Positive Effect of Water in Asymmetric Direct Aldol Reactions with Primary Amine Organocatalyst: Experimental and Computational Studies

Article abstract of DOI:10.1002/asia.201500078

The origin of higher reactivity in water-accelerated asymmetric aldol reactions with our designed primary amine organocatalyst was elucidated by both computational and experimental methods. As suggested by the calculated transition-state structures for wa

Full text of DOI:10.1002/asia.201500078

CHEMISTRY
AN ASIAN JOURNAL
Accepted Article
Title: Positive Effect of Water in Asymmetric Direct Aldol Reactions with Primary-
Amine Organocatalyst: Experimental and Computational Studies
Authors: Shin A. Moteki; Hiroki Maruyama; Keiji Nakayama; Hai-Bei Li; Galina Pe-
trova; Satoshi Maeda; Keiji Morokuma; Keiji Maruoka
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Chemistry - An Asian Journal
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COMMUNICATION
DOI: 10.1002/asia.200((will be filled in by the editorial staff))
Positive Effect of Water in Asymmetric Direct Aldol Reactions with Primary-Amine
Organocatalyst: Experimental and Computational Studies
[
a]
[a]
[a]
[b,c]
[b]
Shin A. Moteki, Hiroki Maruyama, Keiji Nakayama, Hai-Bei Li, [aG] alina Petrova,
[d]
[b]
Satoshi Maeda, Keiji Morokuma,* and Keiji Maruoka*
Dedication ((optional)
reaction via the enamine mechanism, which mimics the behavior of
[
4]
Abstract: The origin of higher reactivity in the water- natural class I aldolase. Such organocatalytic, asymmetric aldol
accelerated asymmetric aldol reactions with our designed
primary-amine organocatalyst was elucidated by both
computational and experimental methods. As suggested by
the calculated transition-state structures for water-promoted
imine-enamine isomerization, anti-selective aldol reaction
and hemiaminal formation, the rate of this aldol reaction was
found experimentally to be even more accelerated by the
addition of cis-2-butene-1,4-diol as additive.
reactions, if carried out in water solvent, are reported to exhibit high
[
5]
reactivity and selectivity, although Armstrong and Blackmond
clarified that the effect of water in the proline-catalyzed aldol
[
6]
reaction was not directly related to the catalytic cycle. In contrast,
acyclic primary-amino acids (alanine, threonine, tryptophan, etc.)
and their derivatives have recently been found to be more effective
in the asymmetric aldol reactions in aqueous solvents than polar
[7]
aprotic solvents. According to the mechanism of natural aldolase
containing a primary amine site, the tautomerization of imine and
enamine, and the subsequent aldol reaction are assisted by water-
[
8]
mediated proton rely system. We assume that the role of water in
primary-amine catalyzed aldol reaction is different from that of
secondary amines such as proline. In this context, we are interested
The asymmetric aldol reaction is one of the most important and
efficient carbon-carbon bond-forming reactions in organic synthesis
[
6,9]
[
1]
in the role of water
in the asymmetric aldol reactions with certain
for the construction of complex chiral polyol architectures. In
addition to aldolase enzymes and chiral metal catalysts, a variety of
small organic molecules, including proline and various other chiral
pyrrolidine derivatives, have been shown to be efficient
primary-amine organocatalysts. Here we wish to report our new
findings on the origin of higher reactivity in the water-accelerated
asymmetric aldol reactions with our designed primary-amine
[
10]
[
2-3]
organocatalyst 1
by both experimental and computational
organocatalysts for asymmetric aldol reactions.
These proline-
methods.
based organocatalysts are believed to catalyze the direct aldol
We first experimentally investigated the asymmetric aldol
reaction of cyclohexanone with aldehydes catalyzed by primary-
amine organocatalyst 1a in polar aprotic solvents in the absence or
presence of water, and selected results of forming anti- and syn-2
are shown in Table 1. The reaction between cyclohexanone and
aromatic aldehydes exhibited generally both higher reactivity and
anti selectivity in aqueous solvents, particularly aqueous MeCN
(entries 2 and 10 vs. 1 and 9, respectively). Furthermore, higher
enantioselectivity was observed in aqueous THF (entries 6 and 12
[a]
Dr. S. A. Moteki, Mr. Hiroki Maruyama, Dr. Keiji Nakayama, Prof. Dr. K.
Maruoka
Laboratory of Synthetic Organic Chemistry and Special Laboratory of
Organocatalytic Chemistry, Department of Chemistry, Graduate School of
Science
Kyoto University, Sakyo, Kyoto 606-8502, Japan
Fax: (+81) 75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
1
vs. 5 and 11, respectively). In a H NMR study of the condensation
[
b]
Dr. H.-B. Li, Dr. G. Petrova, Prof. Dr. K. Morokuma
Fukui Institute for Fundamental Chemistry,
Kyoto University, Sakyo, Kyoto 606-8103, Japan
E-mail: morokuma@fukui.kyoto-u.ac.jp
of p-nitrobenzaldehyde and primary-amine catalyst 1a in CD OD
under standard conditions, we observed a single peak of imine 3a at
3

8.56. Although oxazolidinone formation is a major path in the case
[
6]
of proline catalyst, we were not able to observe any formation of
[
c]
d]
Dr. H.-B. Li
oxazolidinone 4a by using primary-amine catalyst 1a.
School of Ocean, Shandong University, Weihai 264209, China
[
Dr. S. Maeda
Department of Chemistry, Faculty of Science, Hokkaido University,
Sapporo 060-0810, Japan
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.200xxxxxx.((Please delete if not
1

Chemistry - An Asian Journal
10.1002/asia.201500078
Table 1. Effect of water in the asymmetric aldol reactions with primary-amine catalyst
[a]
1a.
[
f]
[h]
Entry
Aldehyde
X)
Solvent
Yield [%]
ee [%]
[
g]
(
(anti/syn)
<5 (- : -)
96 (92:8)
1
2
3
4
5
6
7
8
9
p-NO
2
MeCN
aq. MeCN
neat
94
98
92
97
87
98
97
91
95
97
92
97
[
b]
54 (75:25)
51 (91:9)
43 (75:25)
98 (94:6)
79 (90:10)
83 (80:20)
<5 (- : -)
2
H O
[
c]
THF
Figure 1. Theoretically proposed mechanism of the asymmetric aldol reaction with
primary-amine organocatalyst 1b.
[
d]
aq. THF
iPrOH
In this mechanism, a primary-amine organocatalyst 1b forms an
imine intermediate 5 with cyclohexanone. Subsequently, conversion
of 5 to the corresponding enamine 7-nw is necessary for the
MeOH
MeCN
[
7b,12]
following aldol reaction.
This conversion has been found to
p-CN
occur by a stepwise proton transfer process via intermediate 6. The
sulfonamide proton in 5 is labile due to the strong electron-
withdrawing effect of the Tf group and easily transfers to imine
nitrogen with low free-energy barrier height (~7-10 kcal/mol), with
or without water, to give 6. The subsequent transfer of a proton from
the -carbon of the cyclohexyl group of 6 to the sulfonyl oxygen
(without water) or the sulfonamide nitrogen (with water) gives rise
to different enamine intermediates 7-nw (Figure 1). Without water,
the proton cannot reach the sulfonamide nitrogen, and the resultant
intermediate is very unstable, thereby inducing the reverse reaction
predominantly. At the transition state TS6/7-nw (n = 1, 2) one or two
water molecules relay the proton to the desired sulfonamide nitrogen
[
e]
10
aq. MeCN
93 (91:9)
66 (74:26)
98 (92:8)
11
THF
[
d]
1
2
aq. THF
[
a] Unless otherwise specified, asymmetric direct aldol reaction of cyclohexanone (30
equiv) and p-nitrobenzaldehyde (1 equiv) in the presence of 5 mol% of catalyst 1a in
solvents (1.8 mL) at room temperature. [b] MeCN/H O = 17:1. [c] The change of the
2
conversion with time was measured by NMR analysis with mesitylene as an internal
standard in primary-amine-catalyzed asymmetric aldol reaction in THF-d8 at room
(See Figure 2), with free-energy barrier of ~22-24 kcal/mol, a
temperature. See Supporting Information. [d] THF/H
2 2
O = 1:1. [e] MeCN/H O = 1:1. [f]
possible rate-determining step for the entire reaction, to give stable
intermediates 7-nw (n = 1, 2). Thus, these intermediates are the
starting points for the subsequent reactions.
1
Isolated yield. [g] The anti/syn ratio of aldol products was determined by H NMR
analysis. [h] Enantiopurity of aldol products was determined by HPLC analysis using a
chiral column [DAICEL Chiralpak AD-H].
Based on the proposed mechanism on the proline-catalyzed
[
11]
asymmetric aldol reaction,
the asymmetric aldol reaction of
cyclohexanone and substituted benzaldehydes catalyzed by primary-
amine organocatalyst 1 has been assumed to proceed as shown in
Figure 1. In order to explore the real detailed mechanism on the
asymmetric aldol reaction of cyclohexanone and substituted
benzaldehydes catalyzed by primary-amine organocatalyst 1, we
explored systematically and theoretically various plausible reaction
pathways using the recently developed powerful reaction path
Figure 2. Transition state structures with one or two water molecules
[
12]
search method, AFIR (artificial force induced reaction) method,
and performed density functional calculations for the primary-
amine-catalyzed asymmetric aldol reaction. The AFIR method
applies an artificial force between reacting molecules and efficiently
explores many possible reaction pathways to determine the most
preferred one without prior knowledge to transition states. The
reaction has been found to proceed via the enamine mechanism as
The next step is the C-C bond formation reaction between 7 and p-
substituted benzaldehyde to give the intermediate 8. In this step, a
proton is transferred from the sulfonamide NH to the carbonyl
oxygen via hydrogen bonding network through one or two water
molecules to activate the aldehyde by increasing its electrophilicity,
and the C-C bond is formed between carbonyl carbon and enamine
[
13-15]
illustrated in Figure 1.
2

Chemistry - An Asian Journal
10.1002/asia.201500078

-carbon, via the TS7/8-nw (n = 1, 2) (See Figure 2) to give the
intermediate 8-nw (n = 1, 2) with a free energy barrier of ~4-7
kcal/mol, depending on the stereoselective transition states. This
step is the stereoselectivity determining step, as in the case of
4
5
(5)
(5)
61 (76:24)
92
98
49 (93:7)
[
11,16]
proline-catalyzed aldol reaction.
One notices in Figure 2 that proton transfers take place via two
water molecules forming a hydrogen bond network. This finding
suggests that some solvent molecule that can form a similar di-
hydrogen-bonding structure may be able to play a role of two water
molecules and accelerates the reaction, as illustrated in Figure 3.
6
7
(5)
11 (75:25)
69 (78:22)
91
92
MeOH
[a] Unless otherwise specified, asymmetric direct aldol reaction of cycloalkanone (30
equiv) and p-substituted benzaldehyde (1 equiv) with 10 mol% of catalyst 1a in the
absence or presence of additive in MeCN (1.8 mL) at room temperature. [b] The change
of the conversion with time was measured by NMR analysis with mesitylene as an
internal standard in primary-amine-catalyzed asymmetric aldol reactions in the presence
of cis-2-buten-1,4-diol or water in MeCN-d3. See Supporting Information. [c] Isolated
1
yield. [d] The anti/syn ratio of aldol products was determined by H NMR analysis. [e]
Enantiopurity of aldol products was determined by HPLC analysis using a chiral
column [DAICEL Chiralpak AD-H].
Other selected examples are listed in Table 3, which indicates the
superiority of cis-2-butene-1,4-diol as efficient water replacement in
the asymmetric aldol reaction of cycloalkanone with aldehyde
catalyzed by primary-amine organocatalyst 1a.
Figure 3. Effect of water and diol replacement in the transformation from imine to
enamine by primary-amine 1b.
Table 3. Superiority of cis-2-butene-1,4-diol as additive in asymmetric aldol reaction
catalyzed by primary-amine 1a.
[a]
Based on these computational findings, we further examined the
effect of water by using replacements that may play a similar role of
2
equiv of water. Accordingly, some diol substrates were selected
[
17]
and screened as shown in Table 2.
Interestingly, the rate of this
aldol reaction was even more accelerated by the addition of these
diols in MeCN. Especially, cis-2-butene-1,4-diol afforded anti
selective aldol adduct in excellent yield and enantioselectivity (entry
[
b]
Entry
Substrate
Additive
equiv)
Yield [%]
ee
[d]
[%]
[
c]
(
(anti/syn)
73 (91:9)
89 (92:8)
3
in Table 2). At the transition state TS5/6-diol and TS6/7-diol, two
1
2
3
4
5
6
n = 1; Z = CN
H
2
O (10)
94
97
91
94
90
95
hydroxyl groups are found to play the role of two water molecules
relaying the protons. The barrier heights in the process of enamine
formation are very similar with two waters (TS6/7-2w, ~23.6
kcal/mol) and cis-2-butene-1,4-diol replacement (TS6/7-Diol, ~26.5
kcal/mol). Thus, these theoretical and experimental findings support
each other on the role of water and water replacement.
cis-2-butene-1,4-diol (5)
n = 1; Z = CO
2
Me
H
2
O (10)
77 (90:10)
98 (91:9)
64 (98:2)
88 (98:2)
cis-2-butene-1,4-diol (5)
Table 2. Effect of water and some diol replacements in asymmetric aldol reaction
[a]
catalyzed by primary-amine 1a.
n = 0; Z = NO
2
2
H O (10)
cis-2-butene-1,4-diol (5)
[a] Unless otherwise specified, asymmetric direct aldol reaction of cycloalkanone (30
equiv) and p-substituted benzaldehyde (1 equiv) with 10 mol% of catalyst 1a in the
[
c]
[e]
Entry
Additive
equiv)
Yield [%]
ee [%]
absence or presence of additive in MeCN (1.8 mL) at room temperature. [b] Isolated
[d]
1
(
(anti/syn)
yield. [c] The anti/syn ratio of aldol products was determined by H NMR analysis. [d]
Enantiopurity of aldol products was determined by HPLC analysis using a chiral
column [DAICEL Chiralpak AD-H].
1
2
3
none
<5 (- : -)
94
95
97
[
b]
2
H O (10)
67 (89:11)
91 (90:10)
Conclusions
[
b]
(5)
In summary, we have succeeded in elucidating the origin of higher
reactivity in the water-accelerated asymmetric aldol reactions with
our designed primary-amino organocatalyst 1 by both experimental
3

Chemistry - An Asian Journal
10.1002/asia.201500078
R. Noto, Adv. Synth. Catal. 2009, 351, 33. (e) M. Raj, V. K. Singh, Chem.
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and computational methods. Some diols have been found to work as
replacement of two water molecules and accelerate the rate of the
Aldol reaction. Our interpretation is in principle applicable to other
asymmetric aldol reaction with acyclic primary-amino acids
(
g) R. N. Butler, A. G. Coyne, Chem. Rev. 2010, 110, 6302. (h) J. Mlynarski, S.
Bas, Chem. Soc. Rev. 2014, 43, 577.
[
6]
7]
The role of water in proline-mediated aldol reaction was recently reported: N.
Zotova, A. Franzke, A. Armstrong, D. G. Blackmond, J. Am. Chem. Soc. 2007,
129, 15100.
(alanine, threonine, tryptophan, etc.) and their derivatives as
organocatalysts, and further effort to this end is currently underway
in our laboratories.
[
Representative examples on direct asymmetric aldol reactions mediated by
prim-amino acid-based organocatalysts in aqueous solvent: Reviews: (a) L.-W.
Xu, Y. Lu, Org. Biomol. Chem. 2008, 6, 2047. (b) L.-W. Xu, J. Luo, Y. Lu, Chem.
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Experimental Section
General procedure for asymmetric aldol reaction with primary-amine catalyst 1a: To a
mixture of catalyst 1a (9.6 mg, 10 mol%) in MeCN (1.8 ml) was added aldehyde (0.3
mmol), cis-2-butene-1,4-diol (130 mg, 5 equiv), and cyclohexanone (0.9 ml, 9.0 mmol).
The mixture was stirred at room temperature for 48 hours. Then, saturated NH
solution and ethyl acetate were added with vigorous stirring, the organic layer was
separated and washed with brine. The organic phase was dried over Na SO and
4
Cl
2
4
concentrated in vacuo. The residue was then purified by column chromatography on
silica gel (mixture of ethyl acetate/hexane) to give the 2-(hydroxy-p-
nitrophenylmethyl)cyclohexan-1-one as colorless solid (68 mg, 91% yield).
[8]
A. Heine, G. DeSantis, J. G. Luz, M. Mitchell, C,-H. Wong, I. A. Wilson,
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Acknowledgements
[9]
For the theoretical investigation on the enhanced activity of organocatalysis on
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This work was partially supported by a Grant-in-Aid for Scientific Research from the
MEXT, Japan. The computer resources at the Academic Center for Computing and
Media Studies (ACCMS) at Kyoto University and Research Center of Computer
Science (RCCS) at the Institute for Molecular Science are acknowledged.
2
012, 77, 4784.
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Keywords: aldol • amine • organocatalysis • water •
computation
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1
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The free energies were calculated at 298.15 K and 1 atm.
[
2]
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[
[
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Received: ((will be filled in by the editorial staff))
Revised: ((will be filled in by the editorial staff))
Published online: ((will be filled in by the editorial staff))
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[
Certain proline-derived catalysts are reported to show high reactivity and
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M. Lindstrom, Chem. Rev. 2002, 102, 2751. (d) M. Gruttadauria, F. Giacalone,
4

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Layout 2:
COMMUNICATION
Shin A. Moteki, Hiroki Maruyama,
Keiji Nakayama, Hai-Bei Li, Galina
Petrova, Satoshi Maeda, Keiji
Morokuma,* and Keiji Maruoka*
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Positive Effect of Water in
Asymmetric Direct Aldol Reactions
with Primary-Amine
Organocatalyst: Experimental and
Computational Studies
The origin of higher reactivity in the water-accelerated asymmetric aldol
reactions with our designed primary-amine organocatalyst was elucidated by
both computational and experimental methods.
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