Asymmetric aldol reaction using a very simple primary amine catalyst: Divergent stereoselectivity by using 2,6-difluorophenyl moiety

Article abstract of DOI:10.1016/j.tet.2014.02.059

Asymmetric aldol reactions of aliphatic ketones or aldehydes with aromatic aldehydes or isatins were catalyzed by a very simple and flexible N-(2,6-difluorophenyl)-l-valinamide. Interestingly, stereochemical course of the reaction of hydroxyacetones or α-branched aliphatic aldehydes as aldol donors was different from that of cycloalkanones.

Full text of DOI:10.1016/j.tet.2014.02.059

Tetrahedron 70 (2014) 2816e2821
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric aldol reaction using a very simple primary amine
catalyst: divergent stereoselectivity by using 2,6-difluorophenyl
moiety
*
Yuya Tanimura, Kenji Yasunaga, Kaori Ishimaru
Department of Chemistry, National Defense Academy, Hashirimizu 1-10-20, Yokosuka 239-8686, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric aldol reactions of aliphatic ketones or aldehydes with aromatic aldehydes or isatins were
Received 24 January 2014
Received in revised form 18 February 2014
Accepted 21 February 2014
Available online 2 March 2014
catalyzed by a very simple and flexible N-(2,6-difluorophenyl)-L-valinamide. Interestingly, stereochem-
ical course of the reaction of hydroxyacetones or
different from that of cycloalkanones.
a-branched aliphatic aldehydes as aldol donors was
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Aldol reaction
Asymmetric catalysis
Isatin
Organocatalysis
Valine
1. Introduction
Asymmetric reaction using organocatalysts has been rapidly
developing in recent years because the methodology is metal-free,
non-toxic, and environmentally friendly.1 A great deal of efforts
have been devoted to prepare various chiral organocatalysts,
however, most strategies for the stereocontrol in the reaction rely
on hydrogen bonding interaction and steric repulsion.2 As a result,
large molecules having many chiral centers, or secondary amines
having a rigid structure, such as proline derivatives were thought to
be necessary in the process of catalyst design. Although recent
progress has been shown that primary amine catalysts have also
been effective,3 control of stereoselectivities with simple and
flexible catalysts can be a challenge. In the course of our study, we
Fig. 1. A model for asymmetric aldol reaction catalyzed by 1a.
have developed
difluorophenyl)-
easily prepared from Boc-
a
very simple, small, and flexible N-(2,6-
-valinamide 1a as an organocatalyst, which was
-valine in two steps (Fig. 1).4 The
group of the catalyst 1a.6 As a result, the aldol reaction of aro-
matic aldehydes with cycloalkanones mainly proceeded by the
attack of Si-face of the enamine on the Si-face of aromatic aldehyde
due to the steric hindrance (Fig. 1). The novel approach encouraged
us to explore the reaction of other aldol donors and acceptors for
a wide variety of application. In this work, unexpectedly, stereo-
chemical preference was different from that in the reaction of ar-
omatic aldehyde with cycloalkanone.7 Here we report the
asymmetric aldol reactions of hydroxyacetones or aliphatic alde-
hydes with various aromatic aldehydes or isatins as aldol acceptors
using our catalyst 1.
L
L
asymmetric aldol reaction5 of aldehydes with cycloalkanones using
the catalyst 1a under environmentally friendly conditions gave the
corresponding product in high yields with up to >99% ee. Unlike
the organocatalysts reported thus far, the stereoselectivity of the
products was controlled by using tilted 2,6-difluorophenylamide
* Corresponding author. Tel.: þ81 46 841 3810x3580; e-mail address: kaoriisi@
nda.ac.jp (K. Ishimaru).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.059

Y. Tanimura et al. / Tetrahedron 70 (2014) 2816e2821
2817
2. Results and discussion
67e94% ee (syn:anti¼up to 85:15). Longer reaction time was nec-
essary without electron-withdrawing group on the aromatic ring
(entry 6). It should be noted that the reactions of both cyclo-
alkanones4 and hydroxyacetones proceeded using the catalyst 1a
with high stereoselectivities,10 however, the stereochemistry of the
products in Table 1 was different from that we expected in the
reaction of cycloalkanones.
1,2-Diols are found in many natural and biologically active
compounds.8 In spite of many reports on the reaction of hydrox-
yacetones, most of aldol reactions of hydroxyacetones use toxic
additives, co-catalysts, or organic solvents.9 To the best of our
knowledge, only a few papers have been reported on the reaction
under environmentally relevant conditions.7,9e In addition, stereo-
selective synthesis of (3R, 4S) isomers under environmentally be-
nign conditions has not been reported yet. In our initial studies,
aldol reaction of hydroxyacetone with 4-nitrobenzaldehyde 3a
using organocatalyst 1a was examined, however, the reaction
consistently resulted in moderate diastereo- and enantio-selectiv-
ities under various conditions (syn:anti¼up to 75:25, up to 62% ee
(syn)). Since the limited selectivity was thought owing to partici-
pation of the free hydroxyl group of hydroxyacetone, TBS-protected
hydroxyacetone 2b was used for the reaction (Table 1). After opti-
mizing the reaction conditions, the scope of the reaction was ex-
plored. Reaction of various aromatic aldehydes proceeded with
With these results in hand, DFT calculations were performed for
plausible transition state models (Fig. 2). First, enamine structures
were fully optimized in the gas phase at the B3LYP/6-31G(d,p) level
using Gaussian 09,11 and the transition states for the reaction in-
cluding the enamine were optimized at the same theory.12 It was
found that TS2 giving (3R, 4S) isomer had the lowest, indicating that
the aldol reaction catalyzed by 1a might pass through TS2. Al-
though it is necessary to consider the effect of brine, these models
were in good agreement with experimental results. In addition,
major isomer was the same even though various solvents were
used (66% ee in dry CH2Cl2 and 82% ee in water). Unlike the reaction
of aromatic aldehydes and cycloalkanones, three hydrogen bonding
interactions between oxygen atom of silyloxy group and hydrogen
of enamine, oxygen of benzaldehyde and enamine hydrogen,
and benzaldehyde oxygen and amide hydrogen of 2,6-difloro
phenylamide group would stabilize TS2. Additionally, hydropho-
bic interaction of TBS group of the enamine and phenyl group of
benzaldehyde7 might lead to different course of attack compared to
that of cycloalkanones.
Table 1
Asymmetric aldol reactions of TBS-protected hydroxyacetone 2b with various aro-
matic aldehydes 3a
To demonstrate the utility of our organocatalyst 1, the reaction
of hydroxyacetone with isatins was investigated (Table 2) because
the aldol adducts bearing a chiral 1,2-diol moiety13 are desirable
targets found in drug candidates, such as TMC-95AwD.14 Very re-
cently, Hu et al. have reported the diastereoselective three-
component reaction of
a-diazo esters, water and isatin, and the
Entry R (3)
Time (days)b
4
Yield (%)c syn:antid % eee
corresponding products having a 1,2-diol unit were obtained in
high diastereoselectivity (up to syn:anti¼9:91),15 however, the
enantioselectivity of the products was not evaluated. Although the
asymmetric aldol reactions of ketones with isatins have been de-
scribed, the reaction of hydroxyacetone has not been reported yet
because the reaction proceeded easily with weak bases, such as
potassium carbonate. After optimizing the reaction conditions, we
found that dry MTBE as a solvent was necessary for higher enan-
tioselectivities. The reaction of 2a with 5a was completed within
24 h but with 55% ee (entry 1 in Table 2). The use of the catalyst 1b
derived from phenylalanine gave better ee (entry 3). Addition of
1
2
3
4
5
6
4-NO2C6H4 (3a)
3
4
3
3
5
7
4a
94
83:17
84:16
85:15
82:18
78:22
81:19
85
94
80
84
79
67
2-NO2C6H4 (3b)
3-NO2C6H4 (3c)
4-CF3C6H4 (3d)
4-ClC6H4 (3e)
C6H5 (3f)
4b 92
4c 94
4d 89
4e
4f
79
76
a
All reactions were performed with 10 equiv of 2b and 0.5 mmol of 3 in the
presence of 1a (25 mol %).
b
Monitored by TLC.
c
Isolated yield.
d
Determined by 1H NMR of the crude product.
e
Determined by chiral HPLC analysis of the syn-product.
F
F
NH
O
O
N
F
H
H
F
NH
H
NH
O
O
O
O
TBS
TBS
H
H
TS1
TS2
2.24 Å
1.58 Å
1.85 Å
(top view of TS2)
front view of TS1
(ΔG = 0.0 kcal/mol)
front view of TS2
(ΔG = – 8.8 kcal/mol)
Fig. 2. Calculated 3D structures of TS1 and TS2.

2818
Y. Tanimura et al. / Tetrahedron 70 (2014) 2816e2821
Table 2
found that malonic acid as an additive and dry EtOH as a solvent
played an important role for high yields and enantioselectivities
(Table 3). Notably, the reactions with other additives, such as suc-
cinic acid, acetic acid, or benzoic acid, resulted in low enantiose-
lectivities (up to 32% ee). Changing the equivalent of malonic acid to
isatin largely affected the enantioselectivities (33% ee with
0.5 equiv, 47% ee with 1.5 equiv, and 35% ee with 2.0 equiv). Under
Asymmetric aldol reactions of hydroxyacetone 2a with isatin derivative 5aa
the optimal reaction conditions, the aldol reactions of a-branched
aliphatic aldehydes 7 with isatins 5 proceeded with excellent
enantioselectivities (entries 1e3, up to 94% ee (S)). The reaction of
5-methylisatin gave low ee but the reason is not clear now (entry
4). The absolute configuration of the product 8a was un-
ambiguously assigned by single-crystal X-ray analysis.17 Reaction of
non-branched aldehyde, such as acetaldehyde or hexanal was also
examined but it did not proceed.
Transition state models of the reaction between iso-
butyraldehyde 7a and isatin 5b were also examined by DFT calcu-
lations. After the structures of plausible transition state models
without malonic acid were fully optimized at the B3LYP/6-31G(d,p)
level using PCM model (solvent¼ethanol),11 we found that the
energy difference was only 0.9 kcal/mol between calculated tran-
sition state models giving (S)- and (R)-isomers (see Supplementary
data), indicating that malonic acid would play a key role for both
Entry
1
Additive
Timeb (h)
Yieldc (%)
syn:antid
% eee
1
2
3
4
1a
1a
1b
1b
d
24
1
36
2
89
90
84
89
85:15
84:16
85:15
84:16
55
59
69
70
Boc-
d
L
-valine
-valine
Boc-
L
a
All reactions were performed with 10 equiv of 2a and 0.5 mmol of 5a.
Monitored by TLC.
b
c
Isolated yield.
d
e
Determined by 1H NMR of the crude product.
Determined by chiral HPLC analysis of the syn-product.
Table 3
Enantioselective aldol reactions of aliphatic aldehydes 7 with isatin derivatives 5a
Entry
7
5
8
Timeb(h)
Yield (%)c
% eed
1
2
3
4
7a
7b
7a
7a
5b
5b
5c
5d
8a
8b
8c
8d
48
120
90
82
81
65
82
94
87
87e
33e
48
a
All reactions were carried out with 10 equiv of 7 and 0.5 mmol of 5.
Monitored by TLC.
Isolated yields.
Determined by chiral HPLC analysis.
Determined by chiral HPLC analysis after reduction with NaBH4.
b
c
d
e
commercially available Boc-
L
-valine accelerated the reaction to af-
the acceleration of reactions and high stereoselectivities of the
products. Considering from the equivalent effect of malonic acid on
enantioselectivities, we proposed that a complex having two hy-
drogen bonding interactions as in Fig. 3 (optimized at the same
level of theory using PCM model) might contribute to highly ster-
eoselective reaction affording (S)-isomers.
ford the product 6a with 70% ee (89% yield, syn:anti¼84:16 in entry
4), which was quite similar stereoselectivity in entry 3, indicating
that Boc-L-valine would not affect the stereoselectivity but its
acidity might accelerate the reaction. Other additives, such as p-
TsOH, malonic acid, and benzoic acid lowered the enantiose-
lectivities (up to 23% ee).
Encouraged by these results, we next focused on the reactions of
aliphatic aldehydes with isatin as the same aldol acceptor for fur-
ther application. To the best of our knowledge, one example has
3. Conclusion
In conclusion, we have developed environmentally friendly
asymmetric aldol reactions of TBS-protected hydroxyacetone 2b
with aromatic aldehydes 3 using our organocatalyst 1, which is
small and easily prepared from Boc-
the corresponding products in high diastereo- and enantio-
been reported for the aldol reaction between a-branched aliphatic
aldehydes and isatins in the presence of organocatalysts (up to 84%
ee).16 The reaction of isobutyraldehyde 7a with isatin 5b in the
presence of 1a was examined under various conditions, and we
L-valine in two steps, to afford

Y. Tanimura et al. / Tetrahedron 70 (2014) 2816e2821
2819
anhydrous sodium sulfate, filtered, and concentrated. The residue
was purified by flash column chromatography on SiO2 (n-
hexane:CH3CO2Et¼5:1) to afford the corresponding product. The
products 4a,9a 4bef,9j were identified by comparing with the
spectral data reported in the literature.
H
O
F
1.6 Å
HN
O
HN
H
O
F
1.9 Å
N
H
4.2.1. Deprotection of 4a and determination of the absolute config-
uration. To a stirred solution of aldol adduct 4a (0.39 mmol) in THF
(20 ml) was added TBAF (3.5 mmol) and AcOH (0.66 ml) at room
temperature. After stirring for 2 h, the reaction mixture was
quenched with a small amount of brine. After solution was re-
moved by evaporation, the residue was extracted with CH2Cl2. The
organic layers were washed with brine and dried over anhydrous
sodium sulfate, filtered, and the solvent was concentrated. The
residue was purified by flash column chromatography on SiO2
(hexane:CH3CO2Et¼1:1) to afford the diol as colorless crystal (69%
yield). Compared to the reported chiral HPLC retention time of the
diol,8a the absolute configuration of 4a is (3R, 4S).
H
O
2.0 Å
1.9 Å
O
H
O
O
front view of TS3
TS3
Fig. 3. Plausible transition state model (TS3) and calculated 3D structure.
selectivities (syn:anti¼up to 85:15, up to 94% ee (syn)). Moreover,
we have first succeeded the reaction of hydroxyacetone 2a with
isatin derivative 5a as a different aldol acceptor to give the aldol
product 6a bearing a pharmaceutically attractive unit with 70% ee
(syn:anti¼84:16). The aldol reaction of
a-branched aliphatic alde-
4.3. General procedure for the asymmetric aldol reaction of
hydroxyacetone with N-benzylisatin (Table 2)
hydes 7 as different aldol donors with isatins 5 using catalyst 1a
also gave the corresponding aldol products 8 in excellent enan-
tioselectivities (up to 94% ee), showing that catalyst 1 was appli-
cable for asymmetric aldol reactions of cycloalkanones, hydroxy
To a stirred solution of catalyst (0.125 mmol, 25 mol %), additive
(20 mol %), and hydroxyacetone (5.0 mmol) in dry MTBE (1.0 ml)
was added N-benzylisatin 5a (0.5 mmol) at room temperature
under argon atmosphere. The reaction mixture was stirred at room
temperature for an appropriate time until the reaction was com-
pleted by monitoring TLC. Then the mixture was purified by flash
column chromatography on SiO2 (CH3CO2Et:CH2Cl2¼3:2) to afford
the corresponding product.
acetones, and a-branched aliphatic aldehydes as aldol donors and
aromatic aldehydes, isatins as aldol acceptors. Surprisingly, ste-
reochemical course of all reactions reported here was different
from that in the reaction of aromatic aldehydes with cyclo-
alkanones, indicating that our catalyst having a 2,6-difluorophenyl
moiety has unique properties (Fig. 1).
4. Experimental
4.1. General
4.3.1. 1-Benzyl-3-hydroxy-3-(1-hydroxy-2-oxopropyl)indolin-2-one
(6a). The compound 6a was obtained as colorless oil. (syn-6a) ½a D17
ꢁ
þ3.85 (c 0.1, MeOH); 1H NMR (CDCl3, 300 MHz)
d 7.45 (d, 1H,
J¼7.5 Hz, Ar), 7.32e7.21 (m, 6H, Ar), 7.07 (t,1H, J¼7.5 Hz, Ar), 6.71 (d,
1H, J¼7.5 Hz, Ar), 4.94 (d, 1H, J¼15.6 Hz, eCH2e), 4.81 (d, 1H,
J¼15.6 Hz, eCH2e), 4.54 (d, 1H, J¼3.7 Hz, eCHOH), 3.76 (brs, 1H,
eOH), 3.72 (d, 1H, J¼3.7 Hz, eOH), 2.28 (s, 3H, eCOCH3); 13C NMR
All reactions were performed in oven-dried glassware with
a magnetic stirrer. Solvents for chromatography and extraction
were purchased from commercial suppliers and used without fur-
ther purification. All organic substrates, such as aldehydes,
hydroxyacetone, and isatin were commercially available and were
used without any purification. Thin-layer chromatography (TLC)
analysis of reaction mixtures was performed using Merck TLC
plates (silica gel 60GF-254, 0.25 mm) and visualized by using UV
(254 nm). The products were purified by flash column chroma-
tography on silica gel (Merck 1.09386.9025, 230e400 mesh or
(CDCl3, 75 MHz) d 207.8,175.2,143.3,135.0,130.5,128.8,127.8,127.5,
127.3, 124.4, 123.4, 109.8, 79.4, 44.0, 27.5; IR (KBr):
n 3404, 3061,
ꢁ
3030, 2925,1711, 1361, 1179, 1081, 754 cmꢂ1; (anti-6a) ½a D17
þ3.80 (c
0.1, MeOH); 1H NMR (CDCl3, 300 MHz)
d 7.31e7.19 (m, 6H, Ar), 7.10
(d, 1H, J¼7.3 Hz, Ar), 7.02 (t, 1H, J¼7.3 Hz, Ar), 6.67 (d, 1H, J¼7.3 Hz,
Ar), 5.12 (d, 1H, J¼16.0 Hz, eCH2e), 4.72 (d, 1H, J¼7.3 Hz, eCHOH),
4.66 (d, 1H, J¼16.0 Hz, eCH2e), 3.94 (brs, 1H, eOH), 3.57 (d, 1H,
J¼7.3 Hz, eOH), 2.41 (s, 3H, eCOCH3); 13C NMR (CDCl3, 75 MHz)
Kanto Chemical, 40e100
m
m). 1H NMR spectrum was measured
with JEOL JNM-AL300 BK1 (300 MHz) in CDCl3 or CD3OD. Multi-
plicities are reported using the following abbreviations: s¼singlet,
d¼doublet, t¼triplet, and q¼quartet. The diastereomeric ratios of
the aldol products were determined by 1H NMR. Enantiomeric
excess values of the products were determined by high perfor-
mance liquid chromatography (HPLC) with Daicel Chiralpak AD-H,
Chiralcel OD-H, Chiralcel OJ-H or Chiralpak IA (4.6 mmꢀ25 cm
column). Elemental analyses were performed on Flash EA1112.
d
207.3, 143.8, 134.9, 130.6, 128.8, 127.7, 127.1, 125.7, 124.4, 123.1,
109.9, 79.3, 44.0, 28.9; IR (KBr): n 3404, 3061, 3030, 2925,1711,1361,
1179, 1081, 754 cmꢂ1; Anal. Calcd for C18H17NO4: C, 69.44; H, 5.50;
N, 4.50. Found: C, 69.45; H, 5.50; N, 4.49. Enantiomeric excess was
determined by HPLC with CHIRALPAK AD-H column (hexane:2-
propanol¼90:10), flow rate¼1.0 mL/min; ¼254 nm; tr¼23.5 min
l
(syn-6a), tr¼35.3 min (syn-6a), tr¼42.0 min (anti-6a), tr¼46.3 min
(anti-6a). Relative stereochemistry of the aldol product was iden-
tified by comparing the spectral data of similar compounds re-
ported in the literature.15
4.2. General procedure for the asymmetric aldol reaction of
TBS-protected hydroxyacetone with aromatic aldehydes
(Table 1)
4.3.2. Preparation of 1b (Table 2). N-Methyl morpholine (2.27 ml,
20.0 mmol) and isobutyl chloroformate (2.67 ml, 20.0 mmol) in
5 ml of dry THF were successively added to a stirred solution of N-
To a stirred solution of catalyst (0.125 mmol, 25 mol %) in brine
(0.5 ml) and TBS-protected hydroxyacetone (5.0 mmol) was added
aldehyde (0.5 mmol) at room temperature under an atmosphere of
air. The reaction mixture was stirred at room temperature in
a closed system for an appropriate time until the reaction was
completed by monitoring TLC. Then the mixture was extracted
with CH2Cl2 (2 mlꢀ3) and the organic layers were dried over
Boc-
L
-phenylalanine (5.31 g, 20.0 mmol) in THF (75 ml) at ꢂ20 ꢃC.
After an activation period of 15 min, 2,6-difluoroaniline (2.82 ml,
25.0 mmol) in THF (15 ml) was added to the above solution over
10 min. The reaction mixture was stirred for 24 h at ꢂ5 ꢃC. The
resulting solution was allowed to warm to room temperature and
quenched with 20 ml of 5% aqueous NaHCO3. The mixture was

2820
Y. Tanimura et al. / Tetrahedron 70 (2014) 2816e2821
extracted with CH2Cl2 (50 mlꢀ3), and the organic layers were dried
over MgSO4, filtered, and concentrated to give the crude product as
colorless oil, which was used for the next reaction without further
purification. To a stirred solution of the oil in dry CH2Cl2 (30 ml)
was slowly added TFA (10 ml) at 0 ꢃC. After the reaction mixture
was stirred for 5 h at room temperature, excess reagent and solvent
were removed in vacuo. The resulting oil was neutralized by
aqueous saturated NaHCO3, extracted with CH2Cl2 (50ꢀ3 ml),
dried over MgSO4, and the solvent was evaporated. The crude
product was purified by flash column chromatography on SiO2
(CH3CO2Et:CH2Cl2¼3:7) to afford the organocatalyst 1b in 58% yield
with CH2Cl2. The obtained crude product was purified by flash
column chromatography on SiO2 (CH2Cl2:CH3CO2Et¼7:3) to afford
the corresponding product as a colorless oil (89.4 mg, >99% yield).
½
a 1D8
ꢁ
þ5.38 (c 0.1, MeOH); 1H NMR (CD3OD, 300 MHz)
d 7.20 (s, 1H,
Ar), 7.05 (d, 1H, J¼7.7 Hz, Ar), 6.72 (d, 1H, J¼7.7 Hz, Ar), 3.82 (d, 1H,
J¼10.8 Hz, eCH2e), 3.63 (d, 1H, J¼10.8 Hz, eCH2e), 2.31 (s, 3H,
eCH3), 1.07 (s, 3H, eCH3), 0.86 (s, 3H, eCH3); 13C NMR (CD3OD,
75 MHz) 182.2,140.9,132.6,131.9,130.7,127.9,110.6, 83.3, 69.3, 41.3,
21.2, 20.0, 19.5; IR (KBr): n 3271, 2971, 1720, 1489, 1390, 1210, 1043,
756 cmꢂ1; Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28; N, 5.95.
Found: C, 66.30; H, 7.41; N, 5.91. Enantiomeric excess was de-
termined by HPLC with CHIRALPAK AD-H column (hexane:2-
(3.18 g) as a colorless oil.4 ½a D16
ꢁ
þ4.62 (c 0.1, MeOH); 1H NMR (CDCl3,
300 MHz)
d
8.98 (brs,1H, eNH), 7.37e7.26 (m, 5H, Ar), 7.21e7.14 (m,
propanol¼85:15), flow rate¼1.0 mL/min;
l¼254 nm; tr¼8.7 min
1H, Ar), 6.88e7.02 (m, 2H, Ar), 3.83 (dd, 1H, J¼9.2, 4.0 Hz, eCHNH2),
3.36 (dd, 1H, J¼13.7, 4.0 Hz, eCH2e), 2.88 (dd, 1H, J¼13.7, 9.2 Hz,
eCH2e), 1.58 (brs, 2H, eNH2); 13C NMR (CDCl3, 75 MHz) 172.9,
159.42, 159.35, 156.1, 156.0, 137.4, 129.3, 128.7, 127.3, 126.9, 113.9,
(R), tr¼11.6 min (S).
Supplementary data
Copies of 1H and 13C NMR spectra, calculation of plausible
transition states, HPLC analysis for the products, and X-ray analysis
of 8a are available. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2014.02.059.
111.8, 111.5, 56.5, 40.6; IR (KBr): n 3276, 3028, 2922, 1694, 1241, 781,
702 cmꢂ1; Anal. Calcd for C15H14F2N2O: C, 65.21; H, 5.11; N, 10.14.
Found: C, 65.29; H, 5.07; N, 10.11.
4.4. General procedure for the asymmetric aldol reaction of
aliphatic aldehydes with isatin (Table 3)
References and notes
€
1. (a) Berkessel, A.; Groger, H. Asymmetric Organocatalysis: from Biomimetic Con-
To a stirred solution of catalyst (0.125 mmol, 25 mol %) and al-
dehyde (10.0 mmol) in dry EtOH (1.0 ml) was added isatin
(0.5 mmol) at room temperature under argon atmosphere. The
reaction mixture was stirred at room temperature for an appro-
priate time until the reaction was completed by monitoring TLC.
Then the mixture was purified by flash column chromatography on
SiO2 (CH2Cl2:CH3CO2Et¼7:3) to afford the corresponding product 8.
The products 8a and 8b were identified by comparing with the
spectral data reported in the literature.15 The products 8c and 8d
were identified as follows.
cepts to Applications in Asymmetric Synthesis; Wiley-VCH: Weinheim, Germany,
2005; (b) Dalko, P. I. Enantioselective Organocatalysis: Reactions and Experi-
mental Procedures; Wiley-VCH: Weinheim, Germany, 2007; (c) List, B. Asym-
metric Organocatalysis; Springer: Berlin, Germany, 2009.
2. For selected examples, see: (a) List, B. Tetrahedron 2002, 58, 5573; (b) Dalko, P.
I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (c) List, B. Chem. Commun.
2006, 819; (d) Kano, T.; Maruoka, K. Bull. Chem. Soc. Jpn. 2010, 83, 1421; (e)
Akiyama, T. Chem. Rev. 2007, 107, 5744; (f) Lelais, G.; MacMillan, D. W. C. Al-
drichimica Acta 2006, 39, 79; (g) List, B.; Maruoka, K. Science of Synthesis,
Asymmetric Organocatalysis; Georg Thieme: Stuttgart, Germany, 2012; (h)
Taylor, J. E.; Bull, S. D.; Williams, J. M. J. Chem. Soc. Rev. 2012, 41, 2109; (i)
Maruoka, K. Asymmetric Phase Transfer Catalysis; Wiley-VCH: Weinheim, Ger-
many, 2008; (j) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534; (k)
Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560.
3. For selected reviews using primary amine catalysts, see: (a) Xu, L.-W.; Lu, Y. Org.
Biomol. Chem. 2008, 6, 2047; (b) Bartoli, G.; Melchiorre, P. Synlett 2008, 1759; (c)
Xu, L.-W.; Luo, J.; Lu, Y. Chem. Commun. 2009, 1807; (d) Brazier, J. B.; Tomkinson,
N. C. O. Top. Curr. Chem. 2010, 291, 281; (e) Tsakos, M.; Kokotos, C. G. Tetrahedron
2013, 69, 10199; (f) Serdyuk, O. V.; Heckel, C. M.; Tsogoeva, S. B. Org. Biomol.
Chem. 2013, 11, 7051.
4. Tanimura, Y.; Yasunaga, K.; Ishimaru, K. Eur. J. Org. Chem. 2013, 6535.
5. Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, Germany,
2004; Vols. 1 and 2.
6. The single-crystal X-ray analysis of perfluorophenyl-N-prolinamide has been
reported, where the stereoselectivity of aldol product was attributed to the
enhanced NH acidity and conformation of the perfluorophenyl ring. For details,
see: Moorthy, J. N.; Saha, S. Eur. J. Org. Chem. 2009, 739.
4.4.1. (S)-3-Hydroxy-3-(1-hydroxy-2-methylpropan-2-yl)-5-
methoxyindolin-2-one. The aldol reaction of aldehyde 7a with 5-
methoxyisatin 5c was conducted for 90 h to give a corresponding
aldol product 8c (82% yield). To a stirred solution of product 8c
(82.5 mg, 0.33 mmol) in dry EtOH (10.0 ml) was added NaBH4
(0.05 g, 1.3 mmol) at 0 ꢃC under argon atmosphere. The reaction
mixture was stirred at room temperature for 3 h. After the mixture
was quenched by saturated NH4Cl aq, aqueous layer was extracted
with CH2Cl2. The obtained crude product was purified by flash
column chromatography on SiO2 (CH2Cl2:CH3CO2Et¼7:3) to afford
the corresponding product as a pale yellow oil (82.9 mg, >99%
7. Wu, X.; Jiang, Z.; Shen, H.-M.; Lu, Y. Adv. Synth. Catal. 2007, 349, 812.
8. Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II; Wiley-VCH: Weinheim,
Germany, 2003; and references therein.
9. Recent selected examples on asymmetric aldol reactions of hydroxyacetones or
protected hydroxyacetones, see: (a) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2007, 129, 288; (b) Xu, X.-Y.; Wang, Y.-Z.; Gong,
L.-Z. Org. Lett. 2007, 9, 4247; (c) Li, J.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2009, 74,
1747; (d) Wu, F.-C.; Da, C.-S.; Du, Z.-X.; Guo, Q.-P.; Li, W.-P.; Yi, L.; Jia, Y.-N.; Ma,
X. J. Org. Chem. 2009, 74, 4812; (e) Teo, Y.-C.; Chua, G.-L.; Ong, C.-Y.; Poh, C.-Y.
yield). ½a 1D9
ꢁ
þ3.80 (c 0.1, MeOH); 1H NMR (CD3OD, 300 MHz)
d
7.00e6.99 (m, 1H, Ar), 6.82 (dd, 1H, J¼8.5, 2.0 Hz, Ar), 6.76 (d, 1H,
J¼8.5 Hz, Ar), 3.82 (d, 1H, J¼11.0 Hz, eCH2e), 3.77 (s, 3H, eOCH3),
3.64 (d, 1H, J¼11.0 Hz, eCH2e), 1.08 (s, 3H, eCH3), 0.88 (s, 3H,
eCH3); 13C NMR (CD3OD, 75 MHz) 182.0, 157.0, 136.6, 133.1, 114.9,
114.5, 111.2, 83.5, 69.3, 56.3, 41.4, 20.0, 19.5; IR (KBr):
n 3271, 2971,
1720, 1489, 1390, 1210, 1043, 756 cmꢂ1; Anal. Calcd for C13H17NO4:
C, 62.14; H, 6.82; N, 5.57. Found: C, 62.10; H, 6.84; N, 5.49. Enan-
tiomeric excess was determined by HPLC with CHIRALPAK AD-H
column (hexane:2-propanol¼85:15), flow rate¼1.0 mL/min;
ꢀ
Tetrahedron Lett. 2009, 50, 4854; (f) Paradowska, J.; Rogozinska, M.; Mlynarski,
J. Tetrahedron Lett. 2009, 50, 1639; (g) Jiang, Z.; Yang, H.; Han, X.; Luo, J.; Wong,
M. W.; Lu, Y. Org. Biomol. Chem. 2010, 8, 1368; (h) Sarkar, D.; Harman, K.; Ghosh,
S.; Headley, A. D. Tetrahedron: Asymmetry 2011, 22, 1051; (i) Kumar, A.; Singh, S.;
Kumar, V.; Chimni, S. S. Org. Biomol. Chem. 2011, 9, 2731; (j) Wu, C.; Fu, X.; Li, S.
Tetrahedron: Asymmetry 2011, 22, 1063; (k) Czarnecki, P.; Plutecka, A.; Ga-
l¼254 nm; tr¼12.4 min (R), tr¼22.2 min (S).
ꢀ
wronski, J.; Kacprzak, K. Green Chem. 2011, 13, 1280; (l) Liu, Y.; Wang, J.; Sun, Q.;
Li, R. Tetrahedron Lett. 2011, 52, 3584; (m) Larionova, N. A.; Kucherenko, A. S.;
Siyutkin, D. E.; Zlotin, S. G. Tetrahedron 2011, 67, 1948; (n) Bisai, V.; Bisai, A.;
Singh, V. K. Tetrahedron 2012, 68, 4541; (o) Liu, L.-y.; Wang, B.; Zhu, Y.; Chang,
W.-x.; Li, J. Tetrahedron: Asymmetry 2013, 24, 533.
4.4.2. (S)-3-Hydroxy-3-(1-hydroxy-2-methylpropan-2-yl)-5-
methylindolin-2-one. The aldol reaction of aldehyde 7a with 5-
methylisatin 5d was conducted for 48 h to give the correspond-
ing aldol product 8d (82% yield). To a stirred solution of 8d
(89.4 mg, 0.38 mmol) in dry EtOH (10.0 ml) was added NaBH4
(0.05 g, 1.3 mmol) at 0 ꢃC under argon atmosphere. The reaction
mixture was stirred at room temperature for 3 h. After the mixture
was quenched by saturated NH4Cl aq, aqueous layer was extracted
10. L-Tryptophan-catalyzed aldol reaction between ketones and aldehydes has
been reported, however, no desired products were observed in the case of
hydroxyacetone derivatives. See Ref. 9h.
11. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.;
Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;

Y. Tanimura et al. / Tetrahedron 70 (2014) 2816e2821
2821
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E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.;
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L.; Zhou, J. Adv. Synth. Catal. 2010, 352, 1381; (d) Kumar, A.; Chimni, S. S. RSC
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Adv. 2012, 2, 9748; (e) Mohammadi, S.; Heiran, R.; Herrera, R. P.; Marques-
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Lopez, E. ChemCatChem 2013, 5, 2131.
14. For the total syntheses of TMC-95A, see: (a) Albrecht, B. K.; Williams, R. M. Org.
Lett. 2003, 5, 197; (b) Inoue, M.; Sakazaki, H.; Furuyama, H.; Hirama, M. Angew.
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17. CCDC 978573 contains the supplementary of crystallographic data for this pa-
per. These data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
12. We also examined other transition state models, see Supplementary data.
13. For reviews, see: (a) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007,
46, 8748; (b) Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20; (c) Zhou, F.; Liu, Y.-