Chiral dendritic bis(oxazoline) copper(II) complexes as Lewis acid catalysts for enantioselective aldol reactions in aqueous media

Article abstract of DOI:10.1016/S0040-4039(03)00680-4

A series of copper(II) complexes, with chiral bis(oxazoline) ligands disubstituted at the carbon atom linking the two oxazolines by Fréchet-type polyether dendrimers, have been designed and synthesized. These complexes were used as Lewis acid catalysts in

Full text of DOI:10.1016/S0040-4039(03)00680-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3535–3538
Chiral dendritic bis(oxazoline) copper(II) complexes as
Lewis acid catalysts for enantioselective aldol
reactions in aqueous media
Bai-Yuan Yang,† Xiao-Min Chen,* Guo-Jun Deng,† Yi-Li Zhang† and Qing-Hua Fan*
Laboratory of Chemical Biology, Center for Molecular Science, Institute of Chemistry, The Chinese Academy of Sciences,
Beijing 100080, PR China
Received 28 October 2002; revised 24 February 2003; accepted 7 March 2003
Abstract—A series of copper(II) complexes, with chiral bis(oxazoline) ligands disubstituted at the carbon atom linking the two
oxazolines by Fre´chet-type polyether dendrimers, have been designed and synthesized. These complexes were used as Lewis acid
catalysts in enantioselective aldol reactions in aqueous media. Good yields and moderate enantioselectivities were achieved, which
are comparable with those resulting from the corresponding smaller catalysts. © 2003 Elsevier Science Ltd. All rights reserved.
The design and the development of efficient chiral
catalysts for enantioselective asymmetric syntheses in
aqueous media is one of the most challenging areas of
organic chemical research.1 Chiral Lewis acid-catalyzed
enantioselective reactions have attracted much atten-
tion in modern organic synthesis.2 However, these
Lewis acids generally must be used under strictly anhy-
drous reaction conditions because most Lewis acid
catalysts are water-labile and are easily decomposed by
water. Recently, Kobayashi developed new synthetic
methods for Lewis acid-catalyzed reactions in water-
containing solvents.3 For example, the Mukaiyama
aldol reaction of benzaldehyde with silyl enol ether 1
was catalyzed by chiral bis(oxazoline) copper(II) com-
plexes in an ethanol–water solution with high yields
and moderate to high enantioselectivities (Scheme 1).3a
Scheme 1.
Keywords: chiral bis(oxazoline); dendritic catalyst; Mukaiyama aldol reaction; aqueous.
* Corresponding authors. Fax: 86-10-62559373; e-mail: fanqh@infoc3.icas.ac.cn
† Graduate School of the Chinese Academy of Sciences.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00680-4

3536
B.-Y. Yang et al. / Tetrahedron Letters 44 (2003) 3535–3538
This process, however, still suffered from some problems
such as the separation and recycling of the often expen-
sive and toxic chiral catalysts.4 There is good reason to
believe that an aqueous aldol reaction catalyzed by
immobilized chiral Lewis acids would offer a ‘greener’
process.
Recently, many research groups have been investigating
ways to immobilize chiral bis(oxazoline) ligands on
organic or inorganic supports where the attachment has
been achieved usually at the bridging carbon atom of
the bis(oxazoline) skeleton.7 In our study, bis(oxazo-
line) 312 was selected as a model ligand. The dendritic
substituents were introduced by double alkylations of
the methylene bridge of 3 (Scheme 2). Thus, reaction of
3 with methyllithium proceeded smoothly at −55°C in
THF, followed by reacting with dendritic benzyl
bromide13 to give dendritic chiral bis(oxazoline) ligands
4a–c. For comparison purposes, the model compound 5
was also synthesized using a similar method. These
ligands were purified by column chromatography and
characterized by NMR, MS and elemental analyses. All
results were in full agreement with the proposed struc-
tures.14 For example, the MALDI TOF MS spectra of
4a, 4b and 4c show the mass ions as 961.2 ([M+Na]+),
1809.3 ([M+Na]+) and 3486.9 ([M]+), respectively.
Chiral bis(oxazoline) ligands have been applied in many
enantioselective reactions.5 Recently, studies of the
immobilization of bis(oxazolines) on both soluble and
insoluble supports has been of great interest.6,7 Among
the different methods to anchor the homogeneous cata-
lysts, a soluble, polymer-supported catalyst usually
achieves higher stereoselectivity and activity because the
catalysis can be carried out under homogeneous condi-
tions.8 After the reaction, the catalyst can be separated
and recycled via simple methods such as solvent precip-
itation. Dendrimers are highly branched macromolecules
having precisely defined molecular structures with nano-
scale size. Compared with soluble polymer supports, the
dendrimer architecture may offer better control of the
disposition of the catalytic species in soluble polymer-
based catalysts. Therefore, such catalysts may fill the gap
between homogeneous and heterogeneous catalysis and
combine the advantages of both.9 In the course of our
investigations to develop highly effective chiral dendritic
catalysts, we have recently reported several types of
chiral dendritic ligands for asymmetric catalysis through
the incorporation of BINAP and BINOL into the core
of the Fre´chet-type dendrimers, respectively.10 In this
paper, we report the synthesis of bis(oxazoline)-centered
dendrimers, which are to the best of our knowledge, the
first examples of dendrimer-supported chiral bis(oxazo-
line) ligands.11 This work is also the first example of
aqueous asymmetric aldol reactions catalyzed by poly-
mer-supported chiral catalysts.
With these dendritic ligands in hand, catalysts were
then obtained by reaction with copper triflate.15
Because of the architecture of the dendrimer, the cata-
lytically active center is situated at the core of the
dendrimer. It is possible to fine-tune the chiral micro-
environment by systematically adjusting the size, shape
and peripheral functional groups of the dendritic sub-
stituents. Reactive substrates are expected to concen-
trate in the inner areas of the dendrimer, especially in
aqueous media, due to a hydrophobic effect. This may
help the reactants access the catalytic center. In our
study, the catalytic asymmetric aldol reaction of silyl
enol ether 1 with benzaldehyde was chosen as model
reaction to test the catalytic activity of these chiral
dendritic catalysts in aqueous media.
Scheme 2. Reagents and conditions: (a) −55°C, MeLi, THF; (b) GnCH2Br, reflux, 4 h.

B.-Y. Yang et al. / Tetrahedron Letters 44 (2003) 3535–3538
3537
The effect of reaction solvent and temperature on
diastereoselectivity, enantioselectivity and chemical
yield was firstly evaluated. Considering the insolubility
of catalyst substituted with larger dendrimers in etha-
nol, a mixed solvent system containing water, tetra-
hydrofuran and ethanol was used. The results are
summarized in Table 1.
in the same reaction. As shown in Table 1, the catalysts
derived from all three dendritic bis(oxazolines) 4a–c were
found to be effective. In general, good yields and
moderate enantioselectivities were observed, which were
comparable to those with 5 and 2b. It was found that the
dendritic substituents, which were assumed to affect the
structure of the active center,9 did not decrease the
enantioselectivity or the yield with the increased size. On
the contrary, the copper complexes with higher genera-
tion ligands (4b and 4c) gave slightly higher enantioselec-
tivities and/or yields. In addition, a simple method for
recovery and recycling of the catalyst was tried without
further addition of Cu(OTf)2. At the end of the reaction,
the catalyst could be separated from the reaction mix-
tures through precipitation by adding cold methanol.
The precipitated catalyst was quantitatively recovered by
simple filtration, washed with methanol and used directly
in the second run. Unfortunately, the recycled catalyst
gave a lower yield and enantioselectivity as compared
with the freshly prepared material (entries 13, 14 and 15).
Model ligand 5 was used to optimize the reaction
conditions. As shown in Table 1, catalyst 5-Cu(II) gave
the aldol product in good yield and moderate enan-
tioselectivity in H2O–EtOH (1:9), both of which are
slightly lower than those obtained from 2b-Cu(II)
(entries 1 and 16). When using a mixture of H2O–THF
(1:9) as solvent, in the absence of ethanol, a similar
enantioselectivity, albeit in lower yield, was observed
(entry 2).
Therefore, a three-component solvent system (H2O–
EtOH–THF) was chosen as the reaction medium.
Good yields and moderate enantioselectivities were
achieved with different ratios of H2O/EtOH/THF as
solvent (entries 3–7). The highest yield (80%) with
58% ee was obtained when using H2O:EtOH:THF=
4:9:9 as solvent (entry 7). Increasing the temperature
led to a reduction of both enantioselectivity and yield
(entry 8).
In conclusion, the C2-symmetric bis(oxazolines) 4a–c,
disubstituted with two Fre´chet-type polyether den-
drimers, showed similar reactivities and enantioselectiv-
ities in the asymmetric copper-catalyzed aldol reaction in
aqueous media in comparison to the small molecular
bis(oxazoline) ligands 5 and 2b. Further study of this new
aspect of dendritic chiral copper(II) bis(oxazoline) cataly-
sis is in progress in our laboratory.
Based on the optimized reaction conditions, we then
tested the asymmetric induction of the dendritic ligands
Table 1. Catalytic asymmetric aldol reactionsa catalyzed by dendritic chiral bis(oxazoline) copper(II) catalysts in aqueous
media
Entry
Catalyst
Temp. (°C)
Solventb (v/v)
Yieldc (%)
syn/antid
Ee (%)e,f (syn)
1
2
3
4
5
6
7
8
5-Cu(OTf)2
5-Cu(OTf)2
5-Cu(OTf)2
5-Cu(OTf)2
5-Cu(OTf)2
5-Cu(OTf)2
5-Cu(OTf)2
5-Cu(OTf)2
5-Cu(OTf)2
4a-Cu(OTf)2
4b-Cu(OTf)2
4c-Cu(OTf)2
4b-Cu(OTf)2
4b-Cu(OTf)2
0
0
0
0
0
0
0
25
0
0
0
0
0
0
0
0
H2O:EtOH=1:9
H2O:THF=1:9
90
38
74
72
68
75
80
48
74
78
78
81
53
40
61
98
1.7/1
2.2/1
1.8/1
1.9/1
1.8/1
2.1/1
2.1/1
2.0/1
2.4/1
2.4/1
2.2/1
2.2/1
1.9/1
1.8/1
1.7/1
2.6/1
50
54
55
50
47
60
58
34
54
60
64
57
32
25
30
61
H2O:EtOH:THF=1:9:9
H2O:EtOH:THF=1:9:18
H2O:EtOH:THF=1:18:9
H2O:EtOH:THF=2:9:9
H2O:EtOH:THF=4:9:9
H2O:EtOH:THF=2:9:9
H2O:EtOH:THF=2:9:9
H2O:EtOH:THF=2:9:9
H2O:EtOH:THF=2:9:9
H2O:EtOH:THF=2:9:9
H2O:EtOH:THF=2:9:9
H2O:EtOH:THF=2:9:9
H2O:EtOH:THF=2:9:9
H2O:EtOH=1:9
9
10
11
12
13
14
15
16
g
h
g,i
j
4c-Cu(OTf)2
2b-Cu(OTf)2
a The configuration of substrate 1 was determined by 1H NMR analysis (E/Z=<1/>99).
b In entries 1–7, the total volume of reaction solvent is 1.5 mL. In entries 8–15, the total volume of reaction solvent is 2.5 mL.
c Isolated yield.
d The ratio of syn/anti determined by 1H NMR analysis.
e Determined by HPLC with a Chiracel OD-H column.
f Enantiomeric excess of major product diastereomer.
g The second run.
h The third run.
i The reaction time was extended to 36 h.
j See Ref. 3a.

3538
B.-Y. Yang et al. / Tetrahedron Letters 44 (2003) 3535–3538
Leeuwen, P. W. N. M. Angew. Chem., Int. Ed. 2001, 40,
Acknowledgements
1828–1849; (b) Astruc, D.; Chardac, F. Chem. Rev. 2001,
101, 2991–3023; (c) Van Heerbeek, R.; Kamer, P. C. J.;
Van Leeuwen, P. W. N. M.; Reek, J. N. H. Chem. Rev.
2002, 102, 3717–3756.
We are grateful to National Natural Science Founda-
tion of China (project 20102006 and 20132010),
National Natural Science Foundation of Beijing (pro-
ject 2012015), the Major State Basic Research Develop-
ment Program of China (2002 CCA03100) and the
Chinese Academy of Sciences for financial support.
10. (a) Fan, Q. H.; Chen, Y. M.; Chen, X. M.; Jiang, D. Z.;
Xi, F.; Chan, A. S. C. Chem. Commun. 2000, 789–790; (b)
Fan, Q. H.; Liu, G. H.; Chen, X. M.; Deng, G. J.; Chan,
A. S. C. Tetrahedron: Asymmetry 2001, 12, 1559–1565; (c)
Deng, G. J.; Fan, Q. H.; Chen, X. M.; Liu, D. S.; Chan,
A. S. C. Chem. Commun. 2002, 1570–1571.
11. For achiral dendritic bis(oxazoline) ligands: (a) Chow,
H.; Mak, C. C. J. Org. Chem. 1997, 62, 5116–5127; (b)
Mak, C. C.; Chow, H. Macromolecules 1997, 30, 1228–
1230.
References
1. For recent reviews on organic reactions in aqueous
media: (a) Grieco, P. A., Ed.; Organic Synthesis in Water,
Blackey Academic and Professional: London, 1998; (b)
Li, C. J.; Chan, T. H. Organic Reactions in Aqueous
Media, John Wiley & Sons: New York, 1997.
12. Yang, Z. C.; Zhong, M.; Chen, L. Huaxue xuebao 1994,
52, 1218–1220.
13. Hawker, C. J.; Frechet, J. M. J. J. Am. Chem. Soc. 1990,
112, 7638.
2. Lewis Acids in Organic Synthesis, Yamamoto, H., Ed.
Wiley-VCH: Weinheim, 2000.
14. Representative characterization data of the chiral den-
dritic bis(oxazoline) ligands. 4a: [h]2D0=−16.0 (c 1,
CH2Cl2); mp: 50–51°C; IR (KBr): 2359, 1654, 1593, 1496,
1453, 1153, 1060, 696 cm−1; 1H NMR (300 MHz, CDCl3):
7.39–7.08 (m, 30H, Ar-H), 6.60–6.54 (m, 6H, Ar-H), 4.99
(s, 8H, O-CH2-Ph), 4.34 (m, 2H, 4-H, 4%-H), 4.10 (m, 2H,
5-H), 3.91 (m, 2H, 5-H), 3.34 (m, 4H, Ph-CH2-C-CH2-
Ph), 3.06 (dd, 2H, J1=5.0 Hz, J2=13.6 Hz, CHaPh,
CHa%Ph), 2.36 (dd, 2H, J1=9.8 Hz, J2=13.6 Hz, CHbPh,
CHb% Ph); 13C NMR (75 MHz, CDCl3): 166.8, 159.7,
139.1, 138.1, 136.9, 129.2, 128.6, 128.6, 128.0, 127.6,
126.5, 110.2, 100.1, 72.2, 70.1, 67.6, 48.0, 41.7, 39.3;
MALDI-TOF-MS (m/z): 939.2 [M+H]+, 961.2 [M+Na]+;
anal. calcd for C63H58N2O6: C, 80.57; H, 6.22; N, 2.98.
Found: C, 80.80; H, 6.22; N, 2.70%. 4b: [h]2D0=−8.0 (c 1,
CH2Cl2); mp: 56–57°C; IR (KBr): 2360, 1595, 1496, 1452,
3. For recent examples of catalytic asymmetric aldol reac-
tions in aqueous media reported by Kobayashi, see: (a)
Kobayashi, S.; Nagayama, S.; Busujima, T. Chem. Lett.
1999, 71–72; (b) Nagayama, S.; Kobayashi, S. J. Am.
Chem. Soc. 2000, 122, 11531–11532; (c) Kobayashi, S.;
Hamada, T.; Nagayama, S.; Manabe, K. Org. Lett. 2001,
3, 165–167.
4. For recent reviews on recycling of chiral catalysts, see: (a)
Fodor, K.; Kolmschot, S. G. A.; Sheldon, R. G. Enan-
tiomer 1999, 4, 497; (b) De Vos, D. E.; Vankelecom, I. F.
J.; Jacobs, P. A., Ed.; Chiral Catalyst Immobilization and
Recycling, Wiley-VCH: Weinheim, 2000; (c) Fan, Q. H.;
Li, Y. M.; Chan, A. S. C. Chem. Rev. 2002, 102, 3385–
3466.
5. (a) Fritschi, H.; Leutenegger, U.; Pfaltz, A. Angew.
Chem., Int. Ed. 1986, 25, 1005–1006; (b) Fritschi, H.;
Leutenegger, U.; Siegmann, K.; Pfaltz, A.; Keller, W.;
Kratky, C. Helv. Chim. Acta 1988, 71, 1541–1552; (c)
Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron:
Asymmetry 1998, 9, 1–45.
6. For a recent comprehensive review on the immobilization
of chiral bis(oxazolines), see: Rechavi, D.; Lemaire, M.
Chem. Rev. 2002, 102, 3467–3494.
7. For recent representative examples of supported chiral
bis(oxazoline) ligands and their metallic catalysts, see: (a)
Orlandi, S.; Mandoli, A.; Pini, D.; Salvadori, P. Angew.
Chem., Int. Ed. 2001, 40, 2519–2521; (b) Rechavi, D.;
Lemaire, M. Org. Lett. 2001, 3, 2493–2496; (c) Annunzi-
ata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Pitillo, M.
J. Org. Chem. 2001, 66, 3160–3166; (d) Burguete, M. I.;
Fraile, J. M.; Garcia, J. I.; Verdugo, E. G.; Herrerias, C.
I.; Luis, S. V.; Mayoral, J. A. J. Org. Chem. 2001, 66,
8893–8901.
8. For recent representative examples of soluble polymer-
supported chiral catalysts, see: (a) Han, H.; Janda, K. D.
J. Am. Chem. Soc. 1996, 118, 7632–7633; (b) Bolm, C.;
Gerlach, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 741;
(c) Fan, Q. H.; Ren, C. Y.; Yeung, C. H.; Hu, W. H.;
Chan, A. S. C. J. Am. Chem. Soc. 1999, 121, 7407–7408;
(d) Yu, H.-B.; Hu, Q.-S.; Pu, L. J. Am. Chem. Soc. 2000,
122, 6500–6501.
1155, 1055, 696 cm−1 1H NMR (300 MHz, CDCl3):
;
7.31–6.98 (m, 50H, Ar-H), 6.57–6.45 (m, 18H, Ar-H),
4.91–4.80 (m, 24H, O-CH2-Ph), 4.25 (m, 2H, 4-H, 4%-H),
4.01 (m, 2H, 5-H), 3.90 (m, 2H, 5-H), 3.24 (m, 4H,
Ph-CH2-C-CH2-Ph), 2.94 (dd, 2H, J1=5.0 Hz, J2=13.6
Hz, CHaPh, CHa%Ph), 2.25 (dd, 2H, J1=9.7 Hz, J2=13.6
Hz, CHbPh, CHb% Ph); 13C NMR (75 MHz, CDCl3): 166.7,
160.1, 159.5, 139.3, 138.0, 136.8, 129.2, 128.5, 128.0,
127.6, 126.4, 110.2, 106.4, 101.6, 100.3, 72.0, 70.0, 67.5,
41.6; MALDI-TOF-MS (m/z): 1787.3 [M+H]+, 1809.3
[M+Na]+; anal. calcd for C119H106N2O14: C, 79.93; H,
5.98; N, 1.57. Found: C, 80.24; H, 6.02; N, 1.53%. 4c:
[h]2D0=−4.0 (c 1, CH2Cl2); mp: 60–61°C; IR (KBr): 2360,
1
1653, 1595, 1496, 1451, 1155, 1053, 696 cm−1; H NMR
(300 MHz, CDCl3): 7.61–7.00 (m, 90H, Ar-H), 6.68–6.50
(m, 42H, Ar-H), 5.02–4.80 (m, 56H, O-CH2-Ph), 4.25 (m,
2H, 4-H, 4%-H), 4.10 (m, 2H, 5-H), 3.87 (m, 2H, 5-H),
3.33 (m, 4H, Ph-CH2-C-CH2-Ph), 2.97 (m, 2H, CH2Ph),
2.30 (m, 2H, CH2Ph); 13C NMR (75 MHz, CDCl3):
136.5, 129.0, 128.4, 128.1, 127.8, 127.4, 127.0, 126.2,
125.4, 109.9, 106.2, 105.7, 101.4, 100.3, 100.2, 69.8, 69.7,
67.2; MALDI-TOF-MS (m/z): 3486.9 [M]+; anal. calcd
for C231H202N2O30: C, 79.59; H, 5.84; N, 0.80. Found: C,
80.03; H, 5.93; N, 0.80%.
15. Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D.
M.; Campos, K. R.; Woerpel, K. A. J. Org. Chem. 1998,
63, 4541–4544.
9. For recent reviews on chiral dendritic catalysts, see: (a)
Oosterom, G. E.; Reek, J. N. H.; Kamer, P. C. J.; Van