Joint Experimental, in Silico, and NMR Studies toward the Rational Design of Iminium-Based Organocatalyst Derived from Renewable Sources

Article abstract of DOI:10.1021/acs.joc.5b01214

An efficient organocatalyst for iminium-ion based asymmetric Diels-Alder (DA) reactions has been rationally designed. The most influential structure-activity relationships were determined experimentally, while DFT calculations and NMR studies provided further mechanistic insight. This knowledge guided an in silico screening of 62 different catalysts using an ONIOM(B3LYP/6-31G?:AM1) transition-state modeling, which showed good correlation between theory and experiment. The top-scored compound was easily synthesized from levoglucosenone, a biomass-derived chiral enone, and evaluated in the DA reaction between (E)-cinnamaldehyde and cyclopentadiene. In line with the computational finding, excellent results (up to 97% ee) were obtained. In addition, the catalyst could be easily recovered and reused with no loss in its catalytic activity.

Full text of DOI:10.1021/acs.joc.5b01214

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The Journal of Organic Chemistry
A joint experimental, in silico and NMR studies towards the rational design of iminium-based
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organocatalyst derived from renewable sources
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Gabriela G. Gerosa, Rolando A. Spanevello, Alejandra G. Suárez, Ariel M. Sarotti*
Instituto de Química Rosario (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas,
Universidad Nacional de Rosario, Suipacha 531, Rosario (2000), Argentina
sarotti@iquirꢀconicet.gov.ar
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Abstract
An efficient organocatalyst for iminiumꢀion based asymmetric DielsꢀAlder (DA) reactions has been
rationally designed. The most influential structure/activity relationships were determined
experimentally, while DFT calculations and NMR studies provided further mechanistic insight. This
knowledge guided an in silico screening of 62 different catalysts using an ONIOM(B3LYP/6ꢀ
3
1G*:AM1) transitionꢀstate modeling, that showed good correlation between theory and experiment.
The topꢀscored compound was easily synthesized from levoglucosenone, a biomassꢀderived chiral
enone, and evaluated in the DA reaction between (E)ꢀcinnamaldehyde and cyclopentadiene. In line with
the computational finding, excellent results (up to 97% ee) were obtained. In addition, the catalyst could
be easily recovered and reused with no loss in its catalytic activity.
Introduction
The construction of optically active compounds continues to be of great importance in organic
chemistry. In this regard, asymmetric organocatalysis has brought unprecedent progress in the last
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decades. The use of inexpensive, metalꢀfree, nonꢀtoxic and often cheap organic compounds as catalysts,
along with the functional group tolerance, mild reaction conditions and high enantioselectivities in a
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wide scope of asymmetric reactions represent some of the most important features. These requirements
are often hard to fulfill, and exhaustive experimentation by trial and error (with the concomitant
investment of time, funding and manpower) is the most common attempt to succeed. Although high
throughput methods can notably speed this process, the ability to rationally design the optimal catalyst
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for any given transformation will probably dominate the discipline in years to come. One of the main
challenges lies in anticipating how subtle structural features in the catalyst would affect the
enantioselection of the system under study.
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Modern computational chemistry can be particularly helpful in this area, providing a valuable insight
into the mechanism, unraveling the factors influencing the stereoselectivity and facilitating the design
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and optimization of a wide variety of asymmetric organocatalyzed reactions. Understanding the origins
of the enantioselectivity experimentally found in asymmetric reactions represents the most common
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contribution of computational chemistry in the field. In turn, this knowledge might end up guiding the
design of more powerful organocatalysts. In fact, it is not uncommon the in silico development of novel
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organocatalysts, rationally designed to achieve remarkable levels of stereoselection. However, to the
best of our knowledge, the experimental verification of the computational predictions made beforehand
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(the ultimate goal of any theoretical model) was achieved only in few cases.
Recently, we reported an efficient and straightforward synthesis or novel chiral pyrrolidines via 1,3ꢀ
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dipolar cycloaddition reactions between levoglucosenone (1), a biomass derived chiral enone, and Nꢀ
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metallated azomethine ylides 2 (Figure 1).
R1
OMe
R2
N
O
O
Ag
O
O
O
2
H
R1
O
O
H
MeO C
2
1
HN
R2
promising iminium
ion-based organocatalysts
Figure 1. Chiral pyrrolidines derived from levoglucosenone as promising iminium ionꢀbased organocatalysts.
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The proofꢀofꢀprinciple usefulness of such molecular scaffolds was demonstrated in iminiumꢀion based
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asymmetric DielsꢀAlder (DA) reactions between (E)ꢀcinnamaldehyde and cyclopentadiene. Good
catalytic activity, high exo selectivity and acceptable levels of enantioselection (up to 76% ee), along
with the fact that the catalyst is easily derived from cheap and renewable sources, encouraged us to
invest efforts in the rational design of more efficient chiral organocatalysts. This article illustrates the
journey to pursue our goals by means of a joint experimental, NMR and computational studies.
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Results and discussion
Our initial studies were conceived to explore and understand the catalysts structure/activity relationship
in the cycloaddition between (E)ꢀcinnamaldehyde (6) and cyclopentadiene (7), one of the most valuable
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model reactions to test the efficiency of novel iminiumꢀbased organocatalysts. As shown in Table 1,
the catalytic performance of 21 structurally diverse pyrrolidines 3-5 were evaluated using standard
experimental conditions (MeOH:H O 9:1; 15 mol% catalyst load, 15 mol% HClO as coꢀcatalyst, 25
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4
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°C). This small library, that was synthesized according our previously reported procedure, was chosen
to introduce three dimensions of molecular diversity: the relative stereochemistry at Cꢀ7 and Cꢀ8, and
the nature of the R and R groups at those positions, respectively. Interestingly, all the amines under
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study displayed important catalytic activity comparing with the thermally driven cycloaddition (entry 1),
increasing up to 160 fold the reaction rate. As a general trend, the pyrrolidines with a 7ꢀ(S) configuration
(4 and 5) were much more reactive catalysts than the corresponding 7ꢀ(R) adducts (3), clearly indicating
that the relative stereochemistry of the pyrrolidinic core has a substantial influence in the reactivity of
the system. On the other hand, increasing the bulkiness of R (H>Me>Bn) led to longer reaction times
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for each series, though the aromatic moiety (R ) at Cꢀ7 did not affect significantly the reaction rate. In
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contrast to the thermal cycloaddition (entry 1), all organocatalyzed reactions were exo selective. The
levels of stereoselectivity ranged from poor to good (up to 82:18, entry 18), resulting an interesting
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c,d
observation considering that few organocatalysts lead to a clear preference toward the exo isomers.
Hereagain, the exo/endo ratio is largely governed by the relative stereochemistry at Cꢀ7 and Cꢀ8 of the
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pyrrolidine and the nature of R . While endo adducts 3 afforded the lowest levels of exo selectivity, its
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Cꢀ7 epimers (5) lead to the most selective reactions, mainly those bearing a quaternaty center at Cꢀ8 (R1
= Me or Bn).
Table 1.Effect of the pyrrolidine structure on the DielsꢀAlder reaction between (E)ꢀcinnamaldehyde (6) and
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a
cyclopentadiene (7).
O
O
O
O
O
O
5
1
H
H
H
R1
3
R1
R1
8
O
O
O
MeO C
7
H
MeO C
H
MeO C
H
2
2
2
HN
HN
HN
3
R2
4
1
R2
5
R2
A) R =H, B) R =Me, C) R =Bn
a) R =Ph, b) R =2-Naph, c) R =2-Furyl
1
1
2
2
2
cat (15 mol%)
CHO
CHO
Ph
HClO (15 mol%)
4
+
+
MeOH-H O
Ph
2
Ph
8 exo-(2R)
CHO
8 endo-(2R)
r.t.
6
7
yield
(%)
c,d
exo ee
(%)
endo ee
(%)
entry
cat.
R1
R2
time (h)
b
exo:endo
d
d
1
2
3
4
5
6
7
8
9
ꢀ
ꢀ
H
H
H
H
H
H
H
ꢀ
480
5
5
8
96
3
5
96
3
5
20
8
72
8
72
8
70
48
72
48
72
48
15
87
97
95
71
90
94
84
91
96
45
98
66
99
42
97
18
85
45
87
55
92
26 : 74
68 : 32
68 : 32
72 : 28
71 : 29
74 : 26
76 : 24
70 : 30
76 : 24
73 : 27
68 : 32
81 : 19
72 : 28
81 : 19
68 : 32
79 : 21
47 : 53
82 : 18
72 : 28
78 : 22
71 : 29
80 : 20
ꢀ
ꢀ
3Aa
4Aa
5Aa
3Ab
4Ab
5Ab
3Ac
4Ac
5Ac
3Ba
5Ba
3Bb
5Bb
3Bc
5Bc
3Ca
5Ca
3Cb
5Cb
3Cc
5Cc
Ph
Ph
Ph
6 (2R)
4 (2S)
10 (2S)
6 (2R)
54 (2R)
14 (2S)
24 (2R)
64 (2R)
0
10 (2S)
63 (2R)
34 (2S)
70 (2R)
30 (2S)
72 (2R)
6 (2R)
32 (2R)
8 (2R)
80 (2R)
30 (2R)
76 (2R)
52 (2R)
84 (2R)
56 (2R)
16 (2S)
10 (2S)
44 (2R)
10 (2S)
44 (2S)
52 (2R)
4 (2R)
2ꢀNaph
2ꢀNaph
2ꢀNaph
2ꢀFuryl
2ꢀFuryl
2ꢀFuryl
Ph
H
H
1
1
1
0
1
2
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
Ph
72 (2R)
2 (2S)
13
14
2ꢀNaph
2ꢀNaph
2ꢀFuryl
2ꢀFuryl
Ph
68 (2R)
20 (2R)
58 (2R)
26 (2R)
80 (2R)
72 (2R)
64 (2R)
82 (2R)
84 (2R)
1
1
1
5
6
7
18
Ph
1
2
2
2
9
0
1
2
2ꢀNaph
2ꢀNaph
2ꢀFuryl
2ꢀFuryl
a
b
General reaction conditions: 5 equiv. cyclopentadiene, 15mol% catalyst, 15mol% HClO
chromatography. Determined by H NMR. Determined by chiral GC.
4
, MeOH:H
2
O 9:1, r.t.
Isolated yield after column
c
1
d
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Last, the asymmetric induction capacity of the evaluated amines ranged from poor to very good (up to
4% ee, entry 22). The exo catalysts 4, the most reactive under study, afforded unsatisfactory levels of
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enantioselection (up to 44% ee, entry 9). Similar observations were made with the pyrrolidines with
endo stereochemistry (compounds 3), which with the exceptions of two cases (entries 19 and 21), also
gave poor ee´s (up to 34%, entry 11). In contrast, compounds 5 afforded the highest facial selectivities
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(44%ꢀ84% ee for exo adducts; 32%ꢀ84% ee for endo adducts). In this case, both the substitution at Cꢀ7
and Cꢀ8 affected the reaction outcome. Regarding the nature of R , a general trend was observed: bulkier
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groups at Cꢀ8 leads to higher ee´s, being the derivatives of phenylalanine (R =Bn) the most selective
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organocatalysts under study. On the other hand, the effect of the aromatic moiety at Cꢀ7 depends on the
substituent at Cꢀ8. For instance, R =Ph is preferred when R =H or Me, while R =2ꢀfuryl gave better
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2
results when R =Bn.
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To sum up, the best overall results were obtained with 5B (R =Me) and 5C (R =Bn), but considering a
1
1
balance between reactivity and selectivity the former (5B) was identified as the most promising core for
further optimization. Despite 5C afforded the highest exo/endo and enantiomeric ratios, the selectivities
achieved with their analogs 5B were slightly inferior, but with a great improvement in the reactivity of
the system.
Turning now to the reaction mechanism, whose knowledge is critical for rational design purposes, the
proposed catalytic cycle is depicted in Scheme 1. Condensation of the catalyst 3-5 with aldehyde 6
generates the iminium intermediate Im. The formation of this positively charged species lowers the
LUMO energy of the α,βꢀunsaturated moiety, leading to a more reactive dienophile. This step is crucial
in the success of the catalytic system, both increasing the rate and allowing facial discrimination in the
[4+2] cycloaddition to cyclopentadiene. Finally, iminium adducts P-Im hydrolyze to release the desired
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adducts endo and exo 8 (in both enantiomeric forms) and regenerates the catalyst for the next cycle.
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R
O
O
H
8
CHO
R
O
R
O
6
9
(R=Ph)
(R=Me)
R1
H
HN
H O
2
R2
3-5
H O
2
O
O
O
O
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H
H
R
R
O
O
R1
H
R1
H
N
N
R2
R2
P-Im
Im
R
R
7
Scheme 1. Proposed catalytic cycle.
To gain more evidence and provide confidence in theoretical models for further optimization, we
undertook a B3LYP/6ꢀ31G* computational study of the reaction between (E)ꢀcrotonaldehyde (9) and
cyclopentadiene, both thermally driven and catalyzed by compound 5Ba. Figure 2 shows the most stable
conformations found for the isomeric (E) and (Z) iminium ions derived from the condensation of 5Ba
1
0
and 9. Our calculations suggest that the (Z) isomer is 2.47 kcal/mol less stable than the (E) isomer, due
to steric repulsion between Ha/Cꢀ7 and Hα/CH in the former.
3
2.50
Ha
2.09
Hα
Hβ
(
E)-Im-5Ba
Erel = 0.0 kcal/mol
(Z)-Im-5Ba
Erel = 2.47 kcal/mol
Figure 2. B3LYP/6ꢀ31G* optimized geometries found for (E) and (Z) iminium ion derived from the condensation between
Ba and 9.
5
Conceptual DFT analysis provided theoretical explanation for the notable acceleration of the catalyzed
1
1
reactions. The global electrophilicity index (ω), which measures the stabilization energy when the
1
2
system acquires an additional electronic charge ꢀN from the environment, is much higher for (E)-Im-
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Ba than that for (E)ꢀcrotonaldehyde (8.94 vs. 1.62 eV). This indicates that the former is a much
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powerful electrophile (defined within the scale), increasing the polarity of the DA reaction (as
ω
1
3
measured by the amount of charge transferred from the diene to the dienophile along the TS). On the
+
k
other hand, the computed difference between Cα and Cβ P (Parr function on atom k) are higher for
+
k
0
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(E)-Im-5Ba than that for (E)ꢀcrotonaldehyde (ꢀP = 0.76 vs. 0.47), suggesting that more asynchronous
1
4
transition structures should be expected for the iminiumꢀderived dienophile.
‡
Within the distortion/interaction model, the activation energy (ꢀE ) is decomposed as the sum of the
‡
distortion energy (ꢀE , energy required to distort the reactants from their initial geometries to their
d
‡
transition state geometries), and the interaction energy ꢀE (binding energy between the deformed
i
1
5
reactants in the transition state, normally a negative value). It has been recently found that polar and
asynchronous DA reactions affords highly interacted and low distorted TS, leading to low energy
14
‡
barriers. In this case, the ꢀE computed for the reaction between (E)-Im-5Ba and 7 are only 3.0
kcal/mol (8.8 kcal/mol in solution), much lower than the 20.9 kcal/mol (20.9 kcal/mol in solution)
calculated for the uncatalyzed cycloaddition of 7 and 9. As expected from the conceptual DFT analysis,
the charge transfer found for TS-(E)-Im-5Ba+7 is 0.41e, ∼2.9 times higher than that computed for TS-
‡
9
+7 (0.14e). As a consequence, ꢀE is much lower for the former (ꢀ21.3 kcal/mol vs. ꢀ8.6 kcal/mol).
i
Moreover, the asynchronicity, ꢀd (defined as the difference in the two bond forming distances at the TS)
‡
is higher for TS-(E)-Im-5Ba+7 (0.99Å vs. 0.34Å), leading to lower ꢀE (24.2 kcal/mol vs. 29.5
d
1
7
kcal/mol).
Such difference in energy barriers is fully consistent with the rate increase experimentally found for the
organocatalyzed cycloaddition. In addition, these barriers indicated that >99.9% of the reagents should
react via the catalyzed path (based on the activation barriers difference and assuming that the rate of
formation and hydrolysis of the iminium are much faster than the thermal DA path), the
enantioselectivity of the process can be predicted, at least in principle, from the analysis of the
competing iminiumꢀderived transition structures.
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In this context, we planned to experimentally demonstrate the formation of an iminium ion intermediate.
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The H NMR spectra of 5Ba in CD OD were recorded prior to and after the addition of 1 equiv. of TFA
3
1
7
1
and 5 equiv. of (E)ꢀcinnamaldehyde, in that order. Apart from the H NMR shifts of 6 and protonated
5
Ba (5Ba-H), we were able to detect signals consistent with the formation of an iminium ion in a 1:2.7
1
ratio (relative to 5Ba-H). The H NMR of 5Ba-H showed chemical shifts of Hꢀ7 and the methyl group
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
at Cꢀ8 at δ 5.36 and 1.71 ppm, respectively (Figure 3). In comparison, those signals were shifted
H
downfield to δ 6.49 (ꢀδ 1.13 ppm) and 2.19 ppm (ꢀδ 0.48 ppm), respectively, in the intermediate.
H
H
H
This, along with the observation of key resonances at δ 9.07 ppm (dd, J=10.9 Hz, J=1.8 Hz) and δH
H
8
.06 ppm (d, J=15.2 Hz), were fully consistent with the formation of the proposed iminium. The last
two signals were assigned to Ha and Hβ of Im-5Ba (Figure 3) based on the evident similarity to those
reported for the iminium ion obtained from the condensation of MacMillan imidazolidinone and 6 (δH
1
6
9
.05 ppm and δ 8.15 ppm, respectively). Further evidence for our assignment came from NOE
H
experiments: irradiation at Ha (δ 9.07 ppm) resulted in an enhancement of the signals of Hβ and the
H
1
7
methyl group at Cꢀ8 (Figure 3). This finding allowed us to establish that the preferred geometry of Im-
Ba is (E), in line with our computational results discussed above (Figure 2).
5
O
O
O
CHO
O
Ph
1.71
2.19
H C
3
H
H
H C
6
3
O
O
MeO C
H
MeO C
2
H
2
CD OD
3
H N
2
N
6.49
9
.07
Ph
Ph
Hα
Im-5Ba
Ha
5
.36
8
.06
5
Ba-H
Hβ
Ph
1
Figure 3. Key H NMR signals of 5Ba-H and Im-5Ba, and NOE correlations (red arrows).
The sense of asymmetric induction experimentally found for 5Ba is consistent with selective approach
of cyclopentadiene from the less hindered (re) face of (E)-Im-5Ba. In fact, all competing transition
structures were next located at the B3LYP/6ꢀ31G* level of theory (Figure 4 shows the most stable
conformers found for each mode of addition). In all cases, the TSs are highly asynchronous, with the Cꢀ
C bond formation involving the Cꢀβ of the dienophile (the most electrophilic center) almost fully
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developed (1.99ꢀ2.05 Å) while the second CꢀC bond is only emerging (3.02ꢀ3.04 Å). The calculated
relative activation energies reflect excellent agreement with the experimental findings. As expected, the
TSs arising from the (E)-Im-5Ba are 1.9ꢀ3.7 kcal/mol more stable than those resulting from the (Z)ꢀ
iminium geometries. Good facial discrimination (1.6 kcal/mol) was computed for the (E)-Im-5Ba+7
TSs, mainly because repulsive steric interactions between cyclopentadiene and the phenyl ring directed
towards the βꢀface of the molecule. The Boltzmann distribution using all stable conformers found for
each reaction channel predicts the exoꢀ(2R)ꢀproduct formation in 78% ee, close to the experimentally
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
7
found value of 72% ee.
3
.04
3.02
2.05
2.03
TS-(E)-Im-5Ba+7-Re
TS-(E)-Im-5Ba+7-Si
Erel = 0.0 kcal/mol
Erel = 1.60 kcal/mol
3
.04
3
.03
1
.99
2
.05
TS-(Z)-Im-5Ba+7-Re
TS-(Z)-Im-5Ba+7-Si
Erel = 3.66 kcal/mol
Erel = 3.47 kcal/mol
Figure 4. B3LYP/6ꢀ31G* optimized geometries for the TSs (global minima) found for each mode of addition in the
reaction between Imꢀ5Ba and 7. Selected distances are given in Å.
The enantioselection could be fairly predicted by standard DFT methods, leading to the paramount
opportunity to perform an in silico screening of new organocatalysts. However, considering the size of
the present systems, the CPU time would be prohibitely long for rational design purposes, even at the
often affordable B3LYP/6ꢀ31G* level of theory. To overcome this limitation, we considered the use of
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1
8
the hybrid ONIOM method. In this approach, the small core region involving bond forming and bond
breaking events are modeled using a high level of theory, while the rest of the system is treated with a
less accurate model. The energy of the real system at the high level can be estimated using an
extrapolation scheme as, E(ONIOM,real) = E(high,model) + E(low,real) ꢀ E(low,model). The stereoselectivity of a wide
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
9
variety of organic reactions could be fairly explained using this approach, but to the best of our
knowledge there are no background on the use of ONIOM in iminiumꢀbased asymmetric DielsꢀAlder
reactions. Intrigued by whether such computational method could provide accurate prediction of the
stereochemical outcome in the studied reactions, we selected a small data set comprised with 8
secondary amines that had been already tested as chiral organocatalysts in the DA reaction between (E)ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
cinnamaldehyde and cyclopentadiene (Figure 5).
R
O
Me
N
NH
R
R
R
Me
Me
N
N
H
Bn
H
N
N
H
10A
10B
10C H
10D
4
8% ee (R)
56% ee (R)
58% ee (S)
93% ee (S)
O
O
O
O
O
O
O
O
H
H
H
H
H C
H C
3
3
R
O
O
O
O
H
R
H
R
H
R
H
HN
HN
HN
HN
4Aa
% ee (S)
5Ba
72% ee (R)
5Bb
68% ee (R)
5Ca
80% ee (R)
4
Figure 5. Set of 8 secondary amines that were used as chiral organocatalysts in DA reactions between 6 and 7 (R=CO Me).
2
The ee´s correspond to the experimental selectivity towards the exo adduct.
8a
Amines 10A-D were taken from the seminal publication of MacMillan, while the remaining four were
evaluated in the present work. The data set was chosen to provide structural diversity and a broad range
of experimental ee´s (ranging from 4 to 93% ee). To reduce the computational cost we used (E)ꢀ
crotonaldehyde (9) instead (E)ꢀcinnamaldehyde (6), and only the exo transition structures were taken
2
0
into consideration. Figure 6 illustrates the optimal partitioning scheme that, after preliminary trials,
afforded best results at minimal computational cost. The reacting system (α,βꢀinsaturated iminium and
cyclopentadiene fragments) was optimized at the B3LYP/6ꢀ31G* level of theory, while the remainder of
the system was treated using the semiempirical method AM1. Poor results were obtained using
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molecular mechanics in the lower layer (MMFF), as well as using the ONIOM(B3LYP/6ꢀ31G*:AM1)
relative energies to compute the enantioselection of each catalyst. In contrast, B3LYP/6ꢀ31G* singleꢀ
point energies with the polarizable continuum model (PCM) on the optimized ONIOM structures with
methanol as solvent provided good agreement with the magnitude of the stereoselectivities.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 6. ONIOM(B3LYP/6ꢀ31G*:AM1) partition scheme. Grayedꢀout regions (low layer) were treated with AM1, and
the fullꢀcolored regions (high layer) with B3LYP/6ꢀ31G*.
Table 2 shows the enantioselectvity computed for each organocatalyzed reaction using a Boltzmann
1
7
distribution of all significantly populated conformers (up to 5.0 kcal/mol of the lowestꢀenergy TS).
The agreement between experimental and calculated data is noteworthy, both qualitatively (i.e. the sense
of stereoinduction is correct) and quantitatively. It is also important to point out the impressive reduction
in CPU time that was achieved with this method (more than 40 times faster than standard B3LYP/6ꢀ
31G* treatment).
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 2. Experimental and calculated enantioselectivity in the DA reactions between 6 and 7 catalyzed by the chiral
amines shown in Figure 5 at the PCM/B3LYP/6ꢀ31G*//ONIOM(B3LYP/6ꢀ31G*:AM1) level of theory.
exo ee (%)
experimental
48 (2R)
56 (2R)
58 (2S)
exo ee (%)
calculated
48 (2R)
52 (2R)
50 (2S)
entry
cat.
1
2
3
4
5
6
7
8
10A
10B
10C
10D
4Aa
5Ba
5Bb
5Ca
92 (2S)
4 (2S)
72 (2R)
68 (2R)
80 (2R)
92 (2S)
14 (2R)
80 (2R)
82 (2R)
96 (2R)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
With this model in hand, we foresaw the in silico screening of catalysts with the 5B core and different
R groups at Cꢀ7 as the structural element to modulate the catalyst´s enantioselection. Then, we decided
2
to evaluate the inductive capacity of 62 catalysts (Figure 7) that were selected to provide a wide array of
molecular diversity and because the commercial availability and affordable cost of the corresponding
1
7
aldehyde precursor.
O
O
H
MeO C
O
2
H
Me
HN
5
R2
B
X
R
N
R
R
N
H
0
0
0
0
0
0
0
0
0
1
1
1
1 (H)
13 (p-Ph)
25 (X=O,R=3-CH )
37 (R=H)
42 (2-indoyl)
43 (3-indoyl)
44 (4-indoyl)
45 (6-indoyl)
46 (7-indoyl)
3
2 (o-CH ) 14 (o-Cl)
26 (X=O,R=4-CH )
38 (R=3-CH )
3
3
3
3 (m-CH ) 15 (m-Cl)
27 (X=O,R=5-CH )
39 (R=4-CH )
3
3
3
3
3
3
4 (p-CH ) 16 (p-Cl)
28 (X=O,R=5-Ph)
40 (R=5-CH )
5 (o-OMe) 17 (o-iPr)
29 (X=O,R=5-CF )
41 (R=6-CH )
3
6 (m-OMe) 18 (m-iPr) 30 (X=S,R=3-CH )
3
7 (p-OMe) 19 (p-iPr)
31 (X=S,R=4-CH )
3
3
8 (o-NO ) 20 (o-tBu) 32 (X=S,R=5-CH )
47 (R=9-anthracenyl)
48 (R=2-fluorenyl)
49 (R=9-phenanthryl)
50 (R=1-pyrenyl)
2
2
2
9 (m-NO ) 21 (m-tBu) 33 (X=S,R=5-Ph)
0 (p-NO ) 22 (p-tBu) 34 (X=S,R=5-CF )
R
3
1 (o-Ph)
23 (p-CF
3
)
35 (X=O,R=5-CH OMe)
2
2 (m-Ph) 24 (p-iBu) 36 (X=S,R=5-2-thionyl)
X
NH
X
Y
X
R
R
R
R
5
9 (X=O,R=H)
5
1 (R=CH )
54 (X=C) 56 (X=N,Y=C)
55 (X=N) 57 (X=C,Y=N)
60 (X=S,R=H)
3
53
58
5
2 (R=CF )
61 (X=O,R=Me)
3
62 (X=S,R=Me)
Figure 7. 62 catalysts (5B-01 ꢀ 5B-62) chosen for in silico screening.
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1
2
In an additional simplification, all transition structures arising from the (Z)ꢀiminium ion were neglected,
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
7
as were found to be much higher in energy and not contributing significantly to the overall selectivity.
‡
Once the calculations were done, the predicted ꢀꢀE values were translated into enantioselectivity
1
7
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
values at 25 ºC using Boltzmann averaging (Figure 8).
5
B-52 (top-scored)
1
00.0
9
9
8
8
5.0
0.0
5.0
0.0
5
B-07
75.0
70.0
65.0
60.0
55.0
50.0
5
B-35
1
5
9
13 17 21 25 29 33 37 41 45 49 53 57 61
Catalyst Number
Figure 8. Calculated ee versus catalyst number.
The topꢀscored catalyst was compound 5B-52, bearing a 3,5ꢀbis(trifluoromethyl)phenyl substituent at
the R position. This result was promising as such structural motif is present in many highly asymmetric
2
2
1
inductors. The selected compound was next synthesized following our previously reported general
7
procedure (Scheme 2). Iminoester 11B-52 was prepared in good yield from condensation of
commercially available 3,5ꢀbis(trifluoromethyl)benzaldehyde and alanine methyl ester hydrochloride.
Reaction of levoglucosenone (1) with 11B-52 in the presence of catalytic silver acetate and DBU yielded
the expected endo isomer, that after a short column chromatography to eliminate silver salts and excess
of iminoester, was immediately heated in a 5:95 TFA:CHCl solution at 110 ºC for a period of 40
3
minutes using microwave irradiation. The desired compound 5B-52 was obtained in 73% overall yield,
1
7
and its structure was inequivocally corroborated after extensive NMR experiments.
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2
3
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
F3C
CF3
O
O
O
TFA
CHCl3
ꢁW
O
N
H
H
Me
R
Me
R
Me
R
O
O
O
O
11B-52
110 ºC
H
H
HN
HN
AgOAc
O
DBU
73%
CF3 (2 steps)
CF
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
MeCN, r.t.
5B-52
F3C
F C
3
Scheme 2. Synthesis of the in silico topꢀscored screened catalyst 5B-52 (R=CO Me).
2
With the new catalyst in hand, we were excited to find excellent results when using it in the DA reaction
between 6 and 7 at the standard reaction conditions (96% yield, exo/endo 71:29, 90% ee and 92% ee for
the exo and endo isomers, respectively, entry 1, Table 3). It is important to point out that such
enantioselection could not be achieved with any of the 21 pyrrolidines experimentally evaluated before
(Table 1), highlighting the relevance of the in silico screening. To further evaluate the ranking ability of
our ONIOMꢀbased computational method, we synthesize two additional catalysts: compounds 5B-07
and 5B-35 (highlighted in Figure 8), bearing a pꢀmethoxyphenyl and 5ꢀmethoxymethylꢀ2ꢀfuryl
substituents at the Cꢀ7 position. These compounds were taken as representative examples of medium
and lowꢀscored catalysts, respectively, and were synthesized in 83% and 80% overall yield as described
1
7
for 5B-52. Both pyrrolidines were tested in the standard DA reaction between 6 and 7, and afforded
very good results in terms of yields (99%) and exo selectivity (81:19 and 75:25, respectively). Regarding
the enantioselectivities, we were glad to find that the experimental values (72% ee and 56% ee,
respectively) were in good accord to our predictions (82% ee and 54% ee, respectively), strengthen our
1
7
confidence in the computational model. Moreover, as discussed above, the catalysts 5C (R =Bn)
1
afforded slightly higher selectivities than those with the 5B (R =Me) core, though with a significant
1
decrease in the reactivity (Table 1). Therefore, we wondered whether the introduction of a 3,5ꢀ
bis(trifluoromethyl)phenyl moiety at the Cꢀ7 position of 5C would led to even better enantiomeric ratios
than those obtained with 5B-52. The performance of the resulting catalyst (5C-52, R =Bn, R =3,5ꢀ
1
2
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(
CF ) C H ) was evaluated in silico using our ONIOM approach. Interestingly, the prediction (90% ee)
3 2 6 3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was lower than the computed values for 5B-52 (97% ee), suggesting that such structural modification
would not be favorable in the former. To validate this result, compound 5C-52 was sinthesized in 70%
overall yield, and was evaluated in the DA reaction between 6 and 7 at the standard conditions. After 48
hours the desired adducts 8 were isolated in 66% yield, exo/endo 69:31, 76% ee and 86% ee for the exo
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
7
and endo isomers, respectively. Thus, in line with the computational results, the introduction of a 3,5ꢀ
CF ) C H group at the Cꢀ7 position of 5C did not improve its catalytic activity.
(
3
2
6
3
The effect of the reaction conditions in the outcome of the DA reaction between 6 and 7 catalyzed by the
in silico optimized 5B-52 was next evaluated in detail (Table 3). Several acids were investigated as coꢀ
catalysts (entries 1ꢀ6), and found that the reaction proceeded badly in the presence of the weaker acids
PhCO H and H PO . In contrast, strong acids (HClO , HCl, TFA, CSA) performed well in terms
2
3
4
4
reactivity and selectivity, though slightly better enantioselectivities were obtained with the former.
Screening of solvents (entries 1, 6ꢀ13) indicated that despite THF was not suitable, a wide variety of
aqueous solvents (MeOH, EtOH, CH Cl , MeCN, H O) afforded good results. Lower selectitivies were
2
2
2
observed with acetonitrile (entry 9), while the highest levels of exo/endo ratio and ee´s were obtained
with MeOH:H O 9:1 (entry 1). Higher (entry 12) or lower (entry 13) water content in the methanolic
2
solvent mixture gave slightly lower exo ee´s. Though we have used 15 mol% of catalyst in the above
reactions, loading can be reduced to 5 mol% with minor effects in the reaction outcome. Moreover,
running the reactions at 0 ºC allowed to increase the enantioselection of the process (exo 92%ee, endo
8
97%ee), reaching the levels of selectivity found for leader organocatalysts. Finally, as an additional
important feature of our system, it is noteworthy that compound 5B-52 could be recovered quantitatively
after workꢀup and column chromatography, and reused more than 5 times with no evident loss in its
catalytic capacity. The ease of recovery represent a key aspect in modern organocatalysis, and much
effort has been made in the immobilization of known organocatalysts in solid supports to facilitate the
2
2
recycling process.
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1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 3. Effect of the reaction conditions on the DielsꢀAlder reaction between (E)ꢀcinnamaldehyde (6) and cyclopentadiene
a
(
7) catalyzed by 5B-52.
5
B-52
Coꢀcatalyst
(mol%)
Temp
(°C)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
Time
(h)
12
12
12
12
60
12
12
12
12
12
12
12
12
12
12
Yield
(%)
c,d
exo ee
(%)
endo ee
(%)
Entry
Solvent
b
exo:endo
d
d
(mol%)
15
15
15
15
15
15
15
15
15
15
15
15
15
5
1
2
3
4
5
6
7
8
9
HClO (15)
MeOH:H O 9:1
96
99
99
92
42
50
93
93
97
38
95
99
99
88
71:29
70:30
70:30
70:30
69:31
70:30
69:31
72:28
64:36
65:35
67:33
71:29
70:30
69:31
90
84
84
84
82
84
84
86
76
82
82
84
88
84
92
92
94
92
92
80
90
92
88
90
92
90
90
92
92
97
4
2
TFA (15)
HCl (15)
CSA (15)
MeOH:H O 9:1
2
MeOH:H O 9:1
2
MeOH:H O 9:1
2
PhCO H (15)
MeOH:H O 9:1
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H PO (15)
MeOH:H O 9:1
3
4
2
HClO (15)
EtOH:H O 9:1
4
2
HClO (15)
DCM:H O 9:1
4
2
HClO (15)
MeCN:H O 9:1
4
2
1
0
1
2
3
5
6
HClO (15)
THF:H O 9:1
4
2
1
1
1
1
1
HClO (15)
H O
4
2
HClO (15)
MeOH:H O 7:3
4
2
HClO (15)
MeOH:H O 99:1
4
2
HClO (5)
MeOH:H O 9:1
4
2
15
HClO (15)
MeOH:H O 9:1
82
68:32
4
2
a
b
c
1
d
General reaction conditions: 5 equiv. cyclopentadiene Isolated yield after column chromatography. Determined by H NMR. Determined by chiral GC.
Conclusions
An efficient organocatalyst for iminiumꢀion based asymmetric DA reactions has been rationally
designed combining experimental, NMR and computational studies. The most influential
structure/activity relationships were determined experimentally, while DFT calculations and NMR
studies provided further mechanistic insight. This knowledge guided an in silico screening of 62
different catalysts using an ONIOM(B3LYP/6ꢀ31G*:AM1) transitionꢀstate modeling, that showed good
correlation between theory and experiment. The topꢀscored compound was easily synthesized from
levoglucosenone, a biomassꢀderived chiral enone, and evaluated in the DA reaction between (E)ꢀ
cinnamaldehyde and cyclopentadiene. In line with the computational finding, excellent results (up to
9
7% ee) were obtained. To the best of our knowledge, this type of methodology has no precedent in the
development of efficient asymmetric organocatalysts. In addition, the novel catalyst is easily prepared
from renewable sources and can be recovered and reused with no loss in its catalytic activity. Current
studies on the use of this catalyst in other iminiumꢀpromoted transformations are currently being
undertaken and will be published in due course.
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Computational details
All DFT calculations were carried out with the B3LYP exchangeꢀcorrelation functional coupled with
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
3
2
4
the standard 6ꢀ31G* basis set using Gaussian 09. All stationary points were characterized by frequency
calculations, and all TSs were confirmed to have only one imaginary frequency corresponding to the
2
5
formation of the expected bonds. The CT were computed with the Natural Bond Order (NBO) method.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The global electrophilicity index, ω, was computed according to the following expression, ω
2
=
ꢁ /2η (eV), where ꢁ is the electronic chemical potential and η the chemical hardness. Both quantities
were estimated on the basis of the oneꢀelectron energies from the HOMO and LUMO, ε and ε , as ꢁ ~
H
L
2
6
+
(
ε + ε )/2 and η ~ (ε – ε ). The P (electrophilic Parr function of atom k), was computed using the
H
L
L
H
k
Mulliken atomic spin density (ASD) by singleꢀpoint UB3LYP/6ꢀ31G* calculations of the anion
27
resulting from adding one electron to the optimized neutral B3LYP/6ꢀ31G* geometry. The in silico
screening was carried out as following. Extensive conformational searches were performed to locate the
most stable conformations of all competing transition structures. First, a large number of geometries
were generated exploring the conformational space of the low region of the molecule with the MM+
2
8
29
force field (as implemented in Hyperchem) while keeping the high region frozen at the B3LYP/6ꢀ
1G* geometry. All structures were then reoptimized using the ONIOM(B3LYP/6ꢀ31G*:AM1) level of
theory using the partition scheme discussed above. Finally, B3LYP/6ꢀ31G* singleꢀpoint energy
3
3
0
calculations with the polarizable continuum model (PCM) using methanol as solvent were performed
on the resulting structures and were used to correct the gasꢀphase energies derived from the ONIOM
calculations. The exo R/S ratios were computed using Boltzmann factors based on the relative energies
in solution of all competing TSs.
Experimental Section
Microwave heating was performed in a CEM Discover® System using septumꢀsealed 10 mL vials for
highꢀpressure reaction conditions with stirring and IRꢀmonitored temperature control. All reagents and
solvents were used directly as purchased or purified according to standard procedures. Analytical thin
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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 H SO + 0.25 mL of AcOH + 95 mL of EtOH) with subsequent heating. Column
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
4
chromatography was performed with silica gel 60 H, slurry packed, run under low pressure of nitrogen.
1
13
NMR spectra were recorded at 300 MHz for H, and 75 MHz for C with CDCl as solvent and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
13
(CH ) Si ( H) or CDCl ( C, 76.9 ppm) as internal standards. Chemical shifts are reported in delta (δ)
3
4
3
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 constants are recorded in Hertz (Hz). Isomeric ratios were
1
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 sodium chloride plates pellets.
–
1
Absorbance frequencies are recorded in reciprocal centimeters (cm ). High resolution mass spectra
(HRMS) were obtained on a TOFꢀQ LCꢀMS spectrometer. Optical rotations were determined using a
digital polarimeter in 100 mm cells and the sodium D line (589 nm) at room temperature in the solvent
and concentration indicated. The melting points are uncorrected. Levoglucosenone (1) was prepared
6d
from microwaveꢀassisted pyrolysis of acid pretreated microcrystalline cellulose. The 21 pyrrolidines
7
shown in Table 1 of the manuscript were synthesized following the procedure developed in our group.
The αꢀimino esters 11B-07, 11B-35, 11B-52 and 11C-52 were prepared by condensation of the alanine
or phenylalanine methyl ester hydrochloride and the corresponding aldehyde according to known
3
1
procedures.
General procedure for the synthesis of the levoglucosenone-derived organocatalysts
To a solution of 1 (126 mg, 1 mmol) and the corresponding αꢀiminoester 11 (1.5 mmol) in dry MeCN
(10 mL) was successively added AgOAc (50 mg, 0.3 mmol) and DBU (45 ꢁL, 0.3 mmol). The mixture
was stirred for 1 hour at room temperature under argon atmosphere and in the absence of light (flask
covered in aluminum foil). After filtration through Celite, the filtrate was concentrated to dryness under
reduced pressure. The residue was filtered through a shot path of silica gel, concentrated to dryness, and
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The Journal of Organic Chemistry
dissolved in a 95:5 CHCl :TFA solution (2 mL). The resulting solution was stirred at 110 ºC in the
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
microwave reactor until complete conversion of the starting material (tipically 40 min). The solvent was
removed under reduced pressure, and the crude was purified by column chromatography with elution
with mixtures of hexanes and ethyl acetate to afford pure compounds 5B-07 (83%), 5B-35 (80%), 5B-52
(73%) or 5C-52 (70%).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Adduct 5B-07: white solid; mp = 152ꢀ153 ºC (Hex/CH Cl ); [α] ꢀ96.9 (c 1.27, CHCl ); IR (KBr) ν
2
2
D
3
max
ꢀ1 1
3
358, 2953, 2849, 1738, 1732, 1614, 1510, 1246, 1165, 1111, 1036, 982 cm ; H NMR (CDCl ) δ 7.41
3
(d, J=8.6 Hz, 2H, arom), 6.86 (d, J=8.6 Hz, 2H, arom), 5.11ꢀ5.04 (m, 2H, Hꢀ1 and Hꢀ7), 4.90 (d, J=4.8
Hz, 1H, Hꢀ5), 3.95 (dd, J=7.3 Hz, J=4.8 Hz, 1H, Hꢀ6exo), 3.89 (dd, J=7.3 Hz, J=0.7 Hz, 1H, Hꢀ6endo),
3.79 (s, 3H, Hꢀ12), 3.68 (s, 3H, Hꢀ10), 2.96 (dd, J=4.5 Hz, J=10.3 Hz, 1H, Hꢀ3), 2.52 (d, J=10.3 Hz, 1H,
1
3
Hꢀ4), 2.21 (s, 1H, NH), 1.58 (s, 3H, Hꢀ11); C NMR (CDCl ) δ 198.4 (C, Cꢀ2), 176.0 (C, Cꢀ9), 158.5
3
(C, arom), 137.2 (C, arom), 127.4 (CH,2C arom), 113.7 (CH, 2C arom), 100.7 (CH, Cꢀ1), 71.9 (CH, Cꢀ
5), 68.8 (CH , Cꢀ6), 66.4 (C, Cꢀ8), 59.9 (CH, Cꢀ7), 55.2 (CH , Cꢀ12), 54.9 (CH, Cꢀ4), 53.2 (CH, Cꢀ3),
2
3
+
5
3
2.2 (CH3, Cꢀ10), 25.0 (CH3, Cꢀ11); HRMSꢀESI calc. for C H NNaO [M+Na] 370.12666. Found
18 21 6
70.12644.
Adduct 5B-35: Yellowish oil; [α] ꢀ10,9 (c 1,00, CHCl ); IR (film) ν 3345, 2951, 2922, 2824, 1738,
D
3
max
ꢀ1 1
1
732, 1231, 1113, 980, 881, 797 cm ; H NMR (CDCl ) δ 6.24 (s, 2H, arom), 5.14ꢀ5.07 (m, 2H, Hꢀ1
3
and Hꢀ7), 4.90 (d, J=3.6 Hz, 1H, Hꢀ5), 4.38 (d, J=12.7 Hz, 1H, Hꢀ12a), 4.32 (d, J=12.7 Hz, 1H, Hꢀ12b),
.05ꢀ3.94 (m, 2H, Hꢀ6), 3.68 (s, 3H, Hꢀ10), 3.41ꢀ3.30 (m, 4H, Hꢀ13 and Hꢀ3), 2.62 (d, J=10.0 Hz, 1H,
4
1
3
Hꢀ4), 2.19 (s, 1H, NH), 1.56 (s, 3H, Hꢀ11); C NMR (CDCl ) δ 197.6 (C, Cꢀ2), 175.3 (C, Cꢀ9), 156.1
3
(C, arom), 151.1 (C, arom), 110.2 (CH, arom), 107.2 (CH, arom), 100.7 (CH, Cꢀ1), 72.0 (CH, Cꢀ5),
6
8.8 (CH , Cꢀ6), 66.6 (C, Cꢀ8), 66.3 (CH , Cꢀ12), 57.7 (CH , Cꢀ13), 55.8 (CH, Cꢀ4), 55.2 (CH, Cꢀ7),
2
2
3
+
52.3 (CH3, Cꢀ10), 50.0 (CH, Cꢀ3), 24.9 (CH , Cꢀ11); HRMSꢀESI calc. for C H NNaO [M+Na]
3
17 21
7
3
74.12089. Found 374.12102.
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Adduct 5B-52: Yellowish oil; [α] ꢀ60.4 (c 0.73, CHCl ); IR (film) ν 3346, 2976, 2909, 1738, 1732,
D
3
max
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ꢀ1 1
1435, 1381, 1171, 1126, 984, 683 cm ; H NMR (CDCl ) δ 8.02 (s, 2H, arom), 7.75 (s, 1H, arom), 5.27
3
(d, J=4.7 Hz, 1H, Hꢀ7), 5.15 (s, 1H, Hꢀ1), 4.93 (d, J=4.6 Hz, 1H, Hꢀ5), 3.98 (dd, J=7.3 Hz, J=4.8 Hz,
1
H, Hꢀ6exo), 3.92 (d, J=7.3 Hz, 1H, Hꢀ6endo), 3.71 (s, 3H, Hꢀ10), 2.93 (dd, J=10.2 Hz, J=4.7 Hz, 1H,
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hꢀ3), 2.53 (d, J=10.2 Hz, 1H, Hꢀ4), 1.63 (s, 3H, Hꢀ11); C NMR (CDCl ) δ 197.6 (C, Cꢀ2), 175.9 (C,
3
Cꢀ9), 147.9 (C, arom), 131.5 (2C, q, J=34.4 Hz, arom), 126.7 (CH, 2C, arom), 123.3 (2C, q, J=270.9
Hz, CF ), 120.8 (CH, arom), 100.5 (CH, Cꢀ1), 71.8 (CH, Cꢀ5), 68.8 (CH , Cꢀ6), 66.5 (C, Cꢀ8), 59.2
3
2
(
CH, Cꢀ7), 54.3 (CH, Cꢀ4), 52.8 (CH, Cꢀ3), 52.4 (CH , Cꢀ10), 24.9 (CH , Cꢀ11); HRMSꢀESI calc. for
3 3
+
C H F NNaO [M+Na] 476.08910. Found 476.09031.
1
9
17
6
5
Adduct 5C-52: Yellowish oil; [α] ꢀ99.7 (c 1,00, CHCl ); IR (film) ν 3350, 3032, 2956, 2906, 1732,
D
3
max
ꢀ1
1
1
738, 1381, 1278, 1132, 983, 881, 758, 704, 682 cm ; H NMR (CDCl ) δ 7.95 (s, 2H, arom), 7.73 (s,
3
1H, arom), 7.34ꢀ7.24 (m, 5H, arom), 5.17ꢀ5.15 (m, 2H, Hꢀ1 and Hꢀ7), 5.10 (d, J=4.8 Hz, 1H, Hꢀ5), 4.01
dd, J=7.5 Hz, J=5.0 Hz, 1H, Hꢀ6exo), 3.92 (d, J=7.6 Hz, 1H, Hꢀ6endo), 3.73 (s, 3H, Hꢀ10), 3.52 (d,
J=13.2 Hz, 1H, Hꢀ11a), 3.02 (d, J=13.3 Hz, 1H, Hꢀ11b), 2.87 (dd, J=10.4 Hz, J=4.9 Hz, 1H, Hꢀ3), 2.64
(
1
3
(
d, J=10.4 Hz, 1H, Hꢀ4); C NMR (CDCl ) δ 197.7 (C, Cꢀ2), 174.9 (C, Cꢀ9), 148.1 (C, arom), 135.8 (C,
3
arom), 131.6 (2C, q, J=33.5 Hz, arom), 130.5 (CH, 2C, arom), 128.4 (CH, 2C, arom), 127.3 (CH,
arom), 126.9 (CH, arom), 123.4 (2C, q, J=270.0 Hz, CF ), 120.9 (CH, arom), 100.6 (CH, Cꢀ1), 72.1
3
(
CH, Cꢀ5), 70.5 (C, Cꢀ8), 69.0 (CH , Cꢀ6), 59.1 (CH, Cꢀ7), 52.6 (CH, Cꢀ3), 52.5 (CH , Cꢀ10), 52.3 (CH,
2
3
+
Cꢀ4), 43.4 (CH , Cꢀ11); HRMSꢀESI calc. for C H F NNaO [M+Na] 552.12161. Found 552.12078.
2
25 21
6
5
Typical procedure for organocatalyzed Diels-Alder reaction
To a solution of amine 5B-52 (0.09 mmol) in MeOH/H O 9:1 (2 mL) was added HClO (0.09 mmol)
2
4
and (E)ꢀcinnamaldehyde (76 ꢁL, 0.6 mmol) in that order. The solution was stirred at room temperature
for 10 minutes and cyclopentadiene (0.25 mL, 3 mmol) was next added. Upon consumption of the
aldehyde (12 h), the solvent was removed under reduced pressure. The crude was dissolved in CHCl3ꢀ
H OꢀTFA 2:1:1 (2 mL) and stirred at room temperature for 2 h. Neutralization with sat. aq. NaHCO ,
2
3
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extraction with CH Cl followed by column chromatography afforded compound 8. Product ratios were
2
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
determined by GC analysis: Supelco BetaDEX 325 (30 m x 0.25 mm), 60 ºC, 2 ºC/min gradient, 1
ml/min, exo R isomer t = 62.2 min, exo S isomer t = 62.7 min, endo R isomer t = 63.1 min, endo S
r
r
r
8a,b
isomer t = 63.5 min. NMR data of 8 were consistent with the previously reported values.
r
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Acknowledgements
This research was supported by CONICET, UNR, and ANPCyT from Argentina. G. G. G. thanks
CONICET for the award of a fellowship.
1
13
Supporting Information Available. Copies of H and CNMR spectra of new products, and
computational data associated with this paper. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
1
) a) Enantioselective Organocatalysis; Dalko, P. I., Ed.; WileyꢀVCH VerlagGmb& Co. KGaA:
Weinheim, 2007. (b) Recent Developments in Asymmetric Organocatalysis; Pellissier, H.; The Royal
Society of Chemistry: Cambridge, UK, 2010. c) Grondal, C.; Jeanty, M.; Enders, D. Nature Chemistry
2
010, 2, 167. d) MacMillan, D.W.C. Nature 2008, 455, 304. e) Erkkilä, A.; Majander, I.; Pihko, P.M.
Chem. Rev. 2007, 107, 5416. f) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007,
107, 5471. g) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138. h) Milo, A.; Neel, A. J.;
Toste, F. D.; Sigman, M. S. Science, 2015, 347, 737.
2
) a) Jover, J.; Fey, N. Chem. Asian J. 2014, 9, 1714. b) Corbeil, C.R.; Moitessier, N. J. Mol. Cat. A:
Chemical 2010, 324, 146. c) Brown, J.M.; Deeth, R.J. Angew. Chem. Int. Ed. 2009, 48, 4476. d) Houk,
K.N.; Cheong, P.H.Y. Nature 2008, 455, 309.
3) a) Cheong, P. HꢀY.; Legault, C. Y.; Um, J. M.; ÇelebiꢀÖlçüm, N.; Houk, K. N. Chem. Rev. 2011,
1
11, 5042. For recent references, see: b) Lam, Y.ꢀH.; Houk, K. N. J. Am. Chem. Soc. 2015, 137, 2116. c)
21
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The Journal of Organic Chemistry
Page 22 of 24
Overvoorde, L. M.; Grayson, M. N.; Luo, Y.; Goodman, J. M. J. Org. Chem. 2015, 80, 2634. d) Lam,
Y.ꢀH.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 9556. e) Lee, R.; Zhong, F.; Zheng, B.; Meng, Y.; Lu,
Y.; Huang, K.ꢀW. Org. Biomol. Chem. 2013, 11, 4818. f) Grayson, M. N.; Goodman, J. M. J. Am.
Chem. Soc. 2013, 135, 6142.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
2
5
) a) Yang, H.; Wong, M. W. J. Org. Chem. 2011, 76, 7399. b) Shinisha, C. B.; Sunoj, R. B. Org. Lett.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
009, 11, 3242. c) Shinisha, C. B.; Sunoj, R. B. Org. Biomol.Chem. 2007, 5, 1287.
) a) Odagi, M.; Furukori, K.; Yamamoto, Y.; Sato, M.; Lida, K.; Yamanaka, M.; Nagasawa, K. J. Am.
Chem. Soc. 2015, 137, 1909. b) Fleming, E. M.; Quigley, C.; Rozas, I.; Connor, S. J. J. Org. Chem.
008, 73, 948. c) Mitsumori, S.; Zhang, H.; Cheong, P. HꢀY.; Houk, K. N.; Tanaka, F.; Barbas, C. F.,
2
III. J. Am. Chem. Soc. 2006, 128, 1040.
6) a) Witczak, Z.J.; Ed., Levoglucosenone and Levoglucosans: Chemistry and Applications, ATL
Press, Mount Prospect, USA, 1994. b) Corne, V.; Botta, M.C.; Giordano, E.D.V.; Giri, G.F.;
Llompart, D.F.; Biava, H.D.; Sarotti, A.M.; Mangione, M.I.; Mata, E.G.; Suárez, A.G.; Spanevello, R.A.
Pure Appl. Chem. 2013, 85, 1683. c) Sarotti, A.M.; Zanardi, M.M.; Spanevello, R.A.; Suárez, A.G.
Curr. Org. Synth. 2012, 9, 439. d) Sarotti, A.M.; Spanevello, R.A.; Suárez, A.G. Green Chem. 2007, 9,
1
7
2
8
137.
) Sarotti, A. M.; Spanevello, R. A.; Suárez, A. G.; Echeverría, G. A.; Piro, O. E. Org. Lett. 2012, 14,
556.
) a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243. b) Kano,
T.; Tanaka, Y.; Maruoka, K. Org. Lett. 2006, 8, 2687. c) Gotoh, H.; Hayashi, Y. Org. Lett. 2007, 9,
859. d) Bonini, B. F.; Capitò, E; ComesꢀFranchini, M.; Fochi, M.; Ricci, A.; Zwanenburg, B.
2
Tetrahedron: Asym., 2006, 17, 3135. e) Hayashi Y.; Samanta, S.; Gotoh, H.; Ishikawa, H. Angew.
Chem. Int. Ed., 2008, 47, 6634. f) He, H.; Pei, B.ꢀJ.; Chou, H.ꢀH.; Tian, T.; Chan, W.ꢀH.; Lee, A.W.M.
Org. Lett., 2008, 10, 2421.
9) Lemay, M.; Ogilvie, W. W. J. Org. Chem. 2006, 71, 4663.
1
0) To reduce the computational cost, we used crotonaldehyde instead cinnamaldehyde.
22
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The Journal of Organic Chemistry
1
1) Geerlings, P.; De Proft, F.; Langenaeker, W. Chem. Rev. 2003, 103, 1793.
2) Parr, R. G.; von Szentpaly, L.; Liu, S. J. Am. Chem. Soc. 1999, 121, 1922.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
13) Domingo, L. R.; Aurell, M. J.; Perez, P.; Contreras, R. Tetrahedron 2002, 58, 4417.
1
1
1
4) Sarotti, A. M. Org. Biomol. Chem. 2014, 12, 187.
5) van Zeist, W. ꢀJ.; Bickelhaupt, F. M. Org. Biomol. Chem. 2010, 8, 3118.
6) Brazier, J. B.; Evans, G.; Gibbs, T. J. K.; Coles, S. J.; Hursthouse, M. B.; Platts, J. A.; Tomkinson,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N. C. O. Org. Lett. 2009, 11, 133.
17) For further details on this issue, see the Supporting Information.
1
8) a) Dapprich, S.; Komaromi, I.; Byun, K. S.; Morokuma, K.; Frisch, M. J. THEOCHEM 1999, 462,
. (b) Bersuker, I. B. Comput. Chem. 2001, 6, 69.
1
19) a) Grayson, M. N.; Pellegrinet, S. C.; Goodman, J. M. J. Am. Chem. Soc. 2012, 134, 2716. b)
Shinisha, C. B.; Sunoj, R. B. Org. Biomol. Chem. 2008, 6, 3921. c) Zhang, X.; Du, H.; Wang, Z.; Wu,
Y. D.; Ding, K. J. Org. Chem. 2006, 71, 2862. d) Ananikov, V. P.; Szilagyi, R.; Morokuma, K.;
Musaev, D. G. Organometallics 2005, 24, 1938. e) Balcells, D.; Maseras, F.; Ujaque, G. J. Am. Chem.
Soc. 2005, 127, 3624. f) Dudding, T.; Houk, K. N. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5770.
2
0) a) In general, little difference is found in the reactions between 6 or 9 with cyclopentadiene under
the same reaction conditions (for example, see ref. 20). b) To reduce the computational cost of the
present study, we choose to study only the exo channels of addition based on two main reasons: i) in our
system the exo adducts are the major isolated compounds; ii) as a general trend (and as was
experimentally found in this work), a good organocatalyst affords high levels of enantioselection for
both endo and exo adducts (for other examples, see ref. 20).
21) a) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047. b) B. Vakulya, S.
Varga, A. Czampai, T. Soos, Org. Lett. 2005, 7, 1967. c) Franzén, J.; Marigo, M.; Fielenbach, D.;
Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. d) T. Okino, Y.
Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, 12672.
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The Journal of Organic Chemistry
Page 24 of 24
2
2) a) Puglisi, A.; Benaglia, M.; Annunziata, R.; Chiroli, V.; Porta, R.; Gervasini, A. J. Org. Chem.
013, 78, 11326. b) Hagiwara, H.; Kuroda, T.; Hoshi, T.; Suzuki, T. Adv. Synth. Catal. 2010, 352, 909.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
c) Gruttadauria, M.; Giacalone, F.; Noto, R. Chem. Soc. Rev. 2008, 37, 1666. d) Corma, A.; Garcia, H.
Adv. Synth.Catal. 2006, 348, 1391. e) Benaglia, M.; Pugliesi, A.; Cozzi, F. Chem. Rev. 2003, 103, 3401.
2
9
2
3) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. (b) Becke, A. D. J. Chem. Phys. 1993,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8, 1372. (c) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
4) Frisch, M. J. et al. Gaussian 09, Revision B.01, Gaussian, Inc.: Wallingford CT, 2009.
25) NBO Version 3.1, Glendening, E. D.; Reed, A. E.; Carpenter, J. E.; Weinhold, F. For some original
literature references, see: (a) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985, 83, 735.
(b) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88, 899.
26) a) Parr, R. G.; Pearson, R. G. J. Am. Chem. Soc. 1983, 105, 7512. b) Parr, R. G.; Yang, W. Density
Functional Theory of Atoms and Molecules; Oxford University Press: New York, 1989.
2
7) Domingo, L. R.; Pérez, P.; Sáez, J. A. RSC Adv. 2013, 3, 1486.
28) Allinger, N. L. J. Am. Chem. Soc. 1977, 99, 8127ꢀ8134.
2
3
9) Hyperchem Professional Release 7.52, Hypercube, Inc., 2005.
0) For a review on continuum solvation models, see: Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev.
2005, 105, 2999ꢀ3093.
3
1) Cabrera, S.; Gómez Arrayás, R.; MartínꢀMatute, B.; Cossío, F.; Carretero, J.C. Tetrahedron 2007,
6
3, 6587.
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