Boc-L-proline as a new chiral ligand for enantioselective phenylacetylene addition to aromatic aldehydes

Article abstract of DOI:10.1016/j.tetasy.2004.01.005

The N-terminal protected amino acid (Boc-L-proline) is a chiral ligand for the enantioselective phenylacetylene addition to aromatic aldehydes, thus expanding the utility of the simplest enzyme, proline, in asymmetric catalysis. Good yields and enantiosel

Full text of DOI:10.1016/j.tetasy.2004.01.005

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 589–591
Boc-
L
-proline as a new chiral ligand for enantioselective
phenylacetylene addition to aromatic aldehydes
a
Yi-feng Zhou, Rui Wang,
a,b,
a
a
Zhao-qing Xu, Wen-jin Yan, Lei Liu,
a
*
a
Yan-feng Gao and Chao-shan Da
a
a
Department of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China
b
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
Received 17 December 2003; accepted 5 January 2004
Abstract—The N-terminal protected amino acid (Boc-L-proline) is a chiral ligand for the enantioselective phenylacetylene addition
to aromatic aldehydes, thus expanding the utility of the simplest enzyme, proline, in asymmetric catalysis. Good yields and
enantioselectivities (up to 77% ee) were achieved.
Ó 2004 Elsevier Ltd. All rights reserved.
Enantioselective formation of C–C bonds is an area of
Based on the results of L-proline and its derivatives in
1
;2
intense research. The asymmetric addition of alky-
nylzinc to aldehydes is an important method of syn-
thesizing chiral propargyl alcohols, which are important
precursors to many chiral organic compounds.
Recently, many significant chiral ligands in this area
catalytic asymmetric reactions and our recent report on
catalytic asymmetric addition of alkynylzinc to aromatic
aldehydes, we supposed that natural L-proline or its
derivatives can also catalyze the asymmetric addition of
alkynylzinc to aldehydes. To the best of our knowledge,
no results of N-terminal protected amino acids as chiral
3
have been disclosed including ephedrine, BINOL–Ti
4;5
6
9
complex and sulfonamido alcohols. Though many
significant results have been achieved, large efforts to
develop new types of efficient chiral catalysts for this
important asymmetric reaction are greatly needed to
probe how the chiral catalysts act on the reaction and
how to develop ligands, which can be prepared and
derived from cheap chiral pool, especially from natural
optically active molecules and their simple derivatives. It
is very interesting and challenging.
ligands in this reaction has been disclosed to date.
Herein, we report the initial results of Boc-L-proline,
10
which has been used directly as a chiral ligand in this
reaction.
Initially, we tried to use (S)-proline itself to catalyze the
asymmetric reaction, but it is hard to dissolve the nat-
ural amino acid in general organic solvents. Therefore
we used DMF or DMSO as the solvent, but we obtained
a racemic product. Then we used the readily commercial
L
-Proline and its derivatives have become a series of
available Boc-L-proline to promote the reaction. The
results showed that this change resulted in a surprising
jump in the enantioselectivity.
important molecules in asymmetric catalysis due to its
rigid structure, easy availability, and cheapness. They
have shown powerful utilities in asymmetric aldol,
Mannich, Michael reactions, and so on. Corey and
Hetal, and List and other chemists have reported
many important and significant examples using them as
chiral ligands or chiral resources.
Interestingly, when the salt of Boc-L-proline treated
7
8
with BuLi was used as the chiral ligand, the product had
a low ee (<5% ee). So we supposed that under acidic
condition, the carboxyl group of the amino acid could
i
easily bind with Ti(O Pr) and the carbonyl group of the
4
i
11
t-butoxycarbonyl might chelate with Ti(O Pr)
4
.
This
complex behaved as a Lewis acid so we supposed that
the coordinated complex might catalyze the asymmetric
addition of alkynylzinc to aldehydes. When the BuLi
was added, the carboxyl group of the amino acid could
*
0
Corresponding author. Tel.: +86-931-891-2567; fax: +86-931-891-
561; e-mail: wangrui@lzu.edu.cn
2
957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.01.005

590
Y. Zhou et al. / Tetrahedron: Asymmetry 15 (2004) 589–591
i
not bind with Ti(O Pr)
was not steady (Fig. 1). So the product had a low ee.
4
and the coordinated complex
The chiral propargyl alcohols generated from other
aromatic aldehydes were obtained with 62–77% ee at
room temperature when using the above procedure, and
the results were summarized in Table 2. The reactions of
phenylacetylene with fluoro-, chloro-, bromo-substi-
tuted benzaldehydes containing electron-withdrawing
substituents showed higher eeÕs than those bearing
electron-donating substituents. The reactions of the
phenylacetylene addition to aliphatic aldehydes such
as n-butyl aldehyde and isobutyl aldehyde were also
observed, but only 35% ee was obtained.
O
O
i
OLi
Ti
O Pr
i
O
O Pr
i
N
O
N
O
i
Ti
O Pr
O Pr
O
i
O
O Pr
i
O Pr
i
O Pr
tBu
tBu
Table 2. Asymmetric addition of phenylacetylene to aromatic alde-
a–d
hydes promoted by the ligand Boc- -pro
Figure 1.
L
Entry
Aldehyde
Time (h) Yield (%) Ee (%)
1
Benzaldehyde
12
12
12
12
12
81
75
80
78
83
68
80
84
73
58
81
66
67
67
62
70
75
77
70
73
74
67
We conducted the asymmetric alkynylzinc addition to
aldehydes in these steps (Scheme 1). The conditions
influencing the reaction were summarized in Table 1.
13
2
3-Tolualdehyde
4-Tolualdehyde
3-Anisaldehyde
4-Anisaldehyde
3
4
5
6
4-Chlorobenzaldehyde 12
4-Fluorobenzaldehyde 12
HO
7
O
Et Zn
2
H+
8
a-Naphthaldehyde
b-Naphthaldehyde
4-Bromobenzaldehyde 12
3-Bromobenzaldehyde 12
18
18
H
C
+
HC
C
Ph
9
10
cat
R
C
Ph
R
H
1
1
i
cat=Ti(O Pr)4+(S)-Boc-proline
a
i
2 4
In all of the entries: Et Zn/phenylacetylene/aldehyde/Ti(O Pr) /Boc-
Scheme 1.
L
-pro ¼ 3:3:1:0.6:0.2.
b
All the reactions were processed under argon and at room tempera-
ture.
c
i
We found that this reaction was strongly influenced by
Ti(O Pr)
The ee values were determined by HPLC with Chiracel OD column.
4
was freshly distilled before use.
d
i
the solvents and the amount of Ti(O Pr)
selectivities were afforded in CH Cl (entry 11) and THF
entry 12), or when the amount of Ti(O Pr) was
4
. Low enantio-
2
2
i
(
In conclusion, we have successfully demonstrated the
use of (S)-Boc-proline as an effective chiral ligand for
the catalytic asymmetric addition of phenylacetylene to
aromatic aldehydes under very mild condition. Many
important features such as cheapness and readily com-
mercial availability in both enantiometric forms make it
4
decreased (entry 4). The amount of the ligand was
increased from 10% to 30%, but the eeÕs only increased a
little (entries 1, 2, 5, and 14). The temperature of the
reaction was decreased from room temperature to 0 °C,
and no significant change in ee was observed (entry 10).
a
Table 1. Asymmetric addition of phenylacetylene to benzaldehyde using Boc-L-pro as the ligand
i
b
c
d
e
Entry
Ligand (%)
Ti(O Pr)
4
/ligand
Solvent
Temperature
Ee (%)/configuration
1
2
3
4
5
6
7
8
9
10
15
20
20
20
20
20
20
20
20
20
20
20
30
40
3/1
3/1
Ether/Tol.
Ether/Tol.
Tol./Tol.
rt
53
61
rt
None
1/1
2/1
3/1
4/1
6/1
3/1
3/1
3/1
3/1
3/1
3/1
3/1
0 °C
0 °C
rt
3
Ether/Tol.
Ether/Tol.
Tol./Tol.
3
64
rt
55
66
Ether/Tol.
Ether/Tol.
Ether/Tol.
Ether/Tol.
rt
0 °C
rt
55
66/R
66/R
30/R
54/R
60/R
67/R
61/R
1
1
1
1
1
1
0
1
2
3
4
5
0 °C
rt
DCM/DCM
THF/Tol.
rt
Ether/Ether
Ether/Tol.
Ether/Tol.
rt
rt
rt
a
b
c
Phenylacetylene/Et
2
Zn/benzaldehyde ¼ 3:3:1.
was freshly distilled.
The former solvent dissolved the ligand, and the latter solvent in Et
i
Ti(O Pr)
4
2
Zn. The ratio is 2:0.75.
The enantiomeric excess was determined by HPLC analysis of the corresponding products on a Chiralcel OD column.
The absolute configurations were based on determination of the specific rotation and in comparison with the relevant literature values.
d
e
12

Y. Zhou et al. / Tetrahedron: Asymmetry 15 (2004) 589–591
591
possible to develop a new efficient chiral catalyst in this
asymmetric reaction.
Huang, W. S.; Xu, M. H.; Pu, L. Tetrahedron Lett. 2002,
3, 8831.
4
5
6
. (a) Lu, G.; Li, X. S.; Chan, W. L.; Chan, A. S. C. Chem.
Commun. 2002, 2, 172; (b) Li, X. S.; Lu, G.; Kwok, W. H.;
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Tetrahedron: Asymmetry 2003, 14, 449.
Acknowledgements
. Xu, Z. Q.; Wang, R.; Xu, J. K.; Da, C. S.; Yan, W. J.;
Chen, C. Angew. Chem., Int. Ed. 2003, 42, 5747.
This work was supported by the National Natural Sci-
ence Foundation of China (No.20372028), the Ministry
of Science and Technology of China, the Teaching and
Research Award Program for Outstanding Young
Teachers, and the Specialized Research Fund for the
Doctoral Program in Higher Education Institutions and
the Key Research Program of Science and Technology
of the Ministry of Education of China.
7. Corey, E. J.; Hetal, C. J. Angew. Chem. Int. Ed. 1998, 37,
986.
1
. List, B. Tetrahedron 2002, 58, 5573.
8
9
. (a) Frantz, D. E.; Fassler, R.; Tomooka, C. S.; Carreira,
E. M. Acc. Chem. Res. 2000, 33, 373; (b) Braga, A. L.;
Appelt, H. R.; Silveira, C. C.; Wessjohann, L. A.;
Schneider, P. H. Tetrahedron 2002, 58, 10413; (c) Jiang,
B.; Chen, Z. L.; Xiong, W. N. Chem. Commun. 2002, 14,
1
524; (d) Chen, Z. L.; Xiong, W. N.; Jiang, B. Chem.
Commun. 2002, 18, 2098; (e) Ishizaki, M.; Hoshino, O.
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hyay, V.; DeCamp, A. E.; DiMichele, L.; Reider, P.
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References and notes
1
2
. Pu, L.; Yu, H. B. Chem. Rev. 2001, 101, 757.
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Wang, R.; Xu, J. K.; Da, C. S.; Yan, W. J.; Chen, C.
Angew. Chem., Int. Ed. 2003, 42, 5747; (b) Yang, X. W.;
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W.; Su, W.; Liu, D. X.; Wang, H. S.; Shen, J. H.; Da, C.
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10. The Boc-L-proline was purchased from GL Biochem
(Shanghai) Ltd.
11. Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto,
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13. General addition procedure: Under argon, the ligand Boc-
i
(
d) Yang, X. W.; Shen, J. H.; Da, C. S.; Wang, H. S.; Su,
L
-pro (10.8 mg, 0.05 mmol) and Ti(O Pr)
4
(45 lL,
0.15 mmol) were mixed in dry ether (2.0 mL) at room
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temperature and stirred for 1 h. The solution of Et Zn
2
(1.0 M in toluene, 0.75 mL) was then added. After the
mixture was stirred at room temperature for 2 h, phenyl-
acetylene (82.4 lL, 0.75 mmol) was added and the stirring
continued for 1 h. The orange solution was cooled to 0 °C
and treated with aldehydes (0.25 mmol). The resulting
mixture was allowed to warm to room temperature and to
be stirred for 12–18 h. After the reaction was complete
(monitoring with TLC), it was cooled to 0 °C and
quenched with aqueous HCl (5%). Then the mixture was
extracted with ether. The organic layer was washed with
3
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1
23, 9687; (b) Frantz, D. E.; Fassler, R.; Carreira, E. M.
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2 4
brine, dried over Na SO , and concentrated under vac-
4
uum. The residue was purified by flash column chroma-
tography (silica gel, 20%EtOAc in hexane) to give the
product.
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