Re-Engineering Organocatalysts for Asymmetric Friedel-Crafts Alkylation of Indoles through Computational Studies

Article abstract of DOI:10.1021/acs.joc.0c01256

The discovery of efficient organocatalysts is generally carried out by thorough experimental screening of different candidates. We recently reported an efficient organocatalyst for iminium-ion-based asymmetric Diels-Alder reactions following a rational design approach. This result encouraged us to test this optimal catalyst in the mechanistically related Friedel-Crafts alkylation of indoles, but to our surprise, almost null enantioselectivity was observed. The results did not significantly improve with structurally related catalysts, and a totally unexpected facial selectivity inversion was also noticed. Using DFT calculations by modeling the competing transition structures with ONIOM, we could unravel the origins of those findings, further employed to predict the most efficient catalyst for this new transformation. The computational results were validated experimentally (up to 92:8 er), providing another successful example of a general strategy to accelerate catalyst development which still remains underexplored.

Full text of DOI:10.1021/acs.joc.0c01256

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Article
Re-engineering organocatalysts for asymmetric Friedel-
Crafts alkylation of indoles through computational studies
Gabriela G. Gerosa, Maribel O. Marcarino, Rolando A. Spanevello, Alejandra G. Suarez, and Ariel M. Sarotti
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01256 • Publication Date (Web): 09 Jul 2020
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Re-engineering organocatalysts for asymmetric Friedel-Crafts
alkylation of indoles through computational studies
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Gabriela G. Gerosa, Maribel O. Marcarino, Rolando A. Spanevello , Alejandra G. Suárez, Ariel
M. Sarotti*
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Instituto de Química Rosario (CONICET-UNR), Facultad de Ciencias Bioquímicas y
Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, Rosario 2000, Argentina.
KEYWORDS: rational design, organocatalysis, Friedel-Crafts, ONIOM, DFT, computational
screening.
ABSTRACT: The discovery of efficient organocatalysts is generally carried out by thorough
experimental screening of different candidates. We recently reported an efficient organocatalyst
for iminium-ion based asymmetric Diels-Alder reactions following a rational design approach.
This result encouraged us to test this optimal catalyst in the mechanistically related Friedel-
Crafts alkylation of indoles, but to our surprise almost null enantioselectivity was observed. The
results did not significantly improve with structurally related catalysts, and a totally unexpected
facial selectivity inversion was also noticed. Using DFT calculations by modeling the competing
transition structures with ONIOM we could unravel the origins of those findings, further
employed to predict the most efficient catalyst for this new transformation. The computational
results were validated experimentally (up to 92:8 er), providing another successful example of a
general strategy to accelerate catalysts development which still remains underexplored.
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Introduction
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The synthesis of enantiopure molecules remains one of the leading areas of research in
organic chemistry. Since the beginning of this century, asymmetric organocatalysis has
stood out as a practical strategy to generate optically active compounds using metal-free
and mild reaction conditions.1 A vast arsenal of articles has been published in this field,
with a rich variety of catalysts and activation modes applied over a large set of
asymmetric transformations.2 The process towards finding an optimal catalyst for a given
transformation is typically carried out by trial and error experimentation. Often steric or
electronic modifications in the catalyst and/or reagents end up greatly affecting the
selectivity and reactivity of the reaction. For instance, many organocatalytic systems are
substrate biased,2d or show remarkable differences in mechanistically related
transformations (vide infra). This has led to the development of novel experimental
methodologies to facilitate the search for broadly efficient catalysts, such as the multi-
substrate screening.2e Anticipating the effect of the structural variations in the catalyst
and/or substrate on the system performance is one of the Holy Grails in catalysis, as this
would facilitate the design of efficient inductors for a target transformation.3
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Modern computational chemistry has become a leading tool to unravel the chemical
secrets of interacting systems, hence paving the way to catalyst development.
Historically, the impressive predictive power of quantum-based approaches have been
focused on understanding the origins of reactivity and selectivity of almost all landmark
asymmetric transformations.4 Although the value of those studies is beyond question, it is
also imperative to recognize the importance of reversing the timeline of the events by
incorporating the QM predictions prior the experimental screening, which is the basis of
the rational design of catalysts.3 One popular approach consists in building QSAR
(quantitative structure activity relationship) models by correlating the experimental
information available with descriptors resulting from DFT (density functional theory)
calculations using regression tools.5 A different strategy is based on estimating the
selectivity of a process by computing the relative energy of the competing
stereocontrolling transition structures.6 However, despite the availability of validated
methods and increasingly powerful computational resources it is curious the relative
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scarcity of organocatalysts rationally designed from scratch using DFT calculations and
further validated experimentally.7
As part of our ongoing interest in developing new tools of asymmetric synthesis from
levoglucosenone, a biomass derived chiral enone,8 we recently reported the rational
design of an efficient organocatalyst for the Diels-Alder reaction between E-
cinnamaldehyde (2) and cyclopentadiene (3), Scheme 1. Using an ONIOM-derived in
silico screening pyrrolidine 1a was identified as a hit catalyst, which afforded excellent
enantioselectivities (up to 97% ee) when it was synthesized and evaluated.9
Given the promising results obtained in Diels-Alder reactions (DA), we next turned our
attention to the Friedel-Crafts (FC) alkylation of indoles, one of the oldest but still useful
chemical transformations widely explored in organocatalysis.10 The reaction was studied with a
large variety of catalysts with results ranging from poor to excellent depending on the catalyst,
substrate and reaction conditions.10 However, our best catalyst 1a yielded null selectivity when
tested in the reaction between 2 and N-methylindole (5), Scheme 1. This finding raised the
question whether we could rationally design a new pyrrolidine structurally related to 1a but now
efficient for the FC under study.
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Scheme 1. Performance of catalyst 1a in Diels-Alder and Friedel-Crafts reactions using (E)-cinnamaldehyde as
electrophile.
Results and discussion
We started evaluating our optimal catalyst previously found for DA reactions (pyrrolidine
1a, Scheme 1). After preliminary screening of the reaction conditions between 2 and 5,
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we selected TFA as co-catalyst and a 85:15 mixture of DCM/iPrOH at 0º C. The
alkylation product 6 was obtained in excellent yields and low reaction time, but almost
none enantiomeric purity (~50:50 er). Unfortunately, changing the solvent and co-catalyst
did not improve the result. The reduction of the enantioselectivity observed when using
N-methylindole as the nucleophilic counterpart has been well documented,11 yet such
dramatic reduction in the selectivity outcome caught our attention. In an effort to unveil
the source of the absence of asymmetric induction, we next synthesized and evaluated
few analogues of 1a by modulating the nature of the substituted phenyl group at C-7 and
the alkyl group at C-8. These modifications could be easily achieved following our
previously reported procedure involving a 1,3-dipolar cycloaddition between
levoglucosenone (7) and in situ generated azomethine ylides followed by a tandem acid-
catalyzed retro-Mannich//Mannich isomerization (Scheme 2).12
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Scheme 2. Synthesis of pyrrolidines 1.
The new catalysts were evaluated in the FC reaction under study using the same
experimental conditions, and the results are shown in Table 1.
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Table 1. Effect of the pyrrolidine structure on the FC reaction between 2 and 5a
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R
Ar
t (h) Yield (%)b er (S/R)c
Entry Cat
Me 3,5-CF3-Ph
5
100
100
100
18
50:50
70:30
70:30
53:47
67:33
53:47
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1a
1b
1c
1d
1e
1f
Me
Bn
Ph
Ph
Ph
2
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18
4
iBu
Me
Me
p-OMe-Ph
p-NO2-Ph
100
100
3
aGeneral reaction conditions: 5 (0.45 mmol), 2 (0.9 mmol), 15 mol% catalyst (0.07 mmol), 15 mol% TFA (0.07 mmol), DCM/iPrOH
85:15, 0 ºC. bIsolated yield after column chromatography. cDetermined by 1H NMR using a modified Mosher procedure.
The facial selectivities ranged from poor to modest (up to 70:30 er). Replacement of the
key 3,5-CF3-Ph substituent (entry 1) by an undecorated phenyl group (entry 2) proved
beneficial. The introduction of electron rich groups (entry 5) hardly changed the results,
but electron withdrawing substituents (entry 6) restored the poor enantioselectivity levels.
On the other hand, increasing the bulkiness at C-8 (entries 3-4) enlarged the reaction time
and in the case of 1d coupled with a concomitant e.r. reduction. The decrease of
selectivity as result of a large steric hindrance at the β face of the pyrrolidine (either by
introducing a bulky group at C-7 as in 1a or C-8 as in 1d) was in clear contrast to our
previous findings in DA cycloadditions. The configurational assignment of the reaction
outcome was carried out by a modified Mosher´s method13 using (S)-O-Acetyl mandelic
acid as chiral derivatizing agent,14 and further validated by comparing the optical rotation
reported for 6.11a In all cases the major enantiomer of the organocatalyzed FC reaction
featured an S configuration at the newly created stereocenter, revealing a striking reversal
of the facial selectivity as well. The condensation of 2 with the pyrrolidine 1 under acid
conditions yields the corresponding iminium ion Im with (E)-configuration as
unambiguously demonstrated by combination of DFT calculations and NMR
spectroscopy (Scheme 3).9
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Scheme 3. Facial selectivity observed in organocatalyzed Diels-Alder and Friedel-Crafts reactions using
levoglucosenone-derived pyrrolidines.
Assuming that the iminium ion is configurationally well-behaved, the major (S)-6 is
consistent with the preferred approach of the indole from the β face of the electrophile (si
face attack), contrary to the re face15 addition taking place by switching the nucleophilic
counterpart to cyclopentadiene as in the DA reaction.9,12a The preferred si face addition of
indole was counterintuitive, as it would occur through the more hindered face of the
iminium ion. However, it was consistent with the modest selectivity observed with 1a and
1d.
It is known that changes in the catalyst structure and/or reaction conditions might result in
unexpected inversions in the sense of induction, as observed for a variety of asymmetric
tranformations.16 Whenever these often intriguing results take place, it is always desirable to
fully understand the responsible non-covalent interactions to re-engineer more efficient catalysts
for the desired transformation. Under this philosophy we aimed to rationalize the origins of our
experimental findings through DFT calculations. Recent years witnessed the theoretical interest
in phosphoric acid-catalyzed FC reactions,17 yet there are no reports on the iminium-activated
variant. The key step of the FC reaction, which defines de C-C bond forming and the facial
selectivity, involves the attack of the most nucleophilic atom of the indole (C-2) to the
electrophilic β-carbon of the iminium ion (Scheme 4).
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Scheme 4. Proposed catalytic cycle
We started our study by exploring the energetic preferences of this stage through the
evaluation of the dimethylamine-organocatalyzed reaction between (E)-crotonaldehyde
(9) and 5 as a simplified model to reduce the computational cost. To account for the
catalytic effect exerted by secondary amines, the corresponding uncatalyzed reaction
between 5 and 9 was also computed.
After exhaustive exploration of the potential energy surface we located four possible modes of
addition, namely: N-anti, N-syn, X-anti and X-syn, where N and X accounts for endo and exo
orientation of the two interacting systems, respectively, whereas anti and syn refers to the
relative position of the methyl groups attached to the nitrogen and C-β atoms of the indole and
electrophile, respectively. The calculations were carried out at the SMD/B3LYP/6-311+G**
level of theory using methanol as solvent. Figure 1 shows the results obtained for the uncatalyzed
system, with large activation barriers (25.7-27.9 kcal/mol) consistent with its low reactivity. The
endo orientation is preferred (ΔE = 1.9 kcal/mol and 1.1 kcal/mol for the syn and anti attacks,
respectively). On the other hand, the syn addition is more stable than the anti (0.4 and 1.2
kcal/mol for endo and exo approaches, respectively). Upon iminium formation, the activation
energies drop by ca. 7.2 kcal/mol in coherence with the experimentally observed catalytic effect.
The higher stabilities for the endo and syn modes remain qualitatively similar than those found
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for the uncatalyzed process. We also tested other popular DFT functionals (such as M06-2X and
ωB97X-D) and similar trends were computed, though with a larger endo preference and lower
activation barriers (ΔE± in range 16.0-22.1 kcal/mol and 7.0-14.4 kcal/mol for the uncatalyzed
and catalyzed reactions, respectively). Nevertheless, all levels of theory agreed that the N-syn
channel is the most stable channel.
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Figure 1. Calculated transition structures for the key C-C bond forming stage of the uncatalyzed and
dimethylamine-catalyzed FC reaction between 5 and 9 at the SMD/B3LYP/6-311+G** level of theory, with
activation barriers in kcal/mol and selected distances in angstroms.
Having identified the main energetic features of the simplified system, we focused our
attention to the full system by exploring the competing transition structures of the
reactions between 9 and 5 under 1b catalysis. Each of the four fundamental modes of
addition (Figure 1) can take place through both faces of the resulting (E)- or (Z)-
configured iminium ion, leading to a total number of 16 transition structures, which in
turn exhibit significant conformational freedom. In addition, the size of the full system
precluded a full exploration using standard DFT treatment as the computational demand
would be prohibitively large for a rapid in silico evaluation of plausible organocatalysts,
key aspect in rational design. We therefore considered the use of hybrid schemes to
overcome this problem, in which the core region of the TS involving the bond-forming
and bond-breaking stages are treated with more rigorous DFT levels whereas the rest of
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the system can be described using less demanding models (such as MM or
semiempirical). The ONIOM (our own n-layered integrated molecular orbital and
molecular mechanics) method is a hybrid computational approach developed by
Morokuma and co-workers that allows to tackle efficiently two- and multiple layered
QM/MM and QM/QM calculations.18 It uses an extrapolation scheme to estimate the
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energy of the real system at the high level as: E(ONIOM,real) = E(high,model) + E(low,real)
−
E(low,model). The good performance at low computational cost makes ONIOM a very
popular computational method in the field of asymmetric organocatalysis,19 though to the
best of our knowledge remained unexplored in secondary amine-catalyzed FC reactions
using enals. Figure 2 shows the schematic workflow followed to carry out the
calculations. Using the four fundamental modes of addition found for the simplified
model at the B3LYP/6-311+G** (Figure 1) we generated the 16 different transition
structures. A full conformational sampling was done for each channel at the MM+ level
while freezing the coordinates of the high layer region (vide infra). For each
conformation, the partition scheme shown in Figure 3 was applied, and each conformer
was fully optimized at the ONIOM(B3LYP/6-31G*:AM1) level. Finally, to obtain more
accurate results single point energy calculations were taken at the PCM/B3LYP/6-
311+G** level using methanol as solvent. We have previously shown that this level of
theory and partition scheme afforded satisfactory predictions at modest computational
cost.9
Figure 2. ONIOM calculations workflow.
Figure 3 shows the most stable conformations located for each attack mode. The TSs
resulting from the (E)-configured iminium were in the average 1.1 kcal/mol lower in
energy than their corresponding (Z) counterparts, consistent with the higher stability of
the (E)-Im precursor experimentally found. In conformity with the results collected for
the reduced system, the endo and syn transition structures were in general more stable
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than the corresponding exo and anti ones, respectively. The S/R selectivity calculated at
25 ºC was 76:24, close to the experimental 70:30 ratio for 1b. The methodology also
reproduced the enantioselectivity drop achieved with 1f, featuring a strong withdrawing
group (62:38 S/R prediction considering only the (E)-N-syn channels, vide infra). A closer
inspection of the competing transition structures revealed that the preference towards the
N-syn-Si attack might be given by weak CH/π interaction between the methyl group of 5
with the phenyl group at C-7.20 The mean CH/π distances calculated for TS-1b-(E)-N-
syn-Si and TS-1h-(E)-N-syn-Si were 2.9 Å and 3.3 Å,21a respectively, showing coherent
correlation with the computed ΔERe-Si values (1.05 kcal/mol and 0.30 kcal/mol,
respectively). Gilmour and co-workers invoked CH/π contacts between the aliphatic C-H
bonds in MacMillan’s type iminium cations and the aromatic system of 5 as a key
element to enhance proximity of the reagents.11b However, our calculations suggested that
such β-face directing effect of the methyl group at C-8 should not be a dominant
interaction in this case, with a mean CH/π distance of 3.9 Å.21b While B3LYP has been
widely used to study CH/π-driven interactions,22 its limitations to accurately treat
dispersion-dominated systems have been pointed out. Taking this into account, we
recomputed the ΔERe-Si facial selectivity at the CAM-B3LYP/6-311+G** level. This
functional is a long-range corrected version of B3LYP,23 which was shown suitable to
treat intermolecular CH/π interactions.24 The ΔERe-Si values (1.17 kcal/mol with SMD,
0.82 kcal/mol with PCM) suggested that the B3LYP results (ΔERe-Si 1.05 kcal/mol) were
not biased.
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Figure 3. Most stable conformations found for each channel found for the reaction between 5 and 9 under catalysis
of 1b computed at the PCM/B3LYP/6-311+G**//ONIOM(B3LYP/6-31G*:AM1) level. The full-colored regions
indicate the high layer (N-methylindole and -unsaturated iminium fragment, up to the pyrrolidine nitrogen) and
the gray-out regions indicate the low layer (full catalyst structure without the pyrrolidine nitrogen) in the ONIOM
partition scheme.
Perhaps the CH/π interactions have not been the most exploited elements of stereocontrol
in asymmetric synthesis, yet there are many reports indicating they can be valuable to
improve catalysts’ performance.25 Hence, we decided to exploit the interplay between the
nature of the aromatic group at C-7 with the strength of the hypothetical CH/π contacts.
On the other hand, we speculated that the relative stability of the competing N-syn-Re
channel could be related with the bulkiness of the alkoxy group at R1, with large groups
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leading to more unfavorable steric interactions (Figure 4). In order to prove these
structural hypotheses, we evaluated in silico the performance of different catalysts using
our previously validated ONIOM approach by changing the nature of the aromatic group
at C-7 and the alkoxy group at R1. These changes were intended to understand the effect
of the Ar/R1 groups, and at the same time making the potential catalysts synthetically
accessible.
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Figure 4. Most stable transition structures found for Si and Re attack of 6 to the iminium cation resulting from the
condensation of 8 with 1b with key interactions. The full-colored regions indicate the high layer (N-methylindole
and -unsaturated iminium fragment, up to the pyrrolidine nitrogen) and the gray-out regions indicate the low
layer (full catalyst structure without the pyrrolidine nitrogen) in the ONIOM partition scheme.
To reduce the computational cost to a minimum, only the corresponding TS-(E)-N-syn
were considered as were found to be the most stable modes of attack. In the case of 1b,
the S/R selectivity calculated with this reduced model was higher than that obtained with
the full system (85:15 vs 76:24, respectively) because some of the other channels afforded
non-negligible contributions (Figure 3). However, we speculated that this trend would
remain for the other catalysts.
The compound 1h (with a 2-naphtyl group at C-7) afforded the highest calculated
selectivity among the virtual catalysts featuring R1=Me (Figure 5a). In general we
observed a good correlation between the mean CH/π distances measured from the
corresponding TS-(E)-N-syn-Si geometries with the calculated ΔERe-Si values (Figure 5b)
providing further evidence on the participation of CH/π interactions in the relative
stabilization of the Si-face transition structures. To reinforce this hypothesis we carried
out energy decomposition analyses on three systems (1b, 1f and 1h) that were selected as
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representative examples of transition structures featuring different CH/π distances. The
ΔERe-Si values were decomposed into three components, Eiminium, Eindole and ΔEint,
where the first two terms are the difference in energy between the iminium and indole
fragments in the TS-Re and TS-Si geometries, respectively, whereas the ΔEint is the
difference in interaction energies between both fragments at the competing TSs (see
Supporting Information for further detail).25c The negative values computed for Eiminium
and Eindole indicated that the substrates geometries are more stable in the corresponding
TS-Re, presumably because of the higher distortion involved with the attack of the indole
through the more hindered face of the iminium (si face). However, in the three examples
the Eint was positive and higher in absolute value, accounting for the Si face attack
preference. In the absence of other common non-covalent interactions (such as hydrogen
bonding and π-stacking), the Eint ~ 5 kcal/mol values were consistent with a possible
CH/π interaction as the stabilizing element of the corresponding TS-Si. The inverse
qualitative trend observed between Eint and the mean CH/π distances, along with natural
population analysis (see Supporting Information) supported our proposal.
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The selectivity computed for 1g was lower than expected from the mean CH/π distances,
indicating that additional effects might be taking place (such as steric repulsion).
Regarding the nature of the R1 group our calculations demonstrated a steady improvement
in the selectivity with the size of the alkoxy group by increasing the ΔERe-Si energy gap
due to a selective destabilization of the N-syn-Re channel. Taking collectively, the in
silico screening suggested the incorporation of a 2-naphtyl group at C-7 and a large group
at R1 to increase the facial selectivity. These two elements of stereocontrol were
combined in virtual catalyst 1l, which yielded the highest theoretical enantioselectivity of
our set.
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Figure 5. a) Predicted enantioselectivity versus catalyst number. b) Plot of ΔERe-Si energies (in kcal/mol) computed
at the PCM/B3LYP/6-311+G**//ONIOM(B3LYP/6-31G*:AM1) level considering only the (E)-N-syn channels
versus the mean CH/π distances (in Å) obtained from the corresponding TS-(E)-N-Syn-Si ONIOM optimized
geometries.
With this valuable information in hand, the synthesis of the most prominent catalyst 1l
was envisaged following the general procedure previously shown in Scheme 2. Taking
advantage of the flexibility of our convergent design to introduce structural diversity in
different areas of the molecule, we also prepared the analogues 1m-o in good overall
yields (62-81%) featuring other bulky groups at R1. The key azomethine ylide precursors
could be easily synthesized by condensation of commercially available 2-naphtaldehyde
with the corresponding aminoester prepared by esterification of alanine with different
alcohols in acid media (Scheme 5).
Scheme 5. Synthesis of the most promising catalysts 1l-o according to the in silico screening.
In excellent agreement with the computational findings the selectivities observed with
these new series of pyrrolidines were higher than those previously explored (up to 81:19),
Table 2. Despite all catalysts affording quite similar results, we kept 1o for final
optimization of the reaction conditions. The best results were achieved using TFA as co-
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catalyst and low temperature (-50 ºC), yielding the desired product in 92:8 er, closer to
the enantioselectivity achieved with the optimal MacMillan´s catalyst for the same
transformation.11a Moreover, when comparing the results obtained with the variety of
catalysts evaluated in the reaction between 2 and 5 via iminium-activation,10,11 the results
obtained with 1o were significant. Perhaps even more remarkable is the fact that we were
able to re-engineer a very poor catalyst synergistically combining reduced
experimentation with fast calculations, highlighting the power of this underexplored
approach.
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Table 2. Results obtained with catalysts 1l-o on the FC reaction between 2 and 5a
R1
iPr
Pr
t (h) Yield (%)e er (S/R)f
Entry
Cat
1lb
2
83
100
90
77:23
78:22
79:21
80:20
90:10
92:8
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1mb
1nb
1ob
1oc
1od
2
iBu
Bu
Bu
Bu
2
2
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70
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aGeneral reaction conditions: 5 (0.45 mmol), 2 (0.9 mmol), 15 mol% catalyst (0.07 mmol), 15 mol% TFA (0.07 mmol). bDCM/iPrOH 85:15, 0 ºC.
cDCM/iPrOH 85:15, -50 ºC. dDCM/tBuOH 85:15, -50 ºC. eIsolated yield after column chromatography. fDetermined by 1H NMR using a
modified Mosher´s procedure.
In a final effort to validate the predictive power of our calculations, we synthesized and
evaluated catalysts 1h (Ar=2-naphtyl, R1=Me), 1i (Ar=2-furyl, R1=Me) and 1k (Ar=Ph,
R1=iPr). Despite the experimental selectivities were lower than computed (expected
because a reduced system of only the two (E)-N-syn channels was employed), they
followed the same trends computationally found (Figure 6). We also synthesized catalyst
1p (Ar=1-napthyl, R1=iPr) to prove that the introduction of a 1-naphtyl group would be
detrimental. The observed selectivity was 61:39, lower than those obtained with 1k
(Ar=Ph, R1=iPr) and 1l (Ar=2-naphtyl, R1=iPr) in accordance with the predictions.
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Figure 6. Experimental validation of the computational predictions collected using the reaction conditions indicated
in Table 1.
Conclusions
Following a rational design approach we developed a new levoglucosenone-derived
organocatalyst for asymmetric Friedel-Crafts alkylation of indoles. The use of fast DFT
calculations allowed the identification of the key interactions affecting the
enantioselectivity of the process under study. With this information, the potential
catalysts were screened prior to invest effort in the synthesis and evaluation stage. Only
the most promising candidates were next synthesized and successfully tested
experimentally. This strategy, which to the best of our knowledge has been little explored
in the field of asymmetric organocatalysis, could significantly speed up the discovery of
efficient catalysts for useful chemical transformations.
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 p-anysaldehyde solution (2.5 mL of p-anysaldehyde + 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 300 MHz for H, and 75 MHz for C with CDCl3 as solvent and (CH3)4Si
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(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 constants are recorded
in Hertz (Hz). Isomeric ratios were determined by 1H NMR analysis. The structures of the
products were determined by a combination of spectroscopic methods such as IR, 1D and
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1
2D NMR (including NOE, COSY, HSQC and HMBC experiments) and HRMS. The H
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and C NMR peak assignment was based on COSY, HSQC and HMBC experiments.
Infrared spectra were recorded using sodium chloride plates pellets. Absorbance
frequencies are recorded in reciprocal centimeters (cm–1). High resolution mass spectra
(HRMS) were obtained on a TOF-Q LC-MS 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 (7) was prepared from our microwave-assisted pyrolysis
of acid-pretreated microcrystalline cellulose.26 The α-imino esters 8 were prepared by
condensation of the alanine, phenylalanine or leucine ester hydrochloride and the
corresponding aldehyde according to known procedures.27 The aminoacid ester
hydrochlorides were synthesized by bubbling HCl (g) to a solution of the aminoacid in
the corresponding alcohol following known procedures.28
General Procedure for the synthesis of 1. To a solution of 7 (126 mg, 1 mmol) and the
corresponding α-iminoester 8 (1.5 mmol) in dry MeCN (10 mL) was successively added
AgOAc (50 mg, 0.3 mmol) and DBU (45 μL, 0.3 mmol). The mixture was stirred for 1
hour at room temperature under argon atmosphere and in the absence of light (flask
covered with aluminium 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 dissolved in a 95:5 CHCl3/TFA solution (2 mL). The
resulting solution was stirred at 110 °C in the microwave reactor until complete
conversion of the starting material (typically 40 min). Microwave heating was performed
in a CEM Discover® System using septum-sealed 10 mL vials for high-pressure reaction
conditions with stirring and IR-monitored temperature control. Using the Standard mode,
once the system achieved the desired temperature (typically, in less than one minute), the
applied power varied to maintain the temperature fixed during the experiment. The
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solvent was removed under reduced pressure, and the crude was purified by column
chromatography on silica gel eluting with petroleum ether-ethyl acetate mixture (100:0 to
80:20, v/v) to afford pure compound. The analytical data of 1a, 1b, 1c, 1e, 1f, 1h and 1i
has been already published.9,12
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1d: Purification by flash column chromatography on silica gel eluting with petroleum
ether-ethyl acetate mixture (100:0 to 80:20, v/v) afforded the title compound as colorless
oil; yield: 0.266 g, 74%; [α]D -101.1 (c 1.22, CHCl3); IR (film) νmax 3354, 2954, 2851,
1736, 1732, 1493,1454, 1217, 1161, 1119, 1026, 984 cm-1; 1H NMR (CDCl3, 300 MHz) δ
7.49-7.42 (m, 2H), 7.29-7.12 (m, 3H), 5.06 (d, J4.8 Hz, 1H), 5.03 (s, 1H), 4.88 (d, J 4.9
Hz, 1H), 3.88 (dd,J 7.3 Hz, J4.9 Hz, 1H), 3.79 (dd, J7.3 Hz, J 0.8 Hz, 1H), 3.63 (s, 3H),
2.88 (dd, J 10.3 Hz, J 4.7 Hz, 1H), 2.46 (d, J 10.3 Hz, 1H), 2.20 (dd, J 13.4 Hz, J 6.5 Hz,
1H), 1.82-1.66 (m, 1H), 1.41 (dd, J 13.4 Hz, J 6.5 Hz, 1H), 0.94 (d, J 6.5 Hz, 3H),0.84 (d,
J 6.5 Hz, 3H); 13C{1H} NMR (CDCl3, 75 MHz) δ 198.4 (C), 176.0 (C), 145.4 (C), 128.3
(CH, 2C), 126.8 (CH), 126.3 (CH, 2C), 100.7 (CH), 72.3 (CH), 69.7 (C), 68.9 (CH2), 60.0
(CH), 55.4 (CH), 52.5 (CH), 52.1 (CH3), 47.8 (CH2), 25.5 (CH), 24.1 (CH3), 23.3 (CH3);
HRMS (ESI) m/z: [M+H]+ Calcd for C20H26NO5 360.1805; Found 360.1807.
1l: Purification by flash column chromatography on silica gel eluting with petroleum ether-ethyl
acetate mixture (100:0 to 80:20, v/v) afforded the title compound as yellowish oil; yield: 0.301 g,
76%; [α]D -64.5 (c 0.98, CHCl3); IR (film) νmax 3350, 2978, 2903, 1736, 1721, 1601,1464, 1294,
1229, 1167, 1115, 986 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.99 (s, 1H), 7.88-7.75 (m, 3H), 7.62
(dd, J 8.6 Hz, J 1.6 Hz, 1H), 7.50-7.38 (m, 2H), 5.29 (d, J 4.6 Hz, 1H), 5.14 (s, 1H), 5.09-4.93
(m, 2H), 3.97 (dd, J 7.4 Hz, J 5.0 Hz, 1H), 3.89 (d, J 7.4 Hz, 1H), 3.07 (dd, J 10.3 Hz, J 4.6 Hz,
13
1H), 2.58 (d, J 10.3 Hz, 1H), 1.63 (s, 3H), 1.29 (d, J 6.3 Hz, 3H), 1.26 (d, J 6.3, 3H); C{1H}
NMR (CDCl3, 75 MHz) δ 198.5 (C), 175.1 (C), 142.6 (C), 133.2 (C), 132.6 (C), 128.2 (CH),
127.8 (CH), 127.5 (CH), 125.9 (CH), 125.4 (CH), 124.9 (CH), 124.6 (CH), 100.8 (CH), 71.9
(CH), 69.4 (CH), 68.9 (CH2), 66.7 (C), 60.3 (CH), 55.0 (CH), 53.2 (CH), 25.8 (CH3), 21.6
(CH3), 21.4 (CH3); HRMS (ESI) m/z: [M+H]+ Calcd for C23H26NO5 396.1805; Found 396.1799.
1m: Purification by flash column chromatography on silica gel eluting with petroleum ether-
ethyl acetate mixture (100:0 to 80:20, v/v) afforded the title compound as colorless oil; yield:
0.246 g, 62%; [α]D -56.7 (c 0.76, CHCl3); IR (film) νmax 3348, 2968, 2359, 1732, 1730,
1506,1462, 1261, 1227, 1165, 1115, 984 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.99 (s, 1H), 7.87-
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7.77 (m, 3H), 7.61 (dd, J 8.5 Hz, J 1.6 Hz, 1H), 7.50-7.39 (m, 2H), 5.32 (d, J 4.6 Hz, 1H), 5.14
(s, 1H), 4.94 (d, J 4.9Hz, 1H), 4.16-3.93 (m, 3H), 3.89 (d, J 7.3 Hz, 1H), 3.07 (dd, J 10.2 Hz, J
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4.5 Hz, 1H), 2.59 (d, J 10.2 Hz, 1H), 1.79-1.60 (m, 5H), 0.98 (t, J 7.4 Hz, 3H); C{1H} NMR
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(CDCl3, 75 MHz) δ 198.3 (C), 175.8 (C), 142.6 (C), 133.2 (C), 132.6 (C), 128.2 (CH), 127.8
(CH), 127.5 (CH), 125.9 (CH), 125.5 (CH), 124.9 (CH), 124.6 (CH), 100.8 (CH), 72.0 (CH),
68.9 (CH2), 67.2 (CH2), 66.7 (C), 60.3 (CH), 54.9 (CH), 53.2 (CH), 25.4 (CH3), 21.6 (CH2), 10.4
(CH3); HRMS (ESI) m/z: [M+H]+ Calcd for C23H26NO5 396.1805; Found 396.1808.
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1n: Purification by flash column chromatography on silica gel eluting with petroleum ether-ethyl
acetate mixture (100:0 to 80:20, v/v) afforded the title compound as colorless oil; yield: 0.326 g,
80%; [α]D -58.2 (c 0.99, CHCl3); IR (film) νmax 3348, 2965, 2874, 1736, 1730, 1601,1506, 1470,
1
1261, 1165, 1113, 1042, 984 cm-1; H NMR (CDCl3, 300 MHz) δ 7.99 (s, 1H), 7.87-7.76 (m,
3H), 7.61 (dd, J 8.5 Hz, J 1.6 Hz, 1H), 7.50-7.38 (m, 2H), 5.32 (d, J 4.5Hz, 1H), 5.13 (s, 1H),
4.94 (d, J 4.8 Hz, 1H), 4.00-3.78 (m, 4H), 3.06 (dd, J 10.2 Hz, J 4.5 Hz, 1H), 2.58 (d, J 10.2 Hz,
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1H), 2.06-1.90 (m, 1H), 1.65 (s, 3H), 0.98 (d, J 6.7 Hz, 3H), 0.97 (d, J 6.7 Hz, 3H); C{1H}
NMR (CDCl3, 75 MHz) δ 198.2 (C), 175.8 (C), 142.6 (C), 133.2 (C), 132.6 (C), 128.2 (CH),
127.8 (CH), 127.5 (CH), 125.9 (CH), 125.4 (CH), 124.9 (CH), 124.6 (CH), 100.7 (CH), 72.0
(CH), 71.7 (CH2), 68.8 (CH2), 66.7 (C), 60.3 (CH), 54.8 (CH), 53.1 (CH), 27.4 (CH), 25.4
(CH3), 19.1 (CH3, 2C); HRMS (ESI) m/z: [M+H]+ Calcd for C24H28NO5 410.1962; Found
410.1969.
1o: Purification by flash column chromatography on silica gel eluting with petroleum ether-ethyl
acetate mixture (100:0 to 80:20, v/v) afforded the title compound as colorless oil; yield: 0.332 g,
81%; [α]D -72.0 (c 1.16, CHCl3); IR (film) νmax 3348, 2961, 2872, 1731, 1730, 1601,1506, 1458,
1
1375, 1261, 1229, 1165, 1124, 986 cm-1; H NMR (CDCl3, 300 MHz) δ 7.98 (s, 1H), 7.88-7.74
(m, 3H), 7.61 (dd, J 8.5 Hz, J 1.5 Hz, 1H), 7.50-7.38 (m, 2H), 5.30 (d, J 4.5Hz, 1H), 5.12 (s,
1H), 4.91 (d, J 5.0 Hz, 1H), 4.19-4.00 (m, 2H), 3.94 (dd, J 7.4 Hz, J 5.0 Hz, 1H), 3.85 (d, J 7.4
Hz, 1H), 3.05 (dd, J 10.2 Hz, J 4.5 Hz, 1H), 2.55 (d, J 10.2 Hz, 1H), 1.71-1.58 (m, 5H), 1.41
(sxt, J 7.4, 2H), 0.96 (t, J 7.4 Hz, 3H); 13C{1H} NMR (CDCl3, 75 MHz) δ 198.3 (C), 175.8 (C),
142.6 (C), 133.2 (C), 132.6 (C), 128.1 (CH), 127.7 (CH), 127.5 (CH), 125.9 (CH), 125.4 (CH),
124.8 (CH), 124.5 (CH), 100.7 (CH), 71.9 (CH), 68.8 (CH2), 66.6 (C), 65.4 (CH2), 60.3 (CH),
54.8 (CH), 53.1 (CH), 30.2 (CH2), 25.3 (CH3), 19.1 (CH2), 13.6 (CH3); HRMS (ESI) m/z:
[M+H]+ Calcd for C24H28NO5 410.1962; Found 410.1950.
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1k: Purification by flash column chromatography on silica gel eluting with petroleum ether-ethyl
acetate mixture (100:0 to 80:20, v/v) afforded the title compound as colorless oil; yield: 0.252 g,
73%; [α]D -86.5 (c 0.96, CHCl3); IR (film) νmax 3347, 2978, 2905, 1736, 1722, 1491, 1260, 1229,
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1165, 1107, 1026, 984 cm-1; H NMR (CDCl3, 300 MHz) δ 7.55-7.48 (m, 2H), 7.37-7.18 (m,
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3H), 5.14-5.09 (m, 2H), 5.06-4.90 (m, 2H), 3.96 (dd, J 7.4 Hz, J 5.0 Hz, 1H), 3.88 (d, J 7.4 Hz,
1H), 3.00 (dd, J 10.3 Hz, J 4.7Hz, 1H), 2.52 (d, J 10.3 Hz, 1H), 1.58 (s, 3H), 1.27 (d, J 6.3 Hz,
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3H), 1.23 (d, J 6.3, 3H); C{1H} NMR (CDCl3, 75 MHz) δ 198.5 (C), 175.0 (C), 145.2 (C),
128.3 (CH, 2C), 126.8 (CH), 126.3 (CH, 2C), 100.7 (CH), 71.8 (CH), 69.3 (CH), 68.9 (CH2),
66.6 (C), 60.2 (CH), 54.9 (CH), 53.2 (CH), 25.6 (CH3), 21.6 (CH3), 21.3 (CH3); HRMS (ESI)
m/z: [M+H]+ Calcd for C19H24NO5 346.1649; Found 346.1646.
1p: Purification by flash column chromatography on silica gel eluting with petroleum ether-ethyl
acetate mixture (100:0 to 80:20, v/v) afforded the title compound as colorless oil; yield: 0.269 g,
68%; [α]D -60.3 (c 0.45, CHCl3); IR (film) νmax 3362, 2978, 2934, 1736, 1730, 1595, 1454, 1373,
1258, 1231, 1167, 1117, 982 cm-1; 1H NMR (CDCl3, 300 MHz) δ 8,48 (d, J 8,4 Hz, 1H), 7,95 (d,
J 7,2 Hz, 1H), 7.89-7.82 (m, 1H), 7.75 (d, J 8.1 Hz, 1H), 7.58-7.40 (m, 3H), 5.94 (d, J 3.1 Hz,
1H), 5.14 (s, 1H), 5.03 (sept, J 6.3 Hz, 1H), 4.95 (d J 5.0 Hz, 1H), 3.92 (dd, J 7.4 Hz, J 5.0Hz,
1H), 3.82 (d, J 7.4 Hz, 1H), 3.14 (dd, J 10.0 Hz, J 3.1 Hz, 1H), 2.62 (d, J 10.0 Hz, 1H), 1.68 (s,
3H), 1.31 (d, J 6.3 Hz, 3H), 1.29 (d, J 6.3 Hz, 3H); 13C{1H} NMR (CDCl3, 75 MHz) δ 198,3 (C),
175,25 (C), 140,9 (C), 133,8 (C), 130,7 (C), 128,5 (CH), 127,6 (CH), 126,1 (CH), 125,5 (CH),
125,2 (CH), 123,7 (CH), 123,4 (CH), 101,0 (CH), 72,0 (CH), 69,6 (CH), 68,7 (CH2), 66,7 (C),
56,1 (CH), 55,5 (CH), 53,4 (CH), 26,4 (CH3), 21,6 (CH3), 21,4 (CH3); HRMS (ESI) m/z: [M+H]+
Calcd for C23H26NO5 396.1805; Found 396.1797.
General procedure for the organocatalyzed Friedel-Crafts reaction. To a solution of amine
1 (0.07 mmol) in the solvent indicated in Tables 1 and 2 (0.7 mL) were added TFA (0.06 mmol)
and (E)-cinnamaldehyde (0.9 mmol) in that order. The solution was stirred at the corresponding
temperature for 10 minutes, and N-methylindole (0.45 mmol) was added. After the time
indicated in Tables 1 and 2, the reaction was quenched by the addition of NEt3. The solvent was
removed under reduced pressure and the crude was purified by column chromatography on silica
gel eluting with petroleum ether-ethyl acetate mixture (85:15) to yield 6. The NMR data of 6 was
identical with the previously reported values.11a To demonstrate the scalability of this reaction,
we expanded the scale of the reaction indicated in Table 1, entry 2, to 4 mmol of N-
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methylindole, using 1b (0.62 mmol) as catalyst, 0.6 mmol of TFA as co-catalyst, and 8 mmol of
(E)-cinnamaldehyde in 8 mL of DCM/iPrOH 85:15 at 0 ºC. The desired product 6 (71:29 e.r.)
was obtained in 96% yield (1.01 g).
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General procedure for the derivatization with (S)-O-Acetylmandelic acid. To a solution of 6
(0.1 mmol) in MeOH (1 mL) at 0 ºC was added NaBH4 (0.13 mmol). The solution was stirred at
room temperature for 1 hour, quenched by addition of water (10 mL) and extracted with AcOEt.
The combined organic phase was washed with brine, dried over MgSO4, and the solvent was
evaporated under reduced pressure. The crude was dissolved in dry DCM (1 mL), and then
DMAP (0.01 mmol), (S)-O-acetylmandelic acid (0.18 mmol) and DCC (0.18 mmol) were added
in that order. The mixture was stirred at room temperature for 1 hour under argon. The reaction
was diluted with DCM and filtered through Celite. The filtrate was concentrated under reduced
pressure and purified by column chromatography on silica gel eluting with petroleum ether-ethyl
acetate mixture (90:10) to afford an inseparable mixture of the two diastereoisomeric esters
(S,S)-12 and (R,S)-12 in near quantitative yields (0.428-0.439 g, 97-99%).
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12: colorless oil; IR (film) νmax 3059, 2930, 2851, 1742, 1672, 1454, 1371, 1232, 1177, 1055,
926, 700 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.56-6.92 (m, 28 H), 6.83 (s, 1H, H-2 of (S,S)-12),
6.72 (s, 1H, H-2 of (R,S)-12), 6.14 (s, 1H, H-14 of (R,S)-12), 5.95 (s, 1H, H-14 of (S,S)-12),
4.19-3.98 (m, 6H), 3.71 (s, 3H, H-1 of (S,S)-12), 3.69 (s, 3H, H-1 of (R,S)-12), 2.55-2.39 (m,
1H), 2.32-2.15 (m, 9H); 13C{1H} NMR (CDCl3, 75 MHz) δ 170.2 (C), 168.6 (C), 143.7 (C),
137.1 (C), 133.9 (C), 129.2 (CH), 128.7 (CH, 2C), 128.3 (CH, 2C), 127.6 (CH, 4C), 127.0 (C),
126.1 (CH), 125.8 (CH), 121.5 (CH), 119.3 (CH), 118.6 (CH), 117.4 (C), 109.0 (CH), 74.4 (CH),
63.9 (CH2, C-12 of (S,S)-12), 60.3 (CH2, C-12 of (R,S)-12), 38.7 (CH), 34.4 (CH2), 32.5 (CH3),
20.6 (CH3); HRMS (ESI) m/z: [M+H]+ Calcd for C28H28NO4 442.2013; Found 442.2014.
ASSOCIATED CONTENT
Supporting Information. Copies of 1H and 13C NMR spectra of all compounds, and
computational data associated with this paper.
AUTHOR INFORMATION
Corresponding Author
*A. M. S. E-mail: sarotti@iquir-conicet.gov.ar
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Author Contributions
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The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
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Acknowledgements
This research was supported by UNR (BIO 316, 500 and 504), CONICET (PIP 0660),
ANPCyT
(PICT-2016-0116
and
PICT-2016-2307),
CONICET
(PIP
11220130100660CO) and PhosAgro/UNESCO/IUPAC (Green Chemistry for Life
Program, project 121). G.G.G. and M.O.M thank CONICET for the award of a
fellowship.
References
1
2
(a) Enantioselective Organocatalysis; Dalko, P. I., Ed.; Wiley−VCH: Weinheim, 2007.
(b) Pellissier, H. Recent Developments in Asymmetric Organocatalysis; The Royal
Society of Chemistry: Cambridge, UK, 2010.
(a) MacMillan, D. W. C. The advent and development of organocatalysis. Nature.
2008, 455, 304. (b) Erkkila, A.; Majander, I.; Pihko, P. M. Iminium Catalysis. Chem.
Rev. 2007, 107, 5416. (c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Asymmetric Enamine Catalysis. Chem. Rev. 2007, 107, 5471. (d) Schreyer, L.;
Properzi, R.; List, B. IDPi Catalysis. Angew. Chem. Int. Ed. 2019, 58, 12761. (e) Kim,
H.; Gerosa, G.; Aronow, J.; Kasaplar, P.; Ouyang, J.; Lingnau, J. B.; Guerry, P.; Farés,
C.; List, B. A multi-substrate screening approach for the identification of a broadly
applicable Diels–Alder catalyst. Nature Commun. 2019, 10, 770.
3
4
a) Ahn, S.; Hong, M.; Sundararajan, M.; Ess, D. H. Design and Optimization of
Catalysts Based on Mechanistic Insights Derived from Quantum Chemical Reaction
Modeling. Chem. Rev. 2019, 119, 6509. b) Poree, C.; Schoenebeck, F. A Holy Grail in
Chemistry: Computational Catalyst Design: Feasible or Fiction?. Acc. Chem. Res.
2017, 50, 605.
a) Cheong, P. H-Y.; Legault, C. Y.; Um, J. M.; Çelebi-Ölçüm, N.; Houk, K. N.
Quantum Mechanical Investigations of Organocatalysis: Mechanisms, Reactivities,
ACS Paragon Plus Environment
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Page 23 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
and Selectivities. Chem. Rev. 2011, 111, 5042. For recent leading references, see: b)
Lam, Y.; Grayson, M. N.; Holland, M. C., Simon, A.; Houk, K. N. Theory and
Modeling of Asymmetric Catalytic Reactions. Acc. Chem. Res. 2016, 49, 750. c) Lu,
T.; Zhu, R.; An, Y.; Wheeler, S. E. Origin of Enantioselectivity in the Propargylation
of Aromatic Aldehydes Catalyzed by Helical N-Oxides. J. Am. Chem. Soc. 2012, 134,
3095. d) Lam, Y.-H.; Houk, K. N. Origins of Stereoselectivity in Intramolecular Aldol
Reactions Catalyzed by Cinchona Amines. J. Am. Chem. Soc. 2015, 137, 2116. e)
Reid, J. P.; Goodman, J. M. Goldilocks Catalysts: Computational Insights into the
Role of the 3,3′ Substituents on the Selectivity of BINOL-Derived Phosphoric Acid
Catalysts. J. Am. Chem. Soc. 2016, 138, 7910.
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
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
(a) Kozlowski, M. C.; Dixon, S. L.; Panda, M; Lauri, G. Quantum Mechanical Models
Correlating Structure with Selectivity:ꢀ Predicting the Enantioselectivity of β-Amino
Alcohol Catalysts in Aldehyde Alkylation. J. Am. Chem. Soc. 2003, 125, 6614. b)
Ianni, J. C.; Annamalai, V.; Phuan, P.-W.; Panda, M.; Kozlowski, M. C. A Priori
Theoretical Prediction of Selectivity in Asymmetric Catalysis: Design of Chiral
Catalysts by Using Quantum Molecular Interaction Fields. Angew. Chem. Int. Ed.
2006, 45, 5502. c) Denmark, S. E.; Gould, N. D.; Wolf, L. M. A Systematic
Investigation of Quaternary Ammonium Ions as Asymmetric Phase-Transfer Catalysts.
Application of Quantitative Structure Activity/Selectivity Relationships. J. Org. Chem.
2011, 76, 4337. d) Sigman, M. S.; Harper, K. C.; Bess, E. N.; Milo, A. The
Development of Multidimensional Analysis Tools for Asymmetric Catalysis and
Beyond. Acc. Chem. Res. 2016, 49, 1292. e) Reid, J. P.; Sigman, M. S. Holistic
prediction of enantioselectivity in asymmetric catalysis. Nature. 2019, 571, 343.
(a) Doney, A. C.; Rooks, B. J.; Lu, T.; Wheeler, S. E. Design of Organocatalysts for
Asymmetric Propargylations through Computational Screening. ACS Catal. 2016, 6,
7948. (b) Guan, Y.; Ingman, V. M.; Rooks, B. J.; Wheeler, S. E. AARON: An
Automated Reaction Optimizer for New Catalysts. J. Chem. Theory Comput. 2018, 14,
5249.
6
7
(a) Odagi, M.; Furukori, K.; Yamamoto, Y.; Sato, M.; Lida, K.; Yamanaka, M.;
Nagasawa, K. Origin of Stereocontrol in Guanidine-Bisurea Bifunctional
Organocatalyst That Promotes α-Hydroxylation of Tetralone-Derived β-Ketoesters:
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Page 24 of 27
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3
4
5
6
7
8
9
Asymmetric Synthesis of β- and γ-Substituted Tetralone Derivatives via
Organocatalytic Oxidative Kinetic Resolution. J. Am. Chem. Soc. 2015, 137, 1909. (b)
Fleming, E. M.; Quigley, C.; Rozas, I.; Connor, S. J. Computational Study-Led
Organocatalyst Design:ꢀ A Novel, Highly Active Urea-Based Catalyst for Addition
Reactions to Epoxides. J. Org. Chem. 2008, 73, 948. (c) Mitsumori, S.; Zhang, H.;
Cheong, P. H-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F., III. Direct Asymmetric anti-
Mannich-Type Reactions Catalyzed by a Designed Amino Acid. J. Am. Chem. Soc.
2006, 128, 1040. (d) Pan, L.; Ding, X.; Ding, J.; Li, D.; Chen, J.; Zuo, X.; An, R.
Design and Synthesis of L‐Proline Derivatives as Enantioselective Organocatalysts for
Synthesis of the (S)‐Wieland‐Miescher Ketone. ChemistrySelect. 2017, 2, 11999.
a) Comba, M. B.; Tsai, Y.; Sarotti, A. M.; Mangione, M. I.; Suárez, A. G.; Spanevello,
R. A. Levoglucosenone and Its New Applications: Valorization of Cellulose Residues.
Eur. J. Org. Chem. 2018, 5, 590. 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. Cellulose recycling as a source of raw chirality. Pure
Appl. Chem. 2013, 8, 85.
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
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37
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
9
Gerosa, G. G.; Spanevello, R. A.; Suárez, A. G.; Sarotti, A. M. Joint Experimental, in
Silico, and NMR Studies toward the Rational Design of Iminium-Based
Organocatalyst Derived from Renewable Sources. J. Org. Chem. 2015, 80, 7626.
10 a) Terrasson, V.; de Figueiredo, R. M.; Campagne, J. M. Organocatalyzed Asymmetric
Friedel–Crafts Reactions. Eur. J. Org. Chem. 2010, 2635. b) Bartoli, G.; Bencivenni,
G.; Dalpozzo, R. Organocatalytic strategies for the asymmetric functionalization of
indoles. Chem. Soc. Rev. 2010, 39, 4449.
11 (a) Austin, J. F.; MacMillan, D. W. C. Enantioselective Organocatalytic Indole
Alkylations. Design of a New and Highly Effective Chiral Amine for Iminium
Catalysis. J. Am. Chem. Soc. 2002, 124, 1172. b) Holland, M. C.; Metternich, J. B.;
Daniliuc, C.; Schweizer, W. B.; Gilmour, R. Aromatic Interactions in Organocatalyst
Design: Augmenting Selectivity Reversal in Iminium Ion Activation. Chem. Eur. J.
2015, 21, 10031. c) Grošelj, U.; Podlipnik, Č.; Bezenšek, J.; Svete, J.; Stanovnik, B.
Reversal of the Stereochemical Course of 1‐Methyl‐1H‐indole Addition to
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1
2
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5
6
7
8
9
Cinnamaldehyde with cis‐5‐Benzyl‐(2‐fluoromethyl)‐2,3‐dimethylimidazolidin‐4‐ones
as Catalysts – a Puzzling ‘Fluorine Effect’. Helv. Chim. Acta. 2013, 96, 1815.
12 (a) Sarotti, A. M.; Spanevello, R. A.; Suárez, A. G.; Echeverría, G. A.; Piro, O. E. 1,3-
Dipolar Cycloaddition Reactions of Azomethine Ylides with a Cellulose-Derived
Chiral Enone. A Novel Route for Organocatalysts Development. Org. Lett. 2012, 14,
2556. (b) Gerosa, G. G.; Grimblat, N.; Spanevello, R. A.; Suárez, A. G.; Sarotti, A. M.
Mechanistic insight into the acid-catalyzed isomerization of biomass-derived
polysubstituted pyrrolidines: an experimental and DFT study. Org. Biomol. Chem.
2017, 15, 426.
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
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13 Seco, J. M.; Quiñoá, E.; Riguera, R. The Assignment of Absolute Configuration by
NMR. Chem. Rev. 2004, 104, 17.
14 Pisano, P. L.; Sarotti, A. M.; Pellegrinet, S. C. An experimental/theoretical approach to
determine the optical purity and the absolute configuration of endo- and exo-norborn-
5-en-2-ol using mandelate derivatives. Tetrahedron Lett. 2009, 50, 6121.
15 In Ref. 9 the face topicity analysis was carried out considering the Cα of the iminium
ion. In this work we kept this rule to simplify the discussion, despite Cα does not react
with the nucleophile in FC reactions.
16 Bartók, M. Unexpected Inversions in Asymmetric Reactions: Reactions with Chiral
Metal Complexes, Chiral Organocatalysts, and Heterogeneous Chiral Catalysts. Chem.
Rev. 2010, 110, 1663.
17
(a) Simón, L.; Goodman, J. M. DFT Study on the Factors Determining the
Enantioselectivity of Friedel−Crafts Reactions of Indole with N-Acyl and N-
Tosylimines Catalyzed by BINOL−Phosphoric Acid Derivatives. J. Org. Chem. 2010,
75,
589.
(b)
Hirata,
T.;
Yamanaka,
M.
DFT
Study
of
Chiral‐Phosphoric‐Acid‐Catalyzed Enantioselective Friedel–Crafts Reaction of Indole
with Nitroalkene: Bifunctionality and Substituent Effect of Phosphoric Acid. Chem.
Asian J. 2011, 6, 510.
18 (a) Dapprich, S.; Komáromi, I.; Byun, K. S.; Morokuma, K.; Frisch, M. J. A new
ONIOM implementation in Gaussian98. Part I. The calculation of energies, gradients,
vibrational frequencies and electric field derivatives. Journal of Molecular Structure
(Theochem). 1999, 461, 1. (b) Vreven, T.; Morokuma, K. On the application of the
ACS Paragon Plus Environment
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The Journal of Organic Chemistry
Page 26 of 27
1
2
3
4
5
6
IMOMO (integrated molecular orbital + molecular orbital) method. J. Comput. Chem.
2000, 21, 1419.
19 Chung, L. W.; Sameera, W. M. C.; Ramozzi, R.; Page, A. J.; Hatanaka, M.; Petrova,
G. P.; Harris, T. V.; Li, X.; Ke, Z.; Liu, F.; Li, H. -B.; Ding, L.; Morokuma, K. The
ONIOM Method and Its Applications. Chem. Rev. 2015, 115, 5678.
20 Nishio, M. The CH/π hydrogen bond in chemistry. Conformation, supramolecules,
optical resolution and interactions involving carbohydrates. Phys. Chem. Chem. Phys.
2011, 13, 13873.
7
8
9
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
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
21 a) Distance between the centroid of the phenyl group at C-7 and the closest hydrogen
atom of the N-CH3 group in 5. b) Distance between the centroid of the six membered
ring in 5 and the closest hydrogen atom of the CH3 group at C-8.
22 Krenske, E. H.; Houk, K. N. Aromatic Interactions as Control Elements in
Stereoselective Organic Reactions. Acc. Chem. Res. 2013, 46, 979.
23 Yanai, T.; Tew, D. P.; Handy, N. C. A new hybrid exchange–correlation functional
using the Coulomb-attenuating method (CAM-B3LYP). Chem. Phys. Lett. 2004, 393,
51.
24 Mohan, N.; Vijayalakshmi, K. P.; Koga, N.; Suresh, C. H. Comparison of aromatic
NH···π, OH···π, and CH···π interactions of alanine using MP2, CCSD, and DFT
methods. J. Comput. Chem. 2010, 31, 2874.
25 a) Neel, A. J.; Hilton, M. J.; Sigman, M. S.; Toste, F. D. Exploiting non-covalent π
interactions for catalyst design. Nature. 2017, 543, 637. b) Wheeler, S. E.; Seguin, T.
J.; Guan, Y.; Doney, A. C. Noncovalent Interactions in Organocatalysis and the
Prospect of Computational Catalyst Design. Acc. Chem. Res. 2016, 49, 1061. c)
Seguin, T. J.; Lu, T.; Wheeler, S. E. Enantioselectivity in Catalytic Asymmetric
Fischer Indolizations Hinges on the Competition of π‑Stacking and CH/π Interactions.
Org. Lett. 2015, 17, 3066.
26 Sarotti, A. M.; Spanevello, R. A.; Suárez, A. G. An efficient microwave-assisted green
transformation of cellulose into levoglucosenone. Advantages of the use of an
experimental design approach. Green Chem. 2007, 9, 1137.
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27 Cabrera, S.; Gomez Arrayás, R.; Martín-Matute, B.; Cossío, F.; Carretero, J. C. CuI–
Fesulphos complexes: efficient chiral catalysts for asymmetric 1,3-dipolar
cycloaddition of azomethine ylides. Tetrahedron. 2007, 63, 6587.
7
8
9
28 White, B. D.; Mallen, J.; Arnold, K. A.; Fronczek, F. R.; Gandour, R. D.; Gehrig, L.
M. B.; Gokel, G. W. Peptide side-arm derivatives of lariat ethers and bibracchial lariat
ethers: syntheses, cation binding properties, and solid state structural data. J. Org.
Chem. 1989, 54, 937.
10
11
12
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