Novel chiral gallium Lewis acid catalysts with semi-crown ligands for aqueous asymmetric Mukaiyama aldol reactions

Article abstract of DOI:10.1039/b208411b

Asymmetric Mukaiyama aldol reactions in aqueous media (water-ethanol = 9:1) were catalyzed by chiral gallium catalysts with semi-crown ligands to give aldol products with good yields, syn-diastereoselectivities and enantioselectivities.

Full text of DOI:10.1039/b208411b

Novel chiral gallium Lewis acid catalysts with semi-crown ligands for
aqueous asymmetric Mukaiyama aldol reactions
Hui-Jing Li,a Hong-Yu Tian,a Yong-Jun Chen,a Dong Wang*a and Chao-Jun Li*b
a Center for Molecular Science, Institute of Chemistry, The Chinese Academy of Sciences, Beijing 100080,
P.R. China. E-mail: dwang70118@yahoo.com
b Tulane University, Department of Chemistry, New Orleans, Louisiana, USA. E-mail: cjli@tulane.edu;
Fax: 504-865-5596; Tel: 504-865-5573
Received (in Cambridge, UK) 29th August 2002, Accepted 24th October 2002
First published as an Advance Article on the web 11th November 2002
Asymmetric Mukaiyama aldol reactions in aqueous media
(water–ethanol = 9:1) were catalyzed by chiral gallium
catalysts with semi-crown ligands to give aldol products with
good yields, syn-diastereoselectivities and enantioselectiv-
ities.
Among the Lewis acid catalyzed carbon–carbon bond-forming
reactions, the aldol-type reaction of silyl enol ethers with
Scheme 1
carbonyl compounds (the Mukaiyama reaction)1 has been
recognized as one of the most important. Although several
examples of research on chiral gallium Lewis acid-catalyzed
asymmetric reactions.10 The combination of Ga(OTf)3 and 5b is
able to make the aqueous reaction proceed smoothly with good
yield (89%), diastereoselectivity (syn/anti 89+11) and enantio-
selectivity of syn-3a (ee 87%) (Table 1, entry 3).† It was noticed
that the use of semi-crown ligand 5b is essential to carry out the
aldol reaction in aqueous media. If Ga(OTf)3 was used alone
without 5b, the silyl enol ether 1 in the reaction mixture
disappeared (as shown by TLC) after 10 min of the reaction, but
no aldol product was observed and the hydrolyzed product,
phenylethyl ketone, was obtained (yield 95%) (Table 1, entry
1). In the absence of the aldehyde, the enol silyl ethers also
hydrolyzed under the reaction conditions. When the semi-crown
ligand was used, the side-reactions could be suppressed.
Similarly, as shown in Table 1 (entries 11 and 12), with gallium
trichloride alone (GaCl3, 9) only a trace amount of the aldol
product was obtained, whereas the combination of 9 with 5b
could not only catalyze the aldol reaction (61% yield), but also
provide a good enantioselectivity (78% ee of syn-3a).
successful examples of catalytic asymmetric Mukaiyama aldol
reaction have been developed since 1990,2 most of these
reactions must be conducted at low reaction temperatures in
aprotic anhydrous solvents. Recently, interest has been growing
in the development of asymmetric Mukaiyama-type reactions in
aqueous media.3 Compared with typical Lewis acids such as
TiCl4, SnCl4, BF3 and AlCl3, certain metal triflates possess
stronger Lewis acidities, and they are also water soluble or
water-tolerant, air-stable and easy to handle (not requiring
anhydrous treatment).4 Recently, Kobayashi and co-workers
developed the combinations of Cu(OTf)2 with a chiral bis(ox-
azoline) ligand,5 Pb(OTf)2 with a chiral crown ether,6 and
Ln(OTf)3 [e.g. Nb(OTf)3, Ce(OTf)3 and Pr(OTf)3] with chiral
bis-pyridino-18-crown-67 for asymmetric Mukaiyama aldol
reactions in aqueous ethanol (ethanol–water = 9+1). However,
when the amount of water in the mixture was increased, yields
and selectivities of the reaction decreased remarkably and in
water alone both low yield (4%) and selectivity (ee 15%) were
observed.6 Furthermore, the use of ‘light,’ main-group metal
catalysts has environmental benefits (compared to heavy
metals). A successful catalytic aqueous asymmetric reaction
depends on high binding affinities of chiral ligands to the metal
center and the catalytic ability of the complex in water. For
catalysis, turnover at a reasonable rate must accompany the
molecular recognition events. To satisfy both requirements, a
semi-crown design would provide the opportunity for good
chiral recognition and catalytic ability.8 Herein, we wish to
report novel chiral gallium catalysts with chiral semi-crown
ligands for an aqueous catalytic asymmetric Mukaiyama
reaction.
On the basis of these preliminary results, various chiral
ligands and reaction conditions were selected and investigated.
More recently, Trost developed a chiral semi-crown ligand
(5a)–dinuclear zinc catalyst system, which has been success-
fully applied in direct catalytic enantioselective aldol reac-
tions8,11 and nitroaldol (Henry) reactions.12 We examined chiral
Table 1 Aldol reactions of silyl enol ether 1 with 2a
Yield of
Ee of
syn-3a
(%)
Reaction 3a(%)c
Entry Catalysta Solvent
timeb
(syn/anti)
Chiral Lewis acids were prepared by stirring a mixture of
metal salt and chiral ligands (1+1.2) in dichloromethane at room
temperature for 2 h, then employing the mixture in the aldol
reaction after evaporation of the solvent without further
purification. Initially, the reaction of 1-phenyl-1-trimethylsilox-
ypropene 1 with benzaldehyde 2a in the presence of Lewis
acids, such as Sc(OTf)3, Nd(OTf)3, Pb(ClO4)2, Cu(OTf)2,
Zn(OTf)2 and In(OTf)3, with Trost’s chiral semi-crown ligand
(S,S)-5b8 was carried out in a mixture solvent of ethanol–water
(9+1) (Scheme 1). Although all reactions proceeded smoothly to
give the aldol product 3a in good yields (75–90%) and
diastereoselectivities (syn/anti > 80+20), the enantioselectiv-
ities of syn-3a were very poor (0–5 ee%). Fortunately, the ee of
syn-3a increased remarkably by using a catalytic amount of
Ga(OTf)3 (4, 20 mol%) under the same reaction conditions.
Although extensive research on chiral aluminium Lewis acid in
asymmetric reactions has been reported,9 there are few
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4
H2O/C2H5OH (1+9) 15 min
H2O/C2H5OH (1+9) 36 h
H2O/C2H5OH (1+9) 36 h
H2O/C2H5OH (1+9) 36 h
H2O/C2H5OH (1+9) 36 h
H2O/C2H5OH (1+9) 36 h
—
5a + 4
5b + 4
6 + 4
7 + 4
8 + 4
5b + 4
5b + 4
5b + 4
5b + 4
5b+9
9
80 (87/13)
89 (89/11)
72 (89/11)
78 (85/15)
60 (90/10)
80 (88/12)
84 (82/18)
85 (85/15)
41 (90/10)
61 (84/16)
trace
80
87
5
44
2
80
82
85
84
78
H2O/THF (1+4)
36 h
H2O/C2H5OH (1+1) 36 h
H2O/C2H5OH (9+1) 36 h
H2O
3 d
H2O/C2H5OH (9+1) 36 h
H2O/C2H5OH (9+1) 36 h
5b + 4
5b + 4
C2H5OH
CH2Cl2
36 h
3 d
75 (88/12)
trace
58
a Catalyst loading: 20 mol%. b Reaction temperature: 0–5 °C. c Isolated
yield.
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CHEM. COMMUN., 2002, 2994–2995
This journal is © The Royal Society of Chemistry 2002

aliphatic aldehyde (2h) gave a lower ee (30%) (entry 8). No
reaction was observed with simple ketones under the current
conditions. The configuration of syn-3a and its analogues
produced were determined as 2R, 3R by comparison with the
optical rotation of authentic compounds (see ref. 14).
In conclusion, the combinations of Ga(OTf)3 or GaCl3 with
chiral semi-crown ligands were highly effective chiral Lewis
acid catalysts for catalytic aqueous Mukaiyama aldol reactions
that give good yields, diastereo- and enantioselectivities. The
application of these chiral gallium catalysts in other Lewis acid
catalyzed reactions in aqueous media is in process.
This work was supported by the National Natural Science
Foundation of China and the Chinese Academy of Sciences and
Ministry of Science and Technology (No. 2002CCA03100).
Notes and references
† General procedure for the reaction: Ga(OTf)3 (0.1 mmol) and chiral
ligand 5b (0.12 mmol) were dissolved in 1 mL dichloromethane, followed
by stirring for 2 h at room temperature. Then, the solvent was evaporated in
vacuo to give a yellow solid (catalyst complex). Benzaldehyde 2a (0.5
mmol) and silyl enol ether 1 (0.75 mmol) were added to a solution of the
catalyst complex in a mixture solvent (water–ethanol = 9+1) at 0–5 °C,
followed by stirring for 36 h at the same temperature. The reaction was
quenched with aq. NaHCO3. The mixture was extracted with ether (33),
and the combined organic phase was dried over Na2SO4 and concentrated.
The crude product was purified by flash chromatography on silica gel
(eluent: ethyl acetate–petroleum ether (30–60 °C) = 1+10) to give a mixture
of syn- and anti-3a. Syn-3a was obtained from flash chromatography
purification of the mixture. The ratio of syn/anti and the ee of syn-3a were
determined by 1H NMR and chiral HPLC (column Chiracel OD-H).
ligands 5–8 together with Ga(OTf)3 for a catalytic asymmetric
aldol reaction in water–ethanol (1+9). It was found that chiral
gallium catalysts based on ligands (S,S)-5a and (S,S)-5b had
similar asymmetric inductions and catalytic abilities (Table 1,
entries 2 and 3). Phenol derivatives 5a–b as chiral ligands
exhibited higher enantioselectivities than the use of pyridinol
derivative (S,S)-7,13 although similar yields and diaster-
eoselectivities (entries 2, 3, 5) were observed. Non-C2-
symmetrical mono-prolinol ligands [(S)-6 and (S)-813] did not
show any significant enantioinductive ability (entries 4, 6). It is
noteworthy that both diastereo- and enantioselectivities re-
mained high with an increased amount of water in the mixture
solvent and even with only water as the solvent (entries 8, 9, 10).
However, in water alone the reaction was slow and gave a lower
yield of the aldol product. The addition of a surfactant did not
improve the yield of the reaction. On the other hand, in ethanol
the enantioselectivity of syn-3a decreased noticeably (entry 13)
and only a trace amount of the aldol product was detected when
dichloromethane was used as the solvent (entry 14). Thus, water
is essential to give a good enantioselectivity in the chiral
gallium catalyzed aqueous Mukaiyama aldol reaction.
1 T. Mukaiyama, K. Narasaka and T. Banno, Chem. Lett., 1973, 1011; T.
Mukaiyama, Org. React., 1982, 28, 203.
2 T. Mukaiyama, S. Kobayashi, H. Uchiro and I. Shina, Chem. Lett., 1990,
129; S. Kobayashi, Y. Fujishita and T. Mukaiyama, Chem. Lett., 1990,
1455.
3 S. Kobayashi, M. Sugiura, H. Kitagawa and W. L. Lam, Chem. Rev.,
2002, 102, 2227 and references cited there.
4 C. J. Li and T. H. Chan, Organic Reactions in Aqueous Media, John
Wiley & Sons, New York, 1997; Organic Synthesis in Water, ed. P. A.
Grieco, Blackie Academic & Professional, Glasgow, 1998.
5 S. Kobayashi, S. Nagayama and T. Busujima, Chem. Lett., 1999, 71.
6 S. Nagayama and S. Kobayashi, J. Am. Chem. Soc., 2000, 122,
11531.
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2001, 3, 165.
8 B. M. Trost and H. Ito, J. Am. Chem. Soc., 2000, 122, 12002.
9 For review, see: W. D. Wulff, Chiral Aluminum Lewis Acids in Organic
Synthesis in Lewis Acids in Organic Synthesis, ed. H. Yamamoto,
Wiley-VCH, Weinheim, 2001, vol. 1, p. 283.
10 For gallium-based chiral heterobimetallic multifunctional catalysts in
asymmetric reactions, see: M. Shibasaki, Asymmetric Two-Center
Catalysis, in Stimulating Concepts in Chemistry, ed. F. Vogtle, J. F.
Stoddart and M. Shibasaki, Wiley-VCH, Weinheim, 2000, p. 105; M.
Shibasaki, H. Sasai, T. Arai and T. Iida, Pure Appl. Chem., 1998, 70,
1027; T. Iida, N. Yamamoto, S. Matsunaga, H. G. Woo and M.
Shibasaki, Angew. Chem., Int. Ed., 1998, 37, 2223; S. Matsunaga, J.
Das, J. Roels, E. M. Vogl, N. Yamamoto, T. Iida, K. Yamaguchi and M.
Shibasaki, J. Am. Chem. Soc., 2000, 122, 225.
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Trost, H. Ito and E. R. Silcoff, J. Am. Chem. Soc., 2001, 123, 3367.
12 B. M. Trost and V. S. C. Yeh, Angew. Chem., Int. Ed., 2002, 41, 861; B.
M. Trost, V. S. C. Yeh, H. Ito and N. Bremeyer, Org. Lett., 2002, 4,
2621.
Subsequently, various aromatic aldehydes 2b–g were em-
ployed in the asymmetric aldol reaction in water–ethanol (9+1)
under the same reaction conditions catalyzed by chiral gallium
Lewis acid derived from Ga(OTf)3 and (S,S)-5b. All the
reactions provided good yields (77–90%), diastereoselectivities
(syn/anti = 80/20–90/10) and enantioselectivities of syn-3b–f
(78–88% ee), except the case of p-nitrobenzaldehyde 2g which
gave a relatively low ee of aldol product 3f (62%) (Table 2). An
Table 2 Asymmetric aldol reaction of 1 with 2 catalyzed by Ga(OTf)3/
5ba
Ee of
Yield of 3
syn-3
Entry
Aldehyde (R1)
Product (R1)
(%)b(syn/anti) (%)
1
2
3
4
5
6
7
8
2a, Ph
3a, Ph
85 (85/15)
89 (90/10)
80 (88/12)
77 (82/18)
90 (90/10)
87 (80/20)
82 (77/23)
82 (89/11)
85
88
84
78
86
82
62
30
2b, p-CH3Ph
2c, p-CH3OPh
2d, p-ClPh
2e, PhCHNCH
2f 1-naphthyl
2g, p-NO2Ph
2h, CH3(CH2)4
3b, p-CH3Ph
3c, p-CH3OPh
3d, p-ClPh
3e, PhCHNCH
3f, 1-naphthyl
3g, p-NO2Ph
3h, CH3(CH2)4
13 X. Chen, PhD thesis, Peking University, Beijing, 2002.
14 S. E. Denmark, K. T. Wang and R. A. Stavenger, J. Am. Chem. Soc.,
1997, 119, 2333.
a Reaction conditions: catalyst loading: 20 mol%, solvent: H2O/C2H5OH
(9+1), time: 36 h, temperature: 0–5 °C. b Isolated yield.
CHEM. COMMUN., 2002, 2994–2995
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