding to Hꢀ7a of the major adduct (21) showed a longꢀrange coupling (
J=1.4
Hz) with Hꢀ3ax (the correlation was also observed from 2DꢀCOSY), indicating a
W
disposition of these two hydrogen atoms. Moreover, such coupling was not observed in
the minor isomer (22). On the basis of this evidence, we computed the most stable
geometries of both adducts at the B3LYP/6ꢀ31G* level of theory (Figure 5). Our
calculations showed a clearer
W relationship between Hꢀ7a and Hꢀ3ax protons for
compound 21, whereas a more perpendicular arrangement of both hydrogen atoms was
observed in the case of 22. To provide further evidence of this assignment, we next
computed the coupling constants of 21 and 22 at the B3LYP/6ꢀ31G* level of theory.
The computed J3axꢀ7a were 1.5 Hz (21) and 0.4 Hz (22), in excellent agreement with the
experimentally found values of 1.4 Hz and ~ 0 Hz, respectively. The other coupling
constants were also very well reproduced by our calculations (shown in the SI),
increasing our confidence in this computational model. The inconclusive results
provided by the NOE experiments can be better understood from the optimized
geometries of 21 and 22, in which no significant differences in the distances between Hꢀ
7a/Hꢀ1 and Hꢀ7b/Hꢀ3eq computed for both isomers were observed.
1
1
2.56
3ax
2.67
3ax
2.54
7a
7a
7b
2.51
3eq
3eq
7b
21
22
Figure 5: B3LYP/6ꢀ31G* optimized geometries of compounds 21 and 22, with selected distances (in Å).
The final support of our stereoassignment was possible by the calculation of the CP3
parameter, introduced by the Goodman group to match two candidates with two sets of
experimental data.7 From the NMR shifts computed at the PCM/B3LYP/6ꢀ
31+G**//B3LYP/6ꢀ31G* level, the CP3 computed for the matched pairs (majorꢀ21/
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minorꢀ22) was 0.90 based on both 13C and 1H data, while in the case of the mismatched
pairs (majorꢀ22/ minorꢀ21) the computed CP3 value was ꢀ0.98, with a very high
probability associated to the matched assignment (>99.99999%).
Returning to the original question of what would have happened if only one isomer
would have been isolated, Table 1 shows the DP4+ probability computed for the two
isomers using the experimental NMR data of 21 (entries 1ꢀ3) and 22 (entries 4ꢀ6). We
also included the results obtained using the original DP4 formulation to provide
insightful comparison between these two methods. Interestingly, only DP4+ succeeded
in correctly classifying the two examples under study. On the other hand, DP4 strongly
supported isomer 21 in both cases in high confidence, which is actually correct only for
the first example. Inclusion of unscaled data and higher level of theory afforded a clear
improvement in the overall performance in the stereoassignment of spiroepoxides.
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Table 1: Comparative results obtained in the stereoassignmet of 21 and 22 using DP4 (at the B3LYP/6ꢀ
31G**//MMFF level) and DP4+ (at the PCM/mPW1PW91/6ꢀ31+G**//B3LYP/6ꢀ31G* level).
Exp NMR
DP4
DP4+
Nuclei
from
21
21
21
22
22
22
21
22
0.2
21
22
<0.1
0.1
<0.1
98.3
3.9
1H
99.8
90.0
>99.9
99.1
87.3
>99.9
>99.9
99.9
>99.9
1.7
96.1
30.1
13C
10.0
<0.1
0.9
12.7
<0.1
all data
1H
13C
all data
69.9
Case study 2
Methionine aminopeptidase 2 (MetAP2) is a metalloprotease involved in the
cotranslational cleavage of initiator methionines from proteins synthesized in the
ribosome. This subtype is upꢀregulated in several types of cancer, and its selective
inhibition allows the suppression of vascularization and growth of tumors.2d Therefore,
intense research activities have been devoted to the development of MetAP2 inhibitors.
In this regard, Fumagillin (a metabolite from Aspergillus fumigatus) is a potent and
selective inhibitor of MetAP2, though it suffers from relatively poor pharmacokinetic
profiles.2d In an effort to overcome these limitations, Miller and coꢀworkers reported the
synthesis and biological evaluation of spiroepoxytriazoles, structurally related to
Fumagillin.2b,d The key and final step of the proposed synthetic scheme involved a
DMDO oxidation of the exocyclic alkene present in 34 to afford ~1:1 mixtures of the
two epimeric epoxides, 35 and 36 (Figure 6). According to the authors, the relative
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configuration of both compounds could not be assigned on the basis of NMR
experiments. However, one of the isomers could be crystallized, and its structure could
be revealed by Xꢀray analysis. With this pair of compounds with known configuration
(compounds 29 and 30, Figure 2), they subsequently suggested the stereostructure of all
other sets of spiroepoxides on the basis of distinctive differences in the 1H NMR spectra
and Rf values.
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11
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13
14
15
16
17
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21
22
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could not be assigned
using NMR data
O
O
R1
N
N
R1
R1
N
N
N
DMDO
N
+
N
N
N
OR2
OR2
OR2
34
35
36
Figure 6: Key and final step for the synthesis of novel MetAP2 inhibitors.
To understand whether the computational methodologies herein discussed could have
been useful in this case, we computed the NMR shifts of 29 and 30 at the B3LYP/6ꢀ
31G** and PCM/mPW1PW91/6ꢀ31+G**//B3LYP/6ꢀ31G* levels of theory for further
DP4 and DP4+ probabilities, respectively (Table 2). Here again, DP4 afforded modest
results by indicating 30 as the correct isomer when using both the experimental NMR
data corresponding to 29 and 30, which is only correct in the second case. This
inconsistency exhibited by DP4 to strongly support the same isomer regardless of the
experimental NMR data employed has been also found by the Furstner group in their
total synthesis and stereochemical revision of mandelalide A.19 On the other hand,
DP4+ nicely identified the correct stereoisomer in high confidence when using the
experimental shifts of 29 and 30, respectively.
Table 2: Comparative results obtained in the stereoassignmet of 29 and 30 using DP4 (at the B3LYP/6ꢀ
31G**//MMFF level) and DP4+ (at the PCM/mPW1PW91/6ꢀ31+G**//B3LYP/6ꢀ31G* level).
Exp NMR
DP4
DP4+
Nuclei
from
29
29
29
30
30
30
29
30
35.1
90.0
83.0
97.8
98.5
>99.9
29
30
1H
64.9
10.0
17.0
2.2
1.5
<0.1
>99.9
88.2
>99.9
<0.1
0.3
<0.1
11.8
<0.1
>99.9
99.7
>99.9
13C
all data
1H
13C
all data
<0.1
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Case study 3
3
4
Since the present study was aimed to evaluate DP4+ in the determination of the relative
configuration of terminal or spiroepoxides, we assumed that the remaining stereocenters
present in compounds 8-31 (Figure 2) were correctly assigned in the original references.
However, in a more realistic scenario, the configuration of more than one stereocenter
might be needed to define. In order to explore the overall performance of DP4+ in the
assignment of organic molecules bearing several stereocenters, we next computed the
corresponding probabilities for the full set of diastereoisomers of Coriolin and its
epimer at the spiroepoxide carbon (compounds 15 and 16, Figure 2). These compounds
represented an interesting case study as they both provide an extra quaternaryꢀcarbon
epoxide unit whose configuration was herein allowed to change. Thus, all the 64
possible stereoisomers were generated, and the NMR shielding tensors were computed
at the PCM/mPW1PW91/6ꢀ31+G**//B3LYP/6ꢀ31G* on the most significantly
populated conformers of each isomer. As indicated in Figure 7, when using the
experimental NMR data of 15,20 the DP4+ computed for the candidate 4 (the correct
structure of 15) was >99.9%, whereas candidate 36 (the correct structure of 16) was
identified in high confidence when using the experimental NMR shifts of 16.20
Interestingly, in both cases all the remaining 63 incorrect structures were assigned in
very low overall probability (<0.01%), highlighting the relevance of our methodology
for the stereoassignment of complex organic molecules.
5
6
7
8
9
10
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12
13
14
15
16
17
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21
22
23
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29
30
31
32
33
34
35
36
37
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51
52
53
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60
OH
H
O
O
exp. NMR from 15
ꢀ
> 99.9%
DP4+
O
H
OH
OH
O
H
∗
∗
candidate 4
(comp. 15)
O
∗
∗
∗
∗
∗
O
H
OH
OH
O
H
64 candidates
O
ꢀ
DP4+
> 99.9%
O
exp. NMR from 16
H
OH
candidate 36
(comp. 16)
Figure 7: Evaluation of DP4+ in the stereoassignment of compounds 15 and 16. The carbon atoms whose
configurations were varied to generate the candidate isomers are marked with an asterisk.
CONCLUSION
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We have tested the performance of our DP4+ probability in several examples of
terminal or spiroepoxides bearing a wide variety of molecular complexity and
conformational freedom. The excellent levels of correct classification achieved were
interpreted on the basis of a constructive compensation of errors observed when using
both scaled and unscaled proton and carbon shifts. Therefore, in order to strengthen the
confidence in the assignment, both types of data must be used in the DP4+ calculation
procedure. Properly used, the DP4+ methodology emerges as a powerful and simple
alternative to assign the relative configuration of challenging epoxides from which
experimental NMR information affords ambiguous results.
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22
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29
30
31
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35
36
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As a final remark, it is important to stress out that as any other computational method
used for structural determination purposes, the DP4+ results heavily depend on the
quality of the collected experimental and computational NMR data. Incorrectly assigned
NMR signals, improper computational work by missing relevant conformers, and/or
neglection of candidate stereostructures might lead to erroneous results. For that reason,
those sources or errors should be avoided in order to afford consistent and meaningful
predictions.
EXPERIMENTAL SECTION
Computational Methods. All the quantum mechanical calculations were performed
using Gaussian 09.21 In the case of conformationally flexible compounds, the
conformational search was done in the gas phase using the MMFF force field
(implemented in Spartan 08).22 All conformers within 5 kcal/mol of the lowest energy
conformer were subjected to further reoptimization at the B3LYP/6ꢀ31G* level of
theory. The choice for the 5 kcal/mol of cutoff was set as a balance between reducing
the overall CPU calculation time and minimizing the possibility of losing further
contributing conformers. The conformations within 2 kcal/mol from the B3LYP/6ꢀ31G*
global minima were subjected to NMR calculations. The magnetic shielding constants
(σ) were computed using the gauge including atomic orbitals (GIAO) method,23 the
method of choice to solve the gauge origin problem,5 at the B3LYP/6ꢀ31G** (for DP4
calculations) and PCM/mPW1PW91/6ꢀ31+G** (for DP4+ calculations) levels of
theory. The calculations in solution were carried out using the polarizable continuum
model, PCM,24 with chloroform as the solvent). The unscaled chemical shifts (δu) were
computed using TMS as reference standard according to δu = σ0 ꢀ σx, where σx is the
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Boltzmann averaged shielding tensor (over all significantly populated conformations)
and σ0 is the shielding tensor of TMS computed at the same level of theory employed
for σx. The Boltzmann averaging was done according to eq 1:
8
9
(-Ei/RT)
Σ
σixe
σx
i
(eq. 1)
=
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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50
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(-Ei/RT)
Σ
e
i
x
where σi is the shielding constant for nucleus
constant (8.3145 J K−1 mol−1),
is the temperature (298 K), and Ei is the energy of
conformer (relative to the lowest energy conformer), obtained from the singleꢀpoint
x in conformer i, R is the molar gas
T
i
NMR calculation at the corresponding level of theory. The scaled chemical shifts (δs)
were computed as δs = (δu − b)/m, where m and b are the slope and intercept,
respectively, resulting from a linear regression calculation on a plot of δu against δexp
.
The DP4 calculations were carried out using the Applet from the Goodman group (at
wwwꢀjmg.ch.cam.ac.uk/tools/nmr/DP4/). The DP4+ calculations were carried out using
the Excel spreadsheet available for free at sarottiꢀnmr.weebly.com, or as part of the
Supporting Information of the original paper.11
Experimental Section
All reagents and solvents were used directly as purchased or purified according to
standard procedures. Analytical thin layer chromatography was carried out using
commercial silica gel plates and visualization was effected with short wavelength UV
light (254 nm) and a pꢀanysaldehyde solution (2.5 mL of pꢀanysaldehyde + 2.5 mL of
H2SO4 + 0.25 mL of AcOH + 95 mL of EtOH) with subsequent heating. Column
chromatography was performed with silica gel 60 H, slurry packed, run under low
pressure of nitrogen using mixtures of hexane and ethyl acetate. NMR spectra were
1
13
recorded at 200 or 300 MHz for H, and 50 or 75 MHz for C with CDCl3 as solvent
and (CH3)4Si (1H) or CDCl3 (13C, 76.9 ppm) as internal standards. Chemical shifts are
reported in delta (δ) units in parts per million (ppm) and splitting patterns are designated
as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet and br, broad. Coupling
1
constants are recorded in Hertz (Hz). Isomeric ratios were determined by H NMR
analysis. The structure of the products were determined by a combination of
spectroscopic methods such as IR, 1D and 2D NMR (including NOE, DEPT, COSY,
HSQC and HMBC experiments) and HRMS. Infrared spectra were recorded using
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sodium chloride plates pellets. Absorbance frequencies are recorded in reciprocal
centimeters (cm–1). High resolution mass spectra (HRMS) were obtained on a TOFꢀQ
LCꢀMS spectrometer.
8
9
Preparation of spiroepoxides 21 and 22. Levoglucosenone (32) was obtained from the
microwaveꢀassisted pyrolysis of cellulose following our previously reported
procedure.17c To a solution of 32 (1100 mg, 8.73 mmol) in ethyl acetate (15 mL) was
added Pd/C (10%, 110 mg), and the flask was purged by cycles H2/vacuum and stirred
under H2 atmosphere during 5 hours until the total consumption of 32 was determined
by TLC. The solution was filtered over Celite and concentrated under reduced pressure
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
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58
59
60
to obtain 33 (1100 mg, 8.59 mmol) in 99% yield as a colorless oil, with spectroscopical
25
data identical to the reported by Clark and coꢀworkers.25 33: [α]D = ꢀ224.9 (
c
0.635,
1
ꢀ1
CHCl3); IR (film): νmax (cm ) = 2920, 1742(CO), 1111, 986, 883; NMR H (200 MHz,
CDCl3): δ= 5.09 (s, 1 H, Hꢀ1), 4.70 (bs, 1 H, Hꢀ5), 4.04 (d, 1 H,
3.96 (dd, 1 H,
(50 MHz, CDCl
6), 30.9 y 29.7 (2 CH
J
gem= 6.0 Hz, Hꢀ6endo),
13
J
gem
=
J
6ꢀ5= 6.0 Hz, Hꢀ6exo), 2.74ꢀ1.95 (m, 4 H, Hꢀ3 and Hꢀ4); NMR C
3
): δ= 200.0 (C, Cꢀ2), 101.3 (CH, Cꢀ1), 72.9 (CH, Cꢀ5), 67.3 (CH2, Cꢀ
, Cꢀ3 and Cꢀ4). Finally epoxides 21 and 22 were prepared from 33
2
using two different experimental procedures. Procedure 1: To a solution of 33 (820
mg, 6.40 mmol) in 15 mL of CHCl3 at 0 ºC was added a solution of diazomethane in
diethyl ether and stirred during 4 hs. The excess of diazomethane was quenched after
the addition of AcOH, and the solvent was evaporated under reduced pressure. The
crude was purified by flash chromatography giving a mixture of epoxides 21 and 22
1
(496 mg, 3.49 mmol, 55% yield) in a 54:46 ratio determined by integration of the H
NMR spectra of the mixture. Procedure 2: NaH (3.96 mmol, 60% dispersion in mineral
oil) was placed in roundꢀbottomed flask and dimethylsulfoxide (2 mL, distilled from
CaH2) was introduced under argon atmosphere. The resulting mixture was heated with
stirring at 60ꢀ70 ºC. After 30 min, the reaction mixture was diluted with dry
tetrahydrofuran (2 mL) and then cooled to 0 ºC. A solution of trimethylsulfonium iodide
(2.39 mmol) in saturated dimethylsulfoxide was added, follwed by the addition of a
saturated tetrahydrofuran solution of 33 (1.56 mmol) at 0 ºC. Stirring was continued for
30 min at 0 ºC and then 24 h at room temperature. The reaction was quenched by water
(10 mL) and extracted with ethyl acetate (4 x 25 mL). The organic layer was washed
with brine (1 x 25 mL), dried (Na2SO4) and concentrated. The residual oil was purified
by flash chromatography to afford a mixture of epoxides 21 and 22 (0.91 mmol, 58%)
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ꢀ1
in a 90:10 ratio as a colorless oil. IR (film): νmax (cm ) = 2954, 2897, 1653, 1340, 1292,
4
5
6
7
8
9
1104, 1081, 1021, 988, 970, 899, 885. NMR 1H (300 MHz; CDCl
1 of 21), 4.75 (s, 1 H, Hꢀ1 of 22), 4.62 (bs, 1 H, Hꢀ5 of 21), 4.63 (bs, 1 H, Hꢀ5 of 22),
3.98 (d, 2H, gem= 7.4 Hz, Hꢀ6endo of 21 and 22), 3.84 (m, 2H, Hꢀ6exo of 21 and 22),
2.78 (dd, 1 H, gem= 4.4 Hz, 7ꢀ3= 1.4 Hz, Hꢀ7a of 21), 2.75 (d, 1 H, gem= 4.1 Hz, Hꢀ7a
of 22), 2.70 (d, 1 H, gem= 4.4 Hz, Hꢀ7b of 21), 2.62 (d, 1 H, gem= 4.1 Hz, Hꢀ7b of 22),
3
): δ = 4.77 (s, 1H, Hꢀ
J
J
J
J
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
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J
J
2.31 (m, 1 H, Hꢀ3ax of 21), 2.42 (m, 1 H, Hꢀ3ax of 22), 2.22 (m, 1 H, Hꢀ4 of 22), 2.07
(m, 1 H, Hꢀ4 of 21), 1.76 (m, 1 H, Hꢀ4 of 21), 1.63 (m, 1 H, Hꢀ4 of 22), 1.39 (dddd, 1
H,
H,
J
gem= 13.4 Hz,
gem= 14.5 Hz,
J
3ꢀ4= 5.9 Hz,
J
3ꢀ4= 1.7 Hz,
3ꢀ4= 2.7 Hz,
J
3ꢀ5= 1.4 Hz, Hꢀ3eq of 21), 1.29 (dddd, 1
13
J
J
3ꢀ4= 6.1 Hz,
J
J
3ꢀ5= 1.4 Hz, 3eq of 22); NMR C (300
MHz; CDCl
72.7 (CH, Cꢀ5 of 22), 67.7 (CH
56.3(C, Cꢀ2 of 22), 52.1 (CH , Cꢀ7 of 21), 50.6 (CH
26.8 (CH , Cꢀ4 of 22), 23.1 (CH , Cꢀ3 of 21), 23.0 (CH
3
) δ = 104.5 (CH, Cꢀ1 of 21), 103.9 (CH, Cꢀ1 of 22), 73.0 (CH, Cꢀ5 of 21),
, Cꢀ6 of 21), 66.9 (CH , Cꢀ6 of 22), 57.8 (C, Cꢀ2 of 21),
, Cꢀ7 of 22), 28.3 (CH , Cꢀ4 of 21),
, Cꢀ3 of 22); HRMSꢀESI calcd
2
2
2
2
2
2
2
2
for C7H11O3 [M+H]+ 143.07027, found; 143.07018.
ASSOCIATED CONTENT
Supporting Information
Full list of the references of the synthesis or isolation of compounds 8-31, full list of
experimental chemical shifts, GIAO isotropic shielding tensors, B3LYP/6ꢀ31G*
cartesian coordinates (with energies) and detailed DP4+ probabilities computed for all
compounds. Copies of the 1H and 13C NMR spectra of compounds 32, 33, 21 and 22.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: sarotti@iquirꢀconicet.gov.ar
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This research was supported by UNR (BIO 316), ANPCyT (PICT 2011ꢀ0255 and PICTꢀ
2012ꢀ0970), and CONICET (PIP 11220130100660CO). M.M.Z. thank CONICET for
the award of a fellowship.
8
9
REFERENCES
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13) For the complete list of references of the isolation or synthesis of compounds 8-31,
see the Supporting Information.
14) In the case of compound 23, the configuration at the 2´ position was not defined by
the authors. As a result, herein we considered the two corresponding isomeric pairs,
denoted as 23R and 23S. That is, in 23R we compared the two possible configurations
at the epoxide center, and keeping the configuration at Cꢀ2´ as
23S we studied the two possible configurations at the epoxide center, and keeping the
configuration at Cꢀ2´ as . In both cases, the DP4+ probability correctly assigned the
configuration at the epoxide carbon. Moreover, according to the overall DP4+
probabilities, the configuration at Cꢀ2´ should be (>99% probability).
R. On the other hand, in
S
R
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