Chiral ligands for asymmetric synthesis: Enantioselective addition of diethylzinc to aromatic aldehydes catalyzed by chiral N-α-pyridylmethyl amino alcohols

Article abstract of DOI:10.1016/S0040-4039(00)01842-6

A series of chiral ligands 2a-d were conveniently prepared from τ-amino alcohols through a two-step sequence and applied to catalysis of enantioselective addition of diethylzinc to benzaldehyde. Among them ligand 2c was found to show the best asymmetric induction for the reaction and catalyze the addition to various aromatic aldehydes to provide (R)-secondary alcohols in up to 98.3% ee. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01842-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10263–10266
Chiral ligands for asymmetric synthesis: enantioselective
addition of diethylzinc to aromatic aldehydes catalyzed by
chiral N-a-pyridylmethyl amino alcohols
Hongying Yun, Yangjie Wu,* Yusheng Wu, Kuiling Ding and Ying Zhou
Department of Chemistry, Zhengzhou University, Zhengzhou 450052, PR China
Received 31 May 2000; revised 9 October 2000; accepted 19 October 2000
Abstract
A series of chiral ligands 2a–d were conveniently prepared from b-amino alcohols through a two-step
sequence and applied to catalysis of enantioselective addition of diethylzinc to benzaldehyde. Among
them ligand 2c was found to show the best asymmetric induction for the reaction and catalyze the
addition to various aromatic aldehydes to provide (R)-secondary alcohols in up to 98.3% ee. © 2000
Elsevier Science Ltd. All rights reserved.
Amongst asymmetric catalysis of CꢀC bond formation, enantioselective addition of
diorganozinc reagents to aldehydes in the presence of catalytic amounts of chiral b-amino
1
alcohols is a convenient method for the preparation of optically active secondary alcohols.
Various catalysts derived from b-amino alcohols have been reported to catalyze this kind of
2
3
reaction with excellent asymmetric induction. Recently, pyridine derived carbinols and plane-
4
extended pyridyl alcohols have been developed as chiral ligands in the enantioselective addition
of dialkylzinc to aldehydes, but most of them gave only moderate ee. Herein, we demonstrate
an efficient synthesis of novel chiral ligands, N-a-pyridylmethyl-b-amino alcohols 2a–c and
N-benzyl amino alcohol 2d, through a two-step reaction approach and their application to the
enantioselective addition of diethylzinc to various aromatic aldehydes.
The synthesis of ligands 2a–d is shown in Scheme 1. The (S)-amino alcohol 1 (1b is the
commercially available (1R,2S)-(−)-norephedrine) and one equivalent of 2-pyridinecarboxalde-
hyde or benzaldehyde were mixed in dry benzene and refluxed for 2 hours using a Dean–Stark
trap to give the Schiff’s base in quantitative yield. Reduction of the Schiff’s base was carried out
5
in dry 1,2-dichloroethane with two equivalents of sodium triacetoxyborohydride. After a
standard workup, 2a–d were obtained in high yields (72–98%). All of the new chiral ligands were
1
6
characterized by elemental analysis, IR and H NMR spectra. Some of the results are listed in
7
Table 1. Recently, Christopher et al. have reported the synthesis of 2b using a similar method.
*
Corresponding author. E-mail: wyj@mail.zzu.edu.cn
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01842-6

10264
Scheme 1. Synthesis of 2a–d
Table 1
Some data about synthesis and characterization of 2
a
b
Product
Time (h)
Mp (°C)
Yield (%)
[h]D (c=1.0, CH Cl )
2 2
c
c
d
e
2
2
2
2
a
b
c
24
24
96
48
Oil
Oil
119–121
133–134
98
98
81
72
+28.2
+3.90
−68.0
−40.8
d
a
b
c
Refers to the time of reduction of the Schiff’s base.
Isolated yields.
The optical rotation was measured at 20°C.
The optical rotation was measured at 23°C.
The optical rotation was measured at 28°C.
d
e
The novel chiral ligands 2a–d were then evaluated to check their asymmetric induction
efficiency for the addition of diethylzinc to benzaldehyde. As shown in Table 2, 2c shows the
best asymmetric induction, 1-phenylpropanol with 91.8% ee was obtained by using 5 mol% 2c
as catalyst (entry 3 versus entries 1, 2 and 4). Obviously, the presence of two bulky phenyl
groups at the hydroxy-substituted carbon is crucial for the best asymmetric induction. It is
interesting to note that the a-pyridylmethyl group in 2c also plays a very important role for the
enantioselectivity of the reaction (entry 3 versus 4 and 7). Thus, it may be concluded that both
bulky groups at the a-carbon and the a-pyridylmethyl group at the b-amino nitrogen contribute
to the high asymmetric induction obtained using 2c. Temperature has little effect on the optical
yields (entries 3–5).
The chiral ligand 2c was then examined for the asymmetric addition of diethylzinc to a series
of aromatic aldehydes under the optimized conditions. The results are summarized in Table 3.
It was found that 2c was effective for various aromatic aldehydes, including ortho-, para- and
meta-substituted benzaldehydes (entries 1–6), thiophene-2-carboxaldehyde (entry 8) and ferro-
cenyl aldehyde (entry 7). The best asymmetric induction, as high as 98.3% ee, was obtained by
using ferrocenyl aldehyde as substrate.
In conclusion, a series of novel chiral ligands 2a–d has been prepared from b-amino alcohols
through a two-step sequence and 2c was found to be highly efficient for the enantioselective

10265
Table 2
a
Asymmetric addition of diethylzinc to benzaldehyde in the presence of 2
b
c
d
Entry
Catalyst
Temp. (°C)
Solvent
Time (h)
Yield (%)
ee (%)
Confign
e
1
2
3
4
5
6
7
2a
2b
2c
2d
2c
2c
1c
rt
rt
rt
rt
T–H
5
5
5
6
8
69
80
98
85
98
94
71
2.5
3.3
R
S
T–H
T–H
T–H
T–H
T–H
T–H
91.8
34.5
90.1
90.4
4.7
R
R
R
R
R
0
−25
rt
12
12
a
The reaction was carried out in toluene with 5 mol% of catalyst and 2.5 equiv. of diethylzinc (4.17 M solution in
hexane) relative to benzaldehyde.
Isolated yields.
Determined by HPLC using a chiral OD column.
Configurations were determined by comparison of optical rotations with the literature.
Toluene and hexane, 4:1 (v/v).
b
c
d
e
8
Table 3
Asymmetric addition of diethylzinc to aromatic aldehydes in the presence of 2c
a
b
c
d
e
Entry
Aldehyde
Solvent
Time (h)
Yield (%)
ee (%)
Confign
1
2
3
4
5
6
7
8
p-ClC H CHO
T–H
T–H
T–H
T–H
T–H
T–H
T–H
T–H
5
6
5
5
6
5
5
5
97
96
98
70
94
95
88
95
91.5
92.3
96.2
90.2
80.9
88.1
98.3
94.4
R
R
R
R
R
R
R
6
4
p-MeOC H CHO
6
4
g
p-MeC H CHO
6
4
m-ClC H CHO
6
4
a-Naphthaldehyde
o-MeOC H CHO
6
4
f
FcCHO
Thiophene-2-carboxaldehyde
h
Nd
a
The reactions were carried out by using 5 mol% 2c at rt.
Toluene and hexane, 4:1 (v/v).
Isolated yields.
Determined by HPLC using a chiral OD column.
Determined by comparison of optical rotations with the literature.
Ferrocenyl aldehyde.
Determined by comparison of the optical rotation value with the literature value.
Not determined.
b
c
d
e
f
g
h
9
addition of diethylzinc to aromatic aldehydes. The excellent asymmetric induction due to 2c can
be attributed to the presence of steric effect due to the diphenyl groups at the hydroxyl
substituted carbon and the a-pyridylmethyl group at the b-amino nitrogen. This result provides
new information for the design of novel chiral tridentate ligands for this type of reaction.
Further work is undergoing to extend the variety of this type of chiral ligand and applications
of their metallic complexes to other types of asymmetric reactions.

10266
Acknowledgements
We are grateful to the National Natural Sciences Foundation of People’s Republic of China
(
No. 29872034) for financial support.
References
1
. For general discussion and comprehensive reviews, see: (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994. (b) Asymmetric Catalysis; Ojima, I., Ed.; VCH: New York, 1993. (c) Brunner, H.;
Zettlmeier, W. Handbook of Enantioselective Catalysis; VCH: Weinheim, 1993. (d) Lin, G. Q.; Chen, Y. Q.; Chen,
X. Z.; Li, Y. M. Chiral Synthesis: Asymmetric Reactions and Their Applications; Science Press: Beijing, 2000. (e)
Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833. (f) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30,
4
9.
. For recent examples, see: (a) Reddy, K. S.; Sola, L.; Moyano, A.; Pericas, M. A.; Riera, A. Synthesis 2000, 165.
b) Hailes, H. C.; Madden, J. Synlett 1999, 105. (c) Aurich, H. G.; Biesemeier, F.; Geiger M.; Harms, H. Liebig.
2
(
Ann. 1997, 423. (d) Li, Z.; Upadhyay, V.; DeCamp, A. E.; Dimichele, L.; Reider, P. J. Synthesis 1999, 1453. (e)
Kitamura, M.; Suga, S.; Miwa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 4832. (f) Prasad, K. R. K.; Joshi,
N. N. J. Org. Chem. 1997, 62, 3770.
3
. (a) Williams, D. R.; Fromhold, M. G. Synlett 1997, 523. (b) Kotsuki, H.; Nakagawa, Y.; Moriya, N.; Tateishi, H.;
Hirotaka, H.; Ochi, M.; Suzuki, T.; Isobe, K. Tetrahedron: Asymmetry 1995, 6, 1165. (c) Kotsuki, H.; Hayakawa,
.
H.; Tateishi, H.; Wakao, M. Tetrahedron: Asymmetry 1998, 9, 3203. (d) Chelucci, G.; Soccolini, F. Tetrahedron:
Asymmetry 1992, 3, 1235. (e) Zhang, H.; Xue, F.; Mak, T. C. W.; Chan, K. S. J. Org. Chem. 1996, 61, 8002. (f)
Soai, K.; Niwa, S.; Hori, H. Chem. Commun. 1990, 982. (g) Shibata, T.; Morioka, H.; Tanji, S.; Hayase, T.;
Kodaka, Y.; Soai, K. Tetrahedron Lett. 1996, 37, 8783.
4
5
. Kang, J.; Kim, H. Y.; Kim, J. H. Tetrahedron: Asymmetry 1999, 10, 2523.
. The use of triacetoxyborohydride in reduction, see: Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff,
C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
1
6
. Compound 2a: H NMR (400 MHz, CDCl ) l 0.96 (d, J=6.8 Hz, 3H, CH ), 1.02 (d, J=6.8 Hz, 3H, CH ), 1.90
3
3
3
(
m, 1H, CH(CH ) ), 2.55 (m, 1H, CHNH), 3.55 (dd, J=7.2 Hz, 1H, CH OH), 3.73 (dd, J=7.2 Hz, 1H, CH OH),
3
2
A
B
4
.07 (m, 2H, CH Py), 7.21 (m, 1H, PyH), 7.27 (m, 1H, PyH), 7.67 (m, 1H, PyH), 8.56 (d, J=4.4 Hz, 1H, PyH-a).
2
1
Anal. calcd for C H N O: C, 68.00; H, 9.34; N, 14.42. Found: C, 68.21; H, 9.10; N, 14.36. Compound 2b: H
11
18
2
NMR (400 MHz, CDCl ) l 0.95 (d, J=6.4 Hz, 3H, CH ), 3.09 (m, 1H, CHCH ), 4.14 (s, 2H, CH Py), 4.97 (d,
3
3
3
2
J=2.4 Hz, 1H, CHPh), 7.24–7.35 (m, 7H, PhH, PyH), 7.69 (m, 1H, PyH), 8.58 (d, J=4.4 Hz, 1H, PyH-a). Anal.
1
calcd for C H N O: C, 74.35; H, 7.49; N, 11.56. Found: C, 74.29; H, 7.32; N, 11.58. Compound 2c: H NMR
15
18
2
(
400 MHz, CDCl ) l 0.79 (d, J=6.8 Hz, 3H, CH ), 0.95 (d, J=6.8 Hz, 3H, CH ), 2.02 (m, 1H, CH(CH ) ), 3.38
3 3 3 3 2
(
d, J=14 Hz, 1H, CH Py), 3.52 (d, J=14 Hz, 1H, CH Py), 3.62 (d, J=1.6 Hz, 1H, CHNH), 6.89 (d, J=4.8 Hz,
A B
1
H, PhH), 7.12–7.74 (m, 12H, PhH, PyH), 8.52 (d, J=4.8 Hz, 1H, PyH-a). Anal. calcd for C H N O: C, 79.73;
23
26
2
1
H, 7.56; N, 8.09. Found: C, 79.73; H, 7.63; N, 8.10. Compound 2d: H NMR (400 MHz, CDCl ) l 0.92 (m, 3H,
3
CH ), 0.98 (d, J=7.2 Hz, 3H, CH ), 2.06 (m, 1H, CH(CH ) ), 3.28 (d, J=12 Hz, CH Ph), 3.46 (d, J=12 Hz, 1H,
3
3
3 2
A
CH Ph), 3.65 (s, 1H, CHNH), 7.10–7.19 (m, 4H, PhH), 7.22–7.33 (m, 7H, PhH), 7.57 (d, J=7.6 Hz, 2H, PhH),
B
7
.72 (d, J=8.0 Hz, 2H, PhH). Anal. calcd for C H NO: C, 83.44; H, 7.88; N, 4.06. Found: C, 83.43; H, 7.89;
24 27
N, 4.06.
7. Christopher, G. F.; Paul, M. Tetrahedron: Asymmetry 2000, 11, 1845.
8. Soai, K.; Watanabe, M. J. Chem. Soc., Chem. Commun. 1990, 43.
9. Chaloner, P. A.; Renuka Perera, S. A. Tetrahedron Lett. 1987, 28, 3013.