Direct asymmetric aldol reactions between aldehydes and ketones catalyzed by l-tryptophan in the presence of water

Article abstract of DOI:10.1039/b921460g

Primary amino acids and their derivatives were investigated as catalysts for the direct asymmetric aldol reactions between ketones and aldehydes in the presence of water, and l-tryptophan was shown to be the best catalyst. Solvent effects, substrate scope

Full text of DOI:10.1039/b921460g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Direct asymmetric aldol reactions between aldehydes and ketones catalyzed
by L-tryptophan in the presence of water†
Zhaoqin Jiang,a,b Hui Yang,a Xiao Han,a Jie Luo,a Ming Wah Wong*a,b and Yixin Lu*a,b
Received 14th October 2009, Accepted 9th December 2009
First published as an Advance Article on the web 22nd January 2010
DOI: 10.1039/b921460g
Primary amino acids and their derivatives were investigated as catalysts for the direct asymmetric aldol
reactions between ketones and aldehydes in the presence of water, and L-tryptophan was shown to be
the best catalyst. Solvent effects, substrate scope and the influence of water on the reactions were
investigated. Quantum chemical calculations were performed to understand the origin of the observed
stereoselectivity.
organocatalytic reactions in a purely aqueous system is of great
Introduction
current interest.14 Recently, the groups of Hayashi15 and Barbas16
The aldol reaction has been recognized as one of the most
reported asymmetric aldol reactions carried out in the presence
important carbon–carbon bond-forming reactions, yielding b-
hydroxy carbonyl compounds, which are valuable intermediates in
organic synthesis.1 In particular, asymmetric aldol reactions have
drawn great attention from the synthetic community in the past few
decades.2 Following the seminal contributions from Masamune
et al.,3 Evans et al.,4 and Iwasawa and Mukaiyama5 in the early
1980s, transition metal complexes and Lewis bases were shown
to be powerful catalysts in asymmetric aldol reactions, employ-
ing activated silyl enol ethers.6 Catalytic enantioselective aldol
reactions using unmodified ketones or aldehydes catalyzed by
transition metal complexes certainly represent another important
development.7
of water, and hydrophobic proline derivatives were employed as
efficient organocatalysts in their investigations.
We have keen interests in asymmetric organocatalytic reactions
that can be promoted by chiral primary amines.17 In one of our ear-
lier communications,17a we reported that natural tryptophan could
effectively catalyze the direct asymmetric aldol reactions between
cyclic ketones and aromatic aldehydes in the presence of water.
Herein, we present a full study and mechanistic understanding of
the tryptophan-catalyzed direct asymmetric aldol reactions.
Results and discussion
The past few years have witnessed astonishing progress in
asymmetric organocatalysis,8 which has now been established as
one of the most promising and practical methods in asymmetric
synthesis and catalysis. In particular, asymmetric organocatalytic
aldol reactions have been intensively investigated ever since the
renaissance of modern organic catalysis.9 In this regard, proline
and its various structural derivatives have been shown to be
versatile organic catalysts for the intermolecular aldol reactions.10
In contrast to the early studies on the use of proline and primary
amino acids in intramolecular aldol reactions,11 the employment
of primary amino acids as catalysts in asymmetric reactions was
virtually negligible in the early 2000s. It was not until 2004 when
primary amino acids were carefully examined as potential effec-
tive catalysts for intermolecular aldol reactions, and impressive
progress has been made in the past five years, establishing primary
amino acids/amines as privileged organocatalysts.12
Catalyst screening
The aldol reaction of p-nitrobenzaldehyde and cyclohexanone
was selected as a model reaction to evaluate our organocatalysts.
Since tryptophan was the best catalyst in our preliminary study,
we intended to further test the catalytic effects of a few N-
substituted tryptophan derivatives in direct aldol reactions, and
the structures of the catalysts employed in our study are shown in
Scheme 1. N-Methylated tryptophan 3a is commercially available,
and N-arylated tryptophan derivatives can be easily prepared. The
copper-catalyzed N-arylation method developed by Buchwald
et al.18 was employed to install different aromatic moieties on
the indole nitrogen of N-benzyloxycarbonyl-L-tryptophan benzyl
ester 1, yielding N-phenyl-, naphthyl- or biphenyl-substituted
intermediates 2b, 2c or 2d, respectively, and it was found that mi-
crowave irradiation could dramatically shorten the reaction time
in the coupling step. After hydrogenolysis, N-arylated tryptophan
derivatives 3b–d were obtained.
Water is an ideal solvent for chemical reactions, mainly due
to its low cost and environmentally benign nature.13 Developing
The N-arylated tryptophan derivatives and a wide range of
natural amino acids were evaluated in the model reaction under
aqueous reaction conditions, which are summarized in Table 1.
Amino acids with a small side chain (entry 1) or hydrophilic groups
(entries 2–5) were ineffective, yielding the products either in low
yields or with very poor enantioselectivity. With increasing size of
the amino acid side chain, better enantioselectivities were observed
(entries 6–11). Although Cbz-protected lysine was found to be
effective in asymmetric induction (89% ee), the chemical yield was
aDepartment of Chemistry, National University of Singapore, 3 Science
Drive 3, Singapore, 117543, Republic of Singapore. E-mail: chmwmw@
nus.edu.sg, chmlyx@nus.edu.sg; Fax: +65-6779-1691; Tel: +65-6516-1569
bMedicinal Chemistry Program, Life Sciences Institute, National University
of Singapore, Republic of Singapore
† Electronic supplementary information (ESI) available: Details of the
preparation of tryptophan derivatives 3b–d, analytical data and HPLC
spectra of the aldol products, and quantum chemical calculations. See
DOI: 10.1039/b921460g
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Scheme 1 Prepared N-arylated tryptophan derivatives.
low (entry 12). Overall, natural tryptophan was the best catalyst,
yielding the desired product in a short reaction time, in high chemi-
cal yield, and with good diastereoselectivity and excellent enantio-
selectivity (entry 13). The results obtained by employing
N-substituted tryptophan derivatives were disappointing. N-
Methyl tryptophan showed a catalytic effect slightly inferior to
that of natural tryptophan, affording the products in moderate
yield and with good enantioselectivity (entry 14). The substitution
of different aryl groups at the indole nitrogen led to catalysts that
were less effective in promoting the direct aldol reactions, and
the desired products were obtained with only poor to modest
enantioselectivities (entries 15–17).
Table 1 Direct asymmetric aldol reactions catalyzed by primary amino
acids and N-arylated tryptophan derivativesa
Entry Catalyst
Time/h Yield (%)b Syn : antic ee (%)d
1
2
3
4
5
6
7
8
L-Alanine
L-Tyrosine
L-Serine
L-Histidine
L-Arginine
L-Valine
L-Phenylalanine
L-Isoleucine
L-Leucine
L-Threonine
L-Cysteine
L-H-Lys-(Z)-OH 57
L-Tryptophan
109
28
96
57
18
144
48
96
96
82
96
32
<5
<10
59
83
84
75
67
81
30
23
46
85
68
85
50
88
1 : 12
—
—
0
—
—
8
1 : 1.5
1.4 : 1
1 : 4
1 : 4
1 : 5
1 : 3
1 : 2
1 : 3
1 : 5.6
1 : 4
1 : 4
1 : 4
1 : 2
1 : 4
14
65
70
83
79
76
73
89
86
79
25
50
70
Effects of solvents
9
We also examined the influence of various organic solvents on the
tryptophan-catalyzed direct aldol reactions, and the results are
summarized in Table 2. In neat conditions, the reaction proceeded
readily, with moderate diastereoselectivity and excellent enantio-
selectivity (entry 1). DMSO was found to be a good organic sol-
vent, the reaction was completed in one day, and the desired prod-
ucts were obtained in good yield, with good diastereoselectivity
and moderate enantioselectivity (entry 3). THF was less effective,
and a slower reaction and decreased stereoselectivity were ob-
served (entry 4). Common organic solvents, e.g. dichloromethane,
chloroform, toluene, hexane and acetonitrile, were unsuitable for
the tryptophan-promoted direct aldol reactions, and several days
were required for the completion of the reactions, even though
10
11
12
13
14
15
16
17
23
48
19
12
19
3a
3b
3c
3d
a The reaction was performed by employing p-nitrobenzaldehyde
(0.25 mmol), cyclohexanone (1.25 mmol), organocatalyst (0.025 mmol),
and water (0.045 mL) at room temperature. b The combined isolated yield
of the diastereomers. c The diastereoselectivity was determined by 1H
NMR analysis of the crude aldol product. d The ee of the anti isomer
was determined by HPLC analysis on a chiral phase.
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Table 2 Tryptophan-catalyzed direct asymmetric aldol reactions in dif-
Table 3 The influence of amounts of water on the tryptophan-catalyzed
ferent solventsa
direct aldol reactionsa
Entry
H2O (eq.)
Time/h
Yield (%)b
Syn : antic
ee (%)d
Entry
Solvent
Time
Yield (%)b
Syn : antic
ee (%)d
1
2
3
4
5
6
7
8
1
2
3
5
10
15
20
56
111
300
26
26
26
19
23
19
19
38
38
160
90
86
83
86
84
85
91
79
66
40
1 : 4.5
1 : 5
1 : 5
1 : 5
1 : 5
1 : 5
1 : 5
1 : 6
1 : 5
1 : 1.4
92
85
87
86
86
96
96
91
89
83
1
2
3
4
5
6
7
8
Neat
DMF
DMSO
THF
CH2Cl2
CHCl3
Toluene
Hexane
CH3CN
CH3OH
EtOH
1 d
3 d
1 d
2 d
9 d
9 d
6 d
6 d
4 d
9 d
9 d
9 d
41 h
92
72
93
72
23
41
86
88
63
42
77
51
97
1 : 4
1 : 4
1 : 4.6
1 : 1
1 : 5
1 : 4
1 : 2.4
1 : 2
1 : 3
1 : 3
89
46
73
63
87
89
89
87
88
45
53
60
83
9
10
9
10
11
12
13
1 : 5
1 : 4
1 : 2.3
a The reaction was performed by employing p-nitrobenzaldehyde
(0.25 mmol), cyclohexanone (1.25 mmol), L-tryptophan (0.025 mmol)
and water at room temperature. b The combined isolated yield of the
diastereomers. c The diastereoselectivity was determined by 1H NMR
analysis of the crude aldol product. d The ee of the anti isomer was
determined by HPLC analysis on a chiral phase.
i-PrOH
tert-BuOH
a The reaction was performed by employing p-nitrobenzaldehyde
(0.25 mmol), cyclohexanone (1.25 mmol), L-tryptophan (0.025 mmol),
and solvent (0.3 mL) at room temperature. b The combined isolated yield
of the diastereomers. c The diastereoselectivity was determined by 1H
NMR analysis of the crude aldol product. d The ee of the anti isomer
was determined by HPLC analysis on a chiral phase.
reaction was also examined. Buffer solutions with pH values at 6,
7 and 8 were used as the solvent, and similar results were obtained
(pH 6, dr = 1 : 6, 85% ee; pH 7, dr = 1 : 5, 78% ee; pH 8, dr = 1 : 3,
81% ee).
high enantioselectivity was attainable in certain cases (entries 5–
9). Protic solvents, such as methanol, ethanol and isopropanol,
were inappropriate solvents for the reactions (entries 10–12). tert-
Butanol, however, was found to be an appropriate solvent (entry
13). The above results demonstrate that water is indispensable in
the direct aldol reactions mediated by tryptophan. The presence
of water led to shortened reaction time, higher chemical yield,
and improved diastereo- and enantioselectivity, compared to the
reactions performed in organic solvents.
The substrate ratio and catalyst loading
Having established water as the best solvent for the reaction,
and optimized the equivalents of water required in the reaction
system, we then investigated the influence of substrate ratios
on the reaction, and the results are summarized in Table 4. By
Table 4 The effects of substrate ratio and catalyst loadinga
Effects of water
The tryptophan-catalyzed direct aldol reaction using water as a
solvent could be best described as a reaction proceeding “in the
presence of water”. The reaction mixture was a two phase system,
with a solid tryptophan suspension, and this physical state was
maintained throughout the reaction.
Catalyst Aldehyde :
Entry (mol%) ketone
Time/h Yield (%)b Syn : antic ee (%)d
The influence of the amount of water on the tryptophan-
promoted direct aldol reaction was further investigated, and the
results are summarized in Table 3. In general, addition of various
amounts of water favoured the reaction, leading to shortened
reaction times and improved stereoselectivities. The results were
similar when the molar amounts of water were below 10 (entries
1–5). The use of 15 and 20 molar amounts of water turned
out to be optimal, affording the desired products in excellent
yields, and with 5 : 1 dr and 96% ee (entries 6 and 7). Further
increasing the amount of water was detrimental to the reaction,
resulting in much slower reactions, lower chemical yields and
decreased stereoselectivity (entries 8 and 9). When a large excess
of water (300 equivalents) was used, the reaction proceeded
extremely slowly, and the aldol products were obtained in low
yield, with virtually no diastereoselectivity and much decreased
enantioselectivity (entry 10). Moreover, the pH influence on the
1
2
3
4
5
6
7
8
10
10
10
10
10
1
2
3
4
5
1 : 1
1 : 2
1 : 3
1 : 4
1 : 5
1 : 5
1 : 5
1 : 5
1 : 5
1 : 5
1 : 5
1 : 5
36
36
24
24
19
128
73
73
43
36
22
22
82
85
87
89
91
41
79
88
92
85
88
86
1 : 4
1 : 5
1 : 6
1 : 6
1 : 5
1 : 1
1 : 4
1 : 4
1 : 3
1 : 5
1 : 4
1 : 5
74
84
80
80
96
84
71
81
89
92
92
93
9
10
11
12
15
20
a The reaction was performed by employing p-nitrobenzaldehyde
(0.25 mmol), cyclohexanone (1.25 mmol), L-tryptophan (0.025 mmol),
and water (5 mmol) at room temperature. b The combined isolated yield
of the diastereomers. c The diastereoselectivity was determined by 1H
NMR analysis of the crude aldol product. d The ee of the anti isomer
was determined by HPLC analysis on a chiral phase.
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utilizing an equal molar ratio of aldehyde and ketone, moderate
enantioselectivity was attainable (entry 1). With further increases
in the amount of cyclohexanone, the reaction times were shortened
and good enantioselectivities were obtained (entries 2–4). Five
equivalents of cyclohexanone were found to be optimal, and under
such conditions short reaction time, very high chemical yield, good
diastereoselectivity and excellent enantioselectivity were observed
(entry 5). Compared to the results obtained with 10 mol% catalyst,
lowering the catalyst loading resulted in reduced reaction rates,
and slightly decreased stereoselectivity (entries 6–10). When the
catalyst loading was increased to 15 and 20 mol%, no improvement
in the reaction was observed (entries 11 and 12). Taken together,
10 mol% catalyst loading and a 1 : 5 aldehyde : ketone ratio are
the optimal reaction conditions, yielding the desired product with
high enantioselectivity within 1 d.
cyclohexanone and tryptophan is calculated to be a slightly
endothermic process, by 9.4 kJ mol-1. It is instructive to first
examine the structures and energies of this enamine intermediate
involved. Conformational analysis was carried out initially to
determine various possible low-lying conformations. The opti-
mized geometries and calculated relative energies of the 8 lowest-
energy conformations of the enamine intermediate are given in the
ESI.† There are two important lowest-energy conformations of the
enamine intermediate: enam1 and enam2. The amine N–H proton
is on the same side as the cyclohexenyl double bond in enam1
and the opposite side in enam2 (Fig. 1). These two conformers lie
close in energy, with a slight preference for the enam2 form (by
3.8 kJ mol-1).
Substrate scope
The substrate scope was next investigated, as illustrated in Table 5.
Various acyclic ketones, including a number of a-oxygenated
ketones, proved to be unsuitable substrates for the tryptophan-
promoted direct aldol reaction, and no desired product was
observed (entries 1–9). In the case of 3-pentanone, the aldol
products could be obtained, although in low yield and with low
enantioselectivity (entry 10). The observed non/low reactivity of
acyclic ketones in the tryptophan-catalyzed aldol reaction could
be attributed to inefficient formation of the active enamine inter-
mediates from acyclic ketones. In a stark contrast to the acyclic
ketones, cyclic ketones, including cyclopentanone, cyclohexanone
and cycloheptanone, have been demonstrated to be excellent
substrates. In addition, substituted cyclohexanone could also
be employed, yielding the aldol products with three stereogenic
centers (entries 29 and 30).
The scope of aldehyde acceptors was evaluated. Electron-poor
aromatic aldehydes offered the best reactivity, and the desired aldol
products were obtained in good chemical yields, and with anti-
diastereoselectivity and generally high enantioselectivity (entries
11–18). For instance, when o-nitrobenzaldehyde was used, the
anti-aldol adduct 6e was obtained in 77% chemical yield, with
1 : 52 dr and 90% ee (entry 14). However, the reaction with
o-trifluoromethyl-substituted aldehyde turned out to be ineffec-
tive, likely due to the large amount of steric hindrance induced
by the CF3 group (entry 19). Electron-rich or electron-neutral
aromatic aldehydes could be tolerated for the reaction (entries 20–
22), and heteroaromatic aldehydes such as furan-2-carbaldehyde
and thiophene-2-carbaldehyde were also found to be suitable
(entries 23–25). Moreover, halogenated aromatic aldehydes could
be employed, even though longer reaction times were generally
required (entries 26–28).
Fig. 1 Optimized (B3LYP/6-31G**) geometries of the two lowest-energy
conformations of enamine (enam1 and enam2). Bond distances are given
in A.
˚
Both enamine conformations are characterized by two key
structural features: (1) a hydrogen bond between the amine
nitrogen and the carboxyl O–H proton and (2) N–H/p interaction
between the amine N–H and the indole moiety. For comparison, a
similar enam1 conformation with the indole group away from the
N–H has a significantly higher relative energy of 11.4 kJ mol-1. The
stabilizing energetic effect of the N–H/p interaction is further sup-
ported by NBO second-order perturbation theory energy analysis.
A donor–acceptor interaction energy of ~5 kJ mol-1 between an
=
indole C C p-bonding orbital and the N–H antibonding orbital
is estimated for both conformers. The existence of the N–H/p
interaction is further confirmed by topological analysis based on
Bader’s theory of atoms in molecules (AIM). Previous theoretical
studies have shown that an X–H/p (X = C, N or O) interaction
is characterized by a bond path and its associated bond critical
point.23 For the N–H/p contact examined here, there exists a
bond path linking the hydrogen atom with both carbon atoms
Mechanistic investigation: computational studies to understand the
observed stereoselectivities
To shed light on the mechanism and stereoselectivity of the
L-tryptophan-catalyzed aldol reaction between cyclohexanone
and p-nitrobenzaldehyde, quantum chemical calculations were
performed.19 It is well established that amino acid-catalyzed aldol
reactions involve enamine intermediates.20–22 For the catalytic
aldol reaction examined here, the formation of an enamine from
=
of the indole C C bond. The calculated topological properties
at the bond critical points, namely electron density (r), Laplacian
of electron density (—2 r) and ellipticity (e), are similar to the
characteristic topological properties of a weak hydrogen bond,
23
such as CH ◊ ◊ ◊ O24 and C–H ◊ ◊ ◊ p interactions. Due to these
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Table 5 L-Tryptophan-catalyzed direct aldol reactions between various ketones and aldehydesa
Entry
1
Product
Time/h
196
Yield (%)b
Syn : antic
ee (%)d
—
e
—
—
e
2
3
4
5
6
7
8
9
96
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
e
53
—
e
72
—
e
72
—
e
170
170
170
96
—
e
—
e
—
e
—
10
11
216
12
38
74
1 : 1
1 : 1
54
78
12
48
99
4 : 1
82
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Table 5 (Contd.)
Entry
13
Product
Time/h
24
Yield (%)b
73
Syn : antic
ee (%)d
84
2 : 3
14
15
16
24
24
24
77
79
78
1 : 52
1 : 20
1 : 3
90
89
88
17
18
19
48
39
48
73
65
24
1 : 2
75
76
66
1 : 19
5 : 1
20
21
22
42
92
24
42
47
57
1 : 10
1 : 78
1 : 16
87
89
92
23
24
72
24
49
76
1 : 5
85
59
10 : 1
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Table 5 (Contd.)
Entry
25
Product
Time/h
24
Yield (%)b
40
Syn : antic
ee (%)d
60
1 : 2
26
96
66
1 : 17
82
27
28
29
25
96
36
51
74
97
1 : 88
1 : 4
86
79
73
1 : 4
30
41
90
1 : 2
86
a The reactions were performed with aldehyde (0.5 mmol), cyclohexanone (2.5 mmol) and tryptophan (0.05 mmol) in water (10 mmol) at room temperature.
b Isolated yield. c Determined by 1H NMR analysis of the products. d ee of anti isomer. e No product was observed.
two key stabilizing intramolecular interactions, both enamine
forms have a rather rigid geometry. Most importantly, the indole
moiety partially shields one face of the p-bond of the cyclohexene
moiety in the enamine. For instance, the si-face of enam1 is
partially shielded by the indole unit leaving the re-face exposed
for enantioselective C–C bond formation with benzaldehyde (see
the space filling model in Fig. 1).
A previous theoretical study on a related alanine-catalyzed
aldol reaction by Himo et al. showed that the most accessible
pathway corresponds to C–C bond formation coupled with proton
transfer from the carboxylic group of the alanine moiety in the
transition state.22 For the tryptophan-catalyzed aldol reaction
examined here, we have established a similar mechanistic pref-
erence through calculations on the competitive pathways, namely
amino-, enamine- and enaminium-catalyzed mechanisms. Indeed,
this theoretical result strongly supports the experimental finding
that the tryptophan carboxylic acid function is important for the
asymmetric induction, as the tryptophan methyl ester afforded a
virtually racemic product.17a
Next, we consider various plausible transition states of the
carboxylic acid-catalyzed enamine pathway leading to the four
different stereoisomers. Basedonthe factthat there are (1) two low-
lying conformations of the enamine intermediate, (2) two possible
modes of approach (re and si) of the prochiral carbon of enamine
on benzaldehyde, and (3) two orientations of benzaldehyde (with
respect to enamine), there are 8 conceivable transition states to
be examined. This C–C bond forming step is the rate-determining
step25 and governs the stereochemistry of the final product. Fig. 2
shows the four transition state structures (TS1–TS4) that produce
the four different stereoisomers with the lowest energy barriers.
The calculated activation barriers (DG‡298), with respect to enamine
and p-nitrobenzaldehyde, of the four transition states leading
to the formation of the (S,R), (S,S), (R,S) and (R,R) products
are 32.4, 47.4, 58.2 and 62.9 kJ mol-1, respectively. Overall,
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Closer examination of the optimized geometries of these
four low-lying transition-state structures reveals a few important
structural effects that contribute to the stereoselectivity of the
catalytic aldol reaction. All four transition states (TS1–TS4) are
characterized by a strong O–H ◊ ◊ ◊ O hydrogen bond. The O–H
˚
and O ◊ ◊ ◊ H distances are in the ranges 1.06–1.08 A and 1.38–
˚
1.40 A, respectively (Fig. 2). Close contact between the amino
proton and carboxyl oxygen is found in TS1 and TS2 (the N–
˚
H ◊ ◊ ◊ O distances are 2.19 and 2.11 A, respectively). This suggests
that a weak N–H ◊ ◊ ◊ O hydrogen bond is present. Similar findings
were reported in the alanine-catalyzed aldol reaction.22 As in the
case of the enamine intermediates (enam1 and enam2), the N–
H/p interaction has a stabilizing effect on several transition states.
This is readily supported by the NBO second-order perturbation
theory energy analysis. Transition states without this stabilizing
interaction are significantly higher in energy. In other words,
the indole functional group of tryptophan provides a stabilizing
effect on the transition states. This result indicates that the indole
structural motif of the amino acid is essential to catalyze the
direct asymmetric aldol reaction with high stereoselectivity, and
provides a possible explanation for the better stereoselectivity of
tryptophan over other amino acids. Finally, the higher activation
barrier of TS2 compared to TS1 is likely to be attributed to
the non-bonding repulsion between enamine ring protons and
benzaldehyde protons, as reflected in the close H ◊ ◊ ◊ H contact
Fig. 2 Optimized (B3LYP/6-31G**) geometries of the four transition
states (TS1–TS4) leading to the formation of (S,R), (S,S), (R,S) and (R,R)
enantiomeric products. Bond distances are given in A.
˚
the lowest activation barrier corresponds to the formation of
the (S,R) enantiomer (via TS1), which is indeed the product
observed experimentally. In TS1, the re-face of the acceptor
benzaldehyde is approached by the re-face of the catalytically
generated chiral enamine (Fig. 2). The calculated relative energies
of these four transition states are consistent with the observed
high enantioselectivity (96% ee) and anti diastereoselectivity
(anti : syn = 5 : 1).17a In particular, the (R,S) enantiomer is formed
through TS3, which lies 25.8 kJ mol-1 higher in energy than TS1.
Fig. 3 provides a schematic diagram summarizing the structures
and relative energies of species involved in the formation of the
(S,R) enantiomeric product.
˚
distance (2.03 A) in TS2. This differential steric effect is confirmed
by NBO steric analysis.
It is important to note that the quantum chemical calculations
carried out here correspond to gas phase conditions. Several recent
studies have demonstrated that the enamine-based organocatalysis
“in the presence of water” is best described as a “concentrated
organic phase”.14 In other words, the catalytic aldol reaction takes
place in a biphasic reaction mixture. To provide a more realis-
tic description of an organic-phase environment, reaction field
calculations based on the polarizable continuum model (PCM)
Fig. 3 Schematic diagram of the structures and energies of species involved in the formation of the (S,R) enantiomeric product. Calculated relative free
energies (DG298, kJ mol-1) MP2/6-311+G**//B3LYP/6-31G** level, are given in square brackets.
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were also performed in cyclohexane solvent. Not surprisingly, the
solvent effect on energetics is very small. The calculated activation
barriers for the formation of (S,R), (S,S), (R,S) and (R,R) products
are 28.1, 38.6, 52.0 and 55.1 kJ mol-1, respectively. The predicted
stereoselectivity in cyclohexane is very close to that calculated in
the isolated state.
flash chromatography on silica gel (EtOAc–hexane = 1 : 3) to give
2-(hydroxy(4-nitrophenyl)methyl)cyclohexanone as a yellow solid
(0.1137 g, 91%). Reactions employing other catalysts or substrates
were performed in a similar manner.
Computational details
Geometry optimizations were performed with the hybrid B3LYP26
functional in conjunction with the split-valence polarized 6-31G**
basis set. Higher-level relative energies were obtained through
single-point energy calculations at MP2 level using a larger 6-
311+G** basis set. The MP2 theory is important for reliable
prediction of the energies of the transition states and enamine
intermediates which are stabilized by N–H ◊ ◊ ◊ p interactions
since dispersion is a major source of this weak intermolecular
interaction.23b,27 Frequency calculations based on the B3LYP/6-
31G** optimized geometries were performed to verify the nature
of stationary points as equilibrium structures or transition states
and to evaluate zero-point energies (ZPE). Equilibrium structures
are characterized by all real frequencies while transition states have
one and only one imaginary frequency. The identities of several
key transition states were confirmed by intrinsic reaction coor-
dinate (IRC) calculations. The effect of solvent was investigated
by the polarizable continuum model (PCM).28 PCM-B3LYP/6-
311+G** single-point energy calculations in cyclohexane (e =
2.02) were performed on the gas-phase optimized geometries.
Unless otherwise noted, the relative free energies (DG298) in the
text correspond to the MP2/6-311+G**//B3LYP/6-31G** level.
The directly calculated ZPE’s were scaled by a factor of 0.9804.29
All calculations were performed using the Gaussian 03 suite of
programs.30 Natural bond orbital (NBO)31 analysis was carried out
for all transition states. The donor–acceptor interaction energies
of various types of weak molecular interaction in the transition
states were estimated using the second-order perturbation theory
energy analysis.31 Charge density analysis, based on Bader’s theory
of atoms in molecules (AIM)32 was performed to examine the N–
H/p interaction.
Conclusions
We have developed highly efficient organocatalytic aldol reactions
between cyclic ketones and aromatic aldehydes that can be
catalyzed by natural tryptophan in the presence of water. Solvent
studies demonstrated that water is the best reaction medium for
the described direct asymmetric aldol reactions, and the desired
products can be obtained with excellent anti selectivity and
good enantioselectivity. The reaction mechanism was investigated
by performing quantum chemical calculations. We showed that
a carboxylic acid-catalyzed enamine mechanism was involved.
Moreover, our computational studies provide key insights into
the origin of the stereoselectivity, and correctly predict the
stereochemistry of the observed product. In particular, the indole
moiety of tryptophan is found to play an essential role in stabilising
the transition state.
Experimental
General methods
Chemicals and solvents were purchased from commercial suppli-
ers and used as received. 1H and 13C NMR spectra were recorded
on a Bruker ACF300 or AMX500 (500 MHz) spectrometer.
Chemical shifts are reported in parts per million (ppm), and the
residual solvent peak was used as an internal reference: proton
(chloroform d 7.26), carbon (chloroform d 77.0). Multiplicity
is indicated as follows: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), dd (doublet of doublets), br s (broad
singlet). Coupling constants (J) are reported in Hertz (Hz). Low
resolution mass spectra were obtained on a Finnigan/MAT LCQ
spectrometer in ESI mode, and a Finnigan/MAT 95XL-T mass
spectrometer in FAB mode. All high resolution mass spectra
were obtained on a Finnigan/MAT 95XL-T spectrometer. For
thin-layer chromatography (TLC), Merck pre-coated TLC plates
(Merck 60 F254) were used, and compounds were visualized with
a UV light at 254 nm. Further visualization was achieved by
staining with iodine, or ceric ammonium molybdate followed by
heating on a hot plate. Flash chromatography separations were
performed on Merck 60 (0.040–0.063 mm) mesh silica gel. The
enantiomeric excesses of products were determined by chiral phase
HPLC analysis.
Acknowledgements
The authors thank the National University of Singapore for
generous financial support. Y. L. is grateful to the Ministry of
Education (MOE) of Singapore (R-143-000-362-112).
Notes and references
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Representative procedure for the tryptophan-catalyzed direct aldol
reaction
L-Tryptophan (0.0102 g, 0.05 mmol) was added to a suspension
of p-nitrobenzaldehyde (0.0755 g, 0.5 mmol), cyclohexanone
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