Synthesis of a biphenyl-based axially chiral amino acid as a highly efficient catalyst for the direct asymmetric aldol reaction

Article abstract of DOI:10.1016/j.tetlet.2006.08.051

A biphenyl-based axially chiral amino acid (S)-2 has been designed and synthesized. The new amino acid (S)-2 has been found to be a more efficient catalyst than (S)-1 in the direct asymmetric aldol reaction of acetone with aldehydes. For instance, the use

Full text of DOI:10.1016/j.tetlet.2006.08.051

Tetrahedron Letters 47 (2006) 7423–7426
Synthesis of a biphenyl-based axially chiral amino acid as a
highly efficient catalyst for the direct asymmetric aldol reaction
Taichi Kano, Osamu Tokuda and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Received 3 August 2006; revised 12 August 2006; accepted 17 August 2006
Abstract—A biphenyl-based axially chiral amino acid (S)-2 has been designed and synthesized. The new amino acid (S)-2 has been
found to be a more efficient catalyst than (S)-1 in the direct asymmetric aldol reaction of acetone with aldehydes. For instance, the
use of only 0.1 mol % of (S)-2 was sufficient to complete the reaction between acetone and 4-nitrobenzaldehyde, giving the corre-
sponding aldol adduct in good yield with an excellent enantioselectivity.
Ó 2006 Elsevier Ltd. All rights reserved.
Organocatalytic asymmetric synthesis is regarded to
be one of the most active areas in the current organic
OMe
MeO
CO H
CO H
2
2
1
synthesis, and a number of organocatalysts such as
2
3
4
proline and proline derivatives including peptides
MeO
MeO
NH
NH
for the direct asymmetric aldol reaction have been suc-
cessfully developed since the pioneering work of List
2
a
et al. However, a substoichiometric amount of catalyst
20–30 mol %) is often required to achieve reasonable
MeO
(
OMe
yields, and examples of the direct asymmetric aldol reac-
tion at low catalyst loadings (e.g., <1 mol %) are rare.
Since one of the main reasons for high catalyst loadings
was known to be the degradation of proline under the
(S
)-1
(S)-2
Figure 1. Designer axially chiral amino acids.
5
reaction conditions, we previously designed the binaph-
to the low nucleophilicity of the benzylic amine moiety
in (S)-1. Accordingly, we designed a biphenyl-based
amino acid of type (S)-2, which is highly substituted
with electron-donating methoxy groups, with the expec-
tation of the increasing nucleophilicity of the amine
moiety.
thyl-based axially chiral amino acid (S)-1, which is
6
structurally different from proline. Although the direct
asymmetric aldol reaction was efficiently catalyzed by
5
mol % of this new robust amino acid, there is still
room for further improvement in terms of catalyst load-
ing. Herein, we report the synthesis of a highly efficient
biphenyl-based axially chiral amino acid (S)-2 and its
successful application to the direct asymmetric aldol
reaction (see Fig. 1).
The requisite catalyst (S)-2 was prepared from (S)-4,
0
0 0 0
,5,5 ,6,6 -hexamethoxybiphenyl-2,2 -dicarboxylic acid
4
(
7
S)-3, which is readily prepared from commercially
available gallic acid derivative or ellagic acid, in a
seven-step sequence (Scheme 1).
Although a robust binaphthyl-based amino acid (S)-1
gave a higher yield than the proline catalyst in the direct
asymmetric aldol reaction with electron deficient alde-
hydes, somewhat high catalyst loadings (5 mol %) were
8
(
S)-2, the new catalyst thus obtained was applied to the
6
direct asymmetric aldol reaction and the results are
summarized in Table 1. As expected, the aldol reaction
between 4-nitrobenzaldehyde and acetone with
still necessary to achieve high yields, presumably due
5
mol % of (S)-2 in DMF was significantly accelerated
Keywords: Aldol reaction; Amino acid; Organocatalysis.
*
Corresponding author. Tel./fax: +81 75 753 4041; e-mail: maruoka@
kuchem.kyoto-u.ac.jp
in comparison with (S)-1 and the reaction was complete
within 4 h at room temperature (entry 1 vs 2). Only
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.051

7
424
T. Kano et al. / Tetrahedron Letters 47 (2006) 7423–7426
OMe
OMe
OMe
(entry 6). While DMF was less efficient with the lower
MeO
MeO
Br
catalyst loading (0.5 mol %) of (S)-2 (entry 7), the reac-
tion in acetone proceeded smoothly with excellent
enantioselectivity (entry 8). Upon further investigation
of the catalyst loading, it was found that even
R2
MeO
MeO
R1
R1
b
MeO
MeO
d
9
5%
2 steps)
R2
99%
0
.1 mol % of (S)-2 was sufficient to achieve a high yield
(
and an excellent enantioselectivity (entry 9).
MeO
MeO
Br
OMe
To prove the efficiency of this new catalyst, the aldol
reaction of acetone with several other aldehydes was
carried out in the presence of 0.5 mol % of (S)-2 (Table
1
2
(
(
S
)-3 R = CO H
(
(
S
S
)-5 R = OH
2
a
c
78%
1
2
S)-4 R = CH OH
)-6 R = Br
2
9
OMe
OMe
2). Olefinic, heteroaromatic, and aromatic aldehydes
MeO
Br
MeO
CO Et
with electron withdrawing groups were found to be suit-
able substrates (entries 1, 2, 5, 7, and 8). With 2 mol %
of (S)-2, even simple aromatic aldehydes such as benz-
aldehyde and b-naphthylaldehyde gave the correspond-
ing aldol adducts in moderate yields (entries 4 and 6).
Furthermore, the reaction of a,a-dibromoheptanal as
an aliphatic aldehyde substitute was also found to
2
MeO
MeO
e
MeO
MeO
g
N
N R3
(S)-2
4
8%
99%
MeO
Br
MeO
OMe
)-7
OMe
3
1
0
proceed with a high enantioselectivity (entry 9).
(
S
(
(
S
S
)-8 R = allyl
)-9 R = H
f
98%
3
To demonstrate the efficiency of biphenyl-based amino
acid (S)-2 in the direct asymmetric aldol reaction, a
kinetic study using catalysts (S)-1 and (S)-2 was carried
out (Fig. 2). With respect to the reaction rate, the
biphenyl-based amino acid (S)-2 was more effective
than the binaphthyl-based amino acid (S)-1, probably
due to the higher nucleophilicity of (S)-2. Furthermore,
the reaction catalyzed by only 0.1 mol % of (S)-2 in
Scheme 1. Synthesis of biphenyl-based amino acid (S)-2. Reagents and
conditions: (a) BH –SMe , B(OMe) , 0 °C to rt, 5 h; (b) Br , pyridine,
20 °C to 0 °C, 1 h; (c) PBr , CH Cl , rt, 5 h; (d) allylamine, CH CN,
0 °C, 12 h; (e) n-BuLi, THF, ꢀ78 °C, 1 h; (EtO) CO, rt, 1 h; (f)
Pd(OAc) , PPh , N,N-dimethylbarbituric acid, CH Cl , 35 °C, 12 h; (g)
M NaOH, MeOH–THF, reflux, 10 h.
3
2
3
2
ꢀ
3
2
2
3
5
2
2
3
2
2
1
Table 1. Direct asymmetric aldol reaction of 4-nitrobenzaldehyde with
acetone catalyzed by (S)-2
a
Table 2. Direct asymmetric aldol reaction of various aldehydes with
acetone catalyzed by (S)-2
a
O
OH
OHC
+
0.5 mol % (
S
)-2
O
OH
O
O
(
S
)-2
+
RCHO
CHO
rt, 48-72 h
* R
solvent, rt
NO2
NO2
b
c
Entry Aldehyde
Yield (%) ee (%)
b
c
1
Entry
Catalyst
mol %)
Solvent
Time
(h)
Yield
(%)
ee (%)
1
2
3
R = NO
2
90
96 (R)
94 (R)
95 (R)
95 (R)
1
(
R = CN 90
1
d
R = H
19
50
1
5
5
1
1
1
1
0.5
0.5
0.1
DMF
DMF
DMF
24
4
82
86
91
75
7
90
58
90
91
95 (R)
96 (R)
96 (R)
94 (R)
34 (R)
95 (R)
95 (R)
96 (R)
96 (R)
d
1
4
R1
R = H
2
3
4
5
6
7
8
9
24
24
24
24
48
44
96
CHO
Cl
3
CH CN
5
82
50
96 (R)
94 (R)
MeOH
Acetone
DMF
Acetone
Acetone
CHO
CHO
d
6
a
The reaction of 4-nitrobenzaldehyde (0.25 mmol) with acetone
0.5 mL) in solvent (2 mL) was carried out in the presence of (S)-2 at
CHO
(
7
8
9
95
68
58
95
96
91
room temperature.
N
b
c
Isolated yield after silica gel chromatography.
The ee was determined by HPLC on a Chiralpak AS column with
hexane/2-propanol (2:1).
EtO C
2
d
(
S)-1 was used instead of (S)-2.
CHO
Br Br
1
mol % of (S)-2 in DMF was sufficient to obtain the de-
a
The reaction of an aldehyde (0.25 mmol) with acetone (0.5 mL) in
solvent (2 mL) was carried out in the presence of (S)-2 at room
temperature.
Isolated yield after silica gel chromatography.
The ee was determined by HPLC using a chiral column (Chiralpak
AS, AD-H, Chiralcel OD-H, Daicel Chemical Industries).
Use of 2 mol % of (S)-2.
sired aldol adduct in 91% yield with 96% ee (entry 3).
Encouraged by this result, we next examined the solvent
effect with the expectation of further reduction of cata-
lyst loading. Among several solvents examined, acetone,
which could not be used as a solvent for (S)-1 due to its
poor solubility, was also found to be a suitable solvent
b
c
d

T. Kano et al. / Tetrahedron Letters 47 (2006) 7423–7426
7425
100
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(
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003, 42, 2785; (q) Peng, Y.-Y.; Ding, Q.-P.; Li, Z.; Wang,
Figure 2. Direct asymmetric aldol reaction of acetone with 4-
nitrobenzaldehyde using (a) 5 mol % (S)-2 in DMF (0.125 M), (b)
P. G.; Cheng, J.-P. Tetrahedron Lett. 2003, 44, 3871; (r)
Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305,
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mol % (S)-1 in DMF (0.125 M), (c) 0.1 mol % (S)-2 in acetone
1
752; (s) Northrup, A. B.; Mangion, I. K.; Hettche, F.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43,
152; (t) List, B.; Hoang, L.; Martin, H. J. Proc. Natl.
(0.10 M), and (d) 0.1 mol % (S)-1 in acetone (0.10 M) at room
temperature.
2
Acad. Sci. U.S.A. 2004, 101, 5839; (u) Storer, R. I.;
MacMillan, D. W. C. Tetrahedron 2004, 60, 7705; (v)
Ward, D. E.; Jheengut, V. Tetrahedron Lett. 2004, 45,
acetone proceeded gradually to completion, indicating
the robust nature of (S)-2 under the reaction
conditions.
8
347; (w) Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.;
C o´ rdova, A. Angew. Chem., Int. Ed. 2005, 44, 1343;
Recently acyclic amino acids were also found to catalyze
the direct asymmetric aldol reactions, see: (x) C o´ rdova, A.;
Zou, W.; Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao,
W.-W. Chem. Commun. 2005, 3586; (y) Bassan, A.; Zou,
W.; Reyes, E.; Himo, F.; C o´ rdova, A. Angew. Chem., Int.
Ed. 2005, 44, 7028.
. For examples, see: (a) Saito, S.; Nakadai, M.; Yamamoto,
H. Synlett 2001, 1245; (b) Nakadai, M.; Saito, S.;
Yamamoto, H. Tetrahedron 2002, 58, 8167; (c) Tang, Z.;
Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.;
Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125,
In conclusion, we synthesized a novel biphenyl-based
axially chiral amino acid (S)-2 and demonstrated its
effectiveness for the direct asymmetric aldol reaction.
It is worth noting that the catalyst loading could be
decreased to only 0.1 mol % in acetone without loss of
yield or enantioselectivity. Further investigations to
expand the scope of substrates are currently underway.
3
5
262; (d) Berkessel, A.; Koch, B.; Lex, J. Adv. Synth.
Acknowledgments
Catal. 2004, 346, 1141; (e) Hartikaa, A.; Arvidsson, P. I.
Tetrahedron: Asymmetry 2004, 15, 1831; (f) Torii, H.;
Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
Angew. Chem., Int. Ed. 2004, 43, 1983; (g) Mase, N.;
Tanaka, F.; Barbas, C. F., III. Angew. Chem., Int. Ed.
This work was partially supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
2
004, 43, 2420; (h) Hayashi, Y.; Tsuboi, W.; Shoji, M.;
Suzuki, N. Tetrahedron Lett. 2004, 45, 4353; (i) Tang, Z.;
Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.;
Jiang, Y.-Z.; Wu, Y.-D. Proc. Natl. Acad. Sci. U.S.A.
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(
d) List, B. Tetrahedron 2002, 58, 5573; (e) Alcaide, B.;
Almendros, P. Angew. Chem., Int. Ed. 2003, 42, 858; (f)
List, B. Acc. Chem. Res. 2004, 37, 548; (g) Saito, S.;
Yamamoto, H. Acc. Chem. Res. 2004, 37, 570; (h) Notz,
W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004,
3
2
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7, 580; (i) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
004, 43, 5138; (j) Seayad, J.; List, B. Org. Biomol. Chem.
005, 3, 719; (k) Berkessel, A.; Gr o¨ ger, H. Asymmetric
Organocatalysis: From Biomimetic Concepts to Applica-
tions in Asymmetric Synthesis; Wiley-VCH: Weinheim,
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005; Chapter 6, p 130.
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. (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem.
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5. The formation of bicyclic oxazolidinones between proline
and aldehydes or ketones is also known to lead to the

7426
T. Kano et al. / Tetrahedron Letters 47 (2006) 7423–7426
consumption of proline, see: Hartikka, A.; Arvidsson, P. I.
Eur. J. Org. Chem. 2005, 4287, and references therein.
. Kano, T.; Takai, J.; Tokuda, O.; Maruoka, K. Angew.
After stirring for 24–96 h at room temperature, the
reaction mixture was then treated with saturated
ammonium chloride solution and extracted with ethyl
acetate. The organic layer was dried over anhydrous
6
7
8
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. Han, Z.; Yamaguch, Y.; Kitamura, M.; Maruoka, K.
Tetrahedron Lett. 2005, 46, 8555, and references therein.
2 4
Na SO and concentrated. The residue was purified
by flash column chromatography on silica gel (hexane/
ethyl acetate as eluent) to give the corresponding aldol
adduct.
3
0
1
. Analytical data for (S)-2: ½aꢁ ꢀ32:1 (c 0.46, CHCl ); H
D
3
NMR (400 MHz, CDCl
3
/MeOD = 2:1) d 6.87 (1H, s,
ArH), 4.00–4.04 (2H, m, ArCHH), 3.87 (3H, s, OCH
3
),
10. 5,5-Dibromo-4-hydroxydecan-2-one (Table 2, entry 9):
2
9
1
3
.85 (3H, s, OCH ), 3.84 (3H, s, OCH ), 3.79 (3H,
½aꢁ 35.1 (c 1.30, CHCl ; 91% ee); H NMR (400 MHz,
3
3
D
3
s, OCH
3
), 3.58 (3H, s, OCH
3
), 3.57 (3H, s, OCH
3
),
CDCl
3
) d 4.26 (1H, ddd, J = 9.3, 4.8, 2.0 Hz, CHOH),
3
1
.51 (1H, d, J = 12.4 Hz, ArCHH), 3.32 (1H, d, J =
3.2 Hz, ArCHH) ppm; C NMR (100 MHz, CDCl /
3
3.32 (1H, d, J = 4.8 Hz, CHOH), 3.26 (1H, dd, J = 17.7,
2.0 Hz, CHH), 2.96 (1H, dd, J = 17.7, 9.3 Hz, CHH),
2.32–2.44 (2H, m, CH ), 2.26 (3H, s, COCH ), 1.69–1.74
1
3
MeOD = 2:1) d 173.8, 154.5, 152.3, 151.2, 150.1, 147.6,
2
3
1
6
2
43.6, 133.9, 126.4, 126.3, 123.4, 121.3, 109.5, 61.9, 61.4,
(2H, m, CH
2
), 1.34–1.39 (4H, m, CH
2
), 0.92 (3H, t,
1
3
1.3, 61.24, 61.18, 56.5, 46.5, 43.8 ppm; IR (neat) 3404,
3 3
J = 6.8 Hz, CH ) ppm; C NMR (100 MHz, CDCl ) d
207.7, 81.1, 75.4, 47.4, 46.3, 31.0, 30.8, 26.9, 22.4,
ꢀ1
988, 1582, 1458, 1387, 1325, 1096, 1030, 802 cm
;
HRMS (ESI-TOF) Calcd for C H NO : 420.1653
13.9 ppm; IR (neat) 3423, 2955, 2926, 1715, 1362, 1080,
2
1
26
8
+
+
ꢀ1
(
[M+H] ), Found: 420.1653 ([M+H] ).
692 cm ; HRMS (ESI-TOF) Calcd for C10
H18Br
2
O
2
Na:
+
+
9
. General procedure for the aldol reaction of acetone and
aldehydes with (S)-2: To a mixture of amino acid (S)-2
350.9566 ([M+Na] ). Found: 350.9669 ([M+Na] ).
HPLC analysis: Daicel Chiralpak AD-H, hexane/iso-
propanol = 9:1, flow rate = 1.0 mL/min, k = 210 nm,
retention time—11.7 min (major) and 13.1 min (minor).
(
0.52 mg, 1.25 lmol) in anhydrous acetone (2.5 mL) was
added an aldehyde (0.25 mmol) at room temperature.