Synthesis of C2-symmetrical bis-β-amino alcohols and their application in the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/S0040-4039(01)01236-9

The C₂-symmetrical bis-β-amino alcohols 1-6 were prepared and especially attention is focused on bridges, which link the two β-amino alcohol units. These ligands have been applied as chiral catalysts in the asymmetric addition of diethylzinc to aldehydes. sec-Alcohols have been obtained in good yields with up to 95.4% enantiomeric excess.

Full text of DOI:10.1016/S0040-4039(01)01236-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6171–6173
Synthesis of C2-symmetrical bis-b-amino alcohols and their
application in the enantioselective addition of diethylzinc
to aldehydes
Qianyong Xu,a Hui Wang,a Xinfu Pan,a,* Albert S. C. Chanb and Teng-kuei Yangc
aDepartment of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
bOpen Laboratory of Chirotechnology and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hong Kong
cDepartment of Chemistry, National Chung-Hsing University, Taichung, Taiwan
Received 23 April 2001; revised 4 July 2001; accepted 6 July 2001
Abstract—The C2-symmetrical bis-b-amino alcohols 1–6 were prepared and especially attention is focused on bridges, which link
the two b-amino alcohol units. These ligands have been applied as chiral catalysts in the asymmetric addition of diethylzinc to
aldehydes. sec-Alcohols have been obtained in good yields with up to 95.4% enantiomeric excess. © 2001 Elsevier Science Ltd.
All rights reserved.
Enantioselective addition of organometallic reagents to
carbonyl compounds is one of the most efficient meth-
ods for generating optically active secondary alcohols.1
Among the possible reactions, catalytic enantioselective
addition of dialkylzinc to aldehydes has attracted much
attention.2 A wide variety of chiral catalysts, i.e. amino
alcohols,3 diamines,4 disulfonamides,5 and diols6 have
been used successfully to promote the enantioselective
alkylation. Among them, b-amino alcohols are the most
often used chiral auxiliaries. Since it was reported that
the presence of C2 axis within a chiral auxiliary can
serve the very important function of dramatically
reducing the number of possible competing
diastereomeric transition states,7 many C2-symmetrical
auxiliaries have been synthesized and applied in the
catalytic enantioselective reaction.4–6 However, to our
knowledge, there are few C2-symmetrical bis-b-amino
alcohols being studied so far.8 Here, we report easily
available and efficient C2-symmetrical bis-b-amino alco-
hols for the asymmetric addition of diethylzinc to
aldehydes.
C2-Symmetrical bis-b-amino alcohol 19 was obtained by
dimerization of
L
-prolinol10 via 1,2-dibromoethane/
potassium carbonate in dry acetonitrile8a (Scheme 1)
and C2-symmetrical bis-b-amino alcohols 2–611 were
Ar
Ar
BrCH2CH2Br
i. ClCO-Y-COCl
ii. LiAlH4/THF
1
2 - 6
K2CO3
N
OH
H
X =
(CH2)2
(CH2)4
(CH2)6
p-C6H4(CH2)2
m-C6H4(CH2)2
o-C6H4(CH2)2
1
2
3
4
5
6
Ar
Ar
N
X
N
7
8
R = Me
Ar
OH
N
Ar
Ar
Ar
Ar
OH
CH2R
HO
Scheme 1. Synthesis of chiral ligands 1–8.
Keywords: asymmetric addition; diethylzinc; C2-symmetrical bis-b-amino alcohols; aldehyde.
* Corresponding author. Fax: +86 931 8912582; e-mail: panxf@lzu.edu.cn
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01236-9

6172
Q. Xu et al. / Tetrahedron Letters 42 (2001) 6171–6173
symmetrical bis-b-amino alcohol seems to be crucial
for enhancing the enantioselectivity of catalytic asym-
metric addition of diethylzinc to aldehydes. Anymore,
by varying the catalysts’ loading of 1 and 6, there is
no effect both on the yields and enantioselectivities in
the studying range (entries 1–3 and 8–10).
prepared from chloride of dibasic acids in benzene to
give diamides followed by reduction with LiAlH4 in
THF. In order to compare the effect of asymmetric
induction, ‘monomeric’ b-amino alcohol analogous 711
and 810 were synthesized in a manner similar to that
for the synthesis of ligands 2–6. The catalytic asym-
metric addition of diethylzinc to the model substrate
benzaldehyde was first investigated in toluene at 0°C
and the results are summarized in Table 1.
With chiral ligand 6 being the best catalyst, a few
other representative aldehydes have also been investi-
gated in the enantioselective addition reaction by
using 2.5% mol of the ligand 6 and the results are
summarized in Table 2. Chemical yields of the sec-
alcohols were good and enantioselectivities were all
lower than benzaldehyde with (S)-configuration prod-
ucts (entries 1–8). In the case of trans-cinnamalde-
hyde and aliphatic aldehydes, although the yields
were still high, selectivities were moderate (entries 9–
11).
As can be seen from the results, (S)-1-phenylpropanol
is preferentially obtained with catalysts 1–8 in 87–95%
yields and the enantiomeric excesses vary from 2.9 to
95.4%. Interestingly, for corresponding alkylene-
bridged C2-symmetrical bis-b-amino alcohols 1–3, the
enantioselectivities decrease when compared with their
‘monomeric’ b-amino alcohol analogous 7 (entries 1–5
via 11). On the other hand, for xylylene-bridged C2-
symmetrical bis-b-amino alcohols, enantioselectivities
increase for ligand 6 and decrease for ligands 4 and 5
when compared with their ‘monomeric’ b-amino alco-
hol analogous 8 (entries 6–10 via 12). It was expected
that chiral ligands 3 and 4, which have longer
bridges, give high enantioselectivities, because the two
b-amino alcohol groups have less interaction and act
as two ‘monomeric’ b-amino alcohol independently.
However, it is chiral ligand 6, which has a much
crowd structure, to give better enantioselectivity.
Thus, a sterically more demanding structure in C2-
In conclusion, we have successfully synthesized six
C2-symmetric bis-b-amino alcohols and the more
crowd chiral ligand 6 is the most efficient catalyst in
these series when they were applied in the enantiose-
lective addition of diethylzinc to aldehydes. Enan-
tiomeric excess of up to 95.4% was observed with
good yield. Elucidation of the mechanism and further
application of these ligands in other catalytic asym-
metric reactions are in progress.
Table 2. The enantioselective addition of diethylzinc to
aldehydes catalyzed by 6a
O
OH
Table 1. Enantioselective addition of diethylzinc to benz-
aldehyde promoted by chiral ligands 1–8a
cat. 6 (2.5%mol)
R
H
R
ZnEt2, Toluene, 0°C
*
OH
CHO
Yield (%)b
E.e. (%)
cat. 1-8
Entry
Substrate
(config.)c
ZnEt2, Toluene, 0°C
1
2
3
4
5
6
7
8
Benzaldehyde
o-Anisaldehyde
p-Anisaldehyde
o-Chlorobenzaldehyde
p-Chlorobenzaldehyde
3,4-Dimethoxybenzaldehyde
1-Naphthaldehyde
2-Naphthaldehyde
trans-Cinnamaldehyde
Dodecylaldehyde
92
89
79
90
81
78
81
83
79
83
86
94.7 (S)
89.7 (S)
84.3 (S)
85.0 (S)
82.3 (S)
83.3 (S)d
85.0 (S)d
86.7 (S)d
63.3 (S)d
59.8 (S)e
65.0 (S)e
Entry
Ligand (mol%)
Yield (%)b
E.e. (%) (config.)c
1
2
3
4
5
6
7
8
1 (2.5)
1 (5.0)
1 (10.0)
2 (2.5)
3 (2.5)
4 (2.5)
5 (2.5)
6 (2.5)
6 (5.0)
6 (10.0)
7 (5.0)
8 (5.0)
87
86
89
92
89
87
88
92
95
93
88
89
64.9 (S)
57.3 (S)
60.0 (S)
57.8 (S)
60.1 (S)
28.6 (S)
2.9 (S)
94.7 (S)
95.2 (S)
95.4 (S)
87.0 (S)
39.9 (S)
9
10
11
Cyclohexanecarboxaldehyde
9
a The reaction were carried out in toluene at 0°C with
6:aldehyde:diethylzinc=0.125:5.0:10.0 (mmol).
10
11
12
b Based on isolated yield.
c Except as note, the e.e. values were determined by GC with
Chrompack CP-Chirasil-DEX CB capillary column and the configu-
rations were determined by comparison of the sign of the specific
rotation with the known compounds.
a The reactions were carried out in toluene at 0°C. Benzaldehyde/
ZnEt2=5.0/10.0 (mmol).
b Based on isolated product.
d Determined by HPLC with a Chiralcel-OD column from Daicel
with hexane/2-propanol as eluent.
c The e.e. values were determined by GC with Chrompack CP-Chi-
rasil-DEX CB capillary column and the configuration was deter-
mined by comparison of the sign of the specific rotation with the
known compound.
e Determined by GC with Chrompack CP-Chirasil-DEX CB capillary
column after acetylation.

Q. Xu et al. / Tetrahedron Letters 42 (2001) 6171–6173
6173
3.69–3.75 (dd, J=9.4, 4.8 Hz, 2H), 4.75–4.90 (br, 2H),
7.08–7.32 (m, 12H), 7.48–7.53 (m, 4H), 7.64–7.68 (m, 4H).
10. Enders, D.; Kipphardt, H.; Gerdes, P.; Brena-Valle, L. J.;
Bhushan, V. Bull. Soc. Chim. Belg. 1988, 97, 691.
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11. Compound 2: Mp 163–164°C; [h]2D0=+7.0 (c 1.00, CH2Cl2);
1H NMR (CDCl3): 0.61–0.98 (m, 4H), 1.55–1.70 (m, 8H),
1.80–1.92 (m, 4H), 2.24–2.32 (m, 2H), 3.05–3.14 (m, 2H),
3.68–3.74 (dd, J=9.4, 4.8 Hz, 2H), 4.6–5.0 (br, 2H),
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127–128°C; [h]D20=+12.6 (c 1.00, CH2Cl2); 1H NMR
(CDCl3): 0.59–0.75 (m, 4H), 1.02–1.15 (m, 4H), 1.61–1.68
(m, 6H), 1.77–1.95 (m, 6H), 2.28–2.36 (m, 2H), 3.16–3.21
(m, 2H), 3.73–3.79 (dd, J=9.4, 4.8 Hz, 2H), 4.94 (br, 2H),
7.06–7.31 (m, 12H), 7.51–7.61 (m, 8H). Compound 4: Mp
226–227°C; [h]D20=+25.6 (c 0.50, CH2Cl2); 1H NMR
(CDCl3): 1.60–1.68 (m, 4H), 1.74–1.81 (m, 2H), 1.93–2.01
(m, 2H), 2.31–2.37 (m, 2H), 2.87–2.91 (m, 2H), 2.98, 3.17
(AB system, J=12.5 Hz, 4H), 3.96–3.99 (dd, J=9.4, 4.8
Hz, 2H), 4.95 (br, 2H), 6.93 (s, 4H), 7.11–7.21 (m, 4H),
7.28–7.34 (m, 8H), 7.60–7.74 (m, 8H). Compound 5: Mp
170–171°C; [h]D20=+18.8 (c 0.50, CH2Cl2); 1H NMR
(CDCl3): 1.58–1.68 (m, 4H), 1.73–1.80 (m, 2H), 1.92–2.00
(m, 2H), 2.27–2.40 (m, 2H), 2.83–2.88 (m, 2H), 2.95, 3.16
(AB system, J=12.6 Hz, 4H), 3.95–4.02 (dd, J=9.4, 4.8
Hz, 2H), 4.95 (br, 2H), 7.05–7.37 (m, 16H), 7.54–7.71 (m,
8H). Compound 6: Mp 110–112°C; [h]2D0=+4.5 (c 0.53,
CH2Cl2); 1H NMR (CDCl3): 1.60–1.68 (m, 4H), 1.70–1.80
(m, 2H), 1.92–2.06 (m, 2H), 2.18–2.30 (m, 2H), 2.73–2.80
(m, 2H), 2.95, 3.08 (AB system, J=12.6 Hz, 4H), 3.96–4.00
(dd, J=9.4, 4.8 Hz, 2H), 4.80 (br, 2H), 7.05–7.37 (m, 16H),
7.54–7.71 (m, 8H). Compound 7: Mp 78–79°C; [h]2D0=+6.3
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1
(c 0.64, CH2Cl2); H NMR (CDCl3): 0.78 (t, J=7.2 Hz,
9. Compound 1: Mp 174–175°C; [h]2D0=−5.6 (c 1.05, CH2Cl2);
1H NMR (CDCl3): 1.38–1.62 (m, 6H), 1.65–1.70 (m, 2H),
1.72–1.97 (m, 4H), 2.16–2.22 (m, 2H), 2.32–2.39 (m, 2H),
3H), 1.62–1.76 (m, 3H), 1.84–2.08 (m, 3H), 2.33–2.45 (m,
1H), 3.17–3.27 (m, 1H), 3.76–3.80 (dd, J=9.2, 4.8 Hz, 1H),
4.70–5.15 (br, 1H), 7.11–7.32 (m, 6H), 7.52–7.62 (m, 4H).
.