Aqueous asymmetric Mukaiyama aldol reaction catalyzed by chiral gallium Lewis acid with trost-type semi-crown ligands

Article abstract of DOI:10.1002/adsc.200505089

The combination of Ga(OTf)₃ with chiral semi-crown ligands (1a-e) generates highly effective chiral gallium Lewis acid catalysts for aqueous asymmetric aldol reactions of aromatic silyl enol ethers with aldehydes. A ligand-acceleration effect was observed. Water is essential for obtaining high diastereoselectivity and enantioselectivity. The p-phenyl substituent in aromatic silyl enol. ether (2 h) plays an important role and increases the enantioselectivity up to 95% ee. Although aliphatic silyl enol ethers provided low enantioselectivities and silylketene acetal is easily hydrolyzed in aqueous alcohol, the aldol reactions of silylketene thioacetal (12) with aldehydes in the presence of gallium-Lewis acid catalysts give the β-hydroxy thioester with reasonable yields and high diastereo- (up to 99:1) and enantioselectivities (up to 96% ee).

Full text of DOI:10.1002/adsc.200505089

FULL PAPERS
Aqueous Asymmetric Mukaiyama Aldol Reaction Catalyzed by
Chiral Gallium Lewis Acid with Trost-Type Semi-Crown Ligands
Hui-Jing Li,a Hong-Yu Tian,a Yan-Chao Wu,a Yong-Jun Chen,a Li Liu,a
Dong Wang,a,* Chao-Jun Lib,*
a
Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080,
Peopleꢀs Republic of China
Fax: (þ86)-10-6255-4449, e-mail: dwang210@iccas.ca.cn
b
Department of Chemistry, McGill University, Montreal, Quebec, Canada H3A2K6
Fax: (þ1)-514-398-3797, e-mail: cj.li@mcgill.ca
Received: February 13, 2005; Accepted: April 18, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The combination of Ga(OTf)3 with chiral hydrolyzed in aqueous alcohol, the aldol reactions of
semi-crown ligands (1a–e) generates highly effective silylketene thioacetal (12) with aldehydes in the pres-
chiral gallium Lewis acid catalysts for aqueous asym- ence of gallium-Lewis acid catalysts give the b-hy-
metric aldol reactions of aromatic silyl enol ethers droxy thioester with reasonable yields and high dia-
with aldehydes. Aligand-acceleration effect was ob-
stereo- (up to 99:1) and enantioselectivities (up to
served. Water is essential for obtaining high diastereo- 96% ee).
selectivity and enantioselectivity. The p-phenyl sub-
stituent in aromatic silyl enol ether (2 h) plays an im-
portant role and increases the enantioselectivity up to Keywords: aqueous asymmetric C C bond-forming
95% ee. Although aliphatic silyl enol ethers provided reaction; chiral semi-crown ligand; gallium-Lewis
low enantioselectivities and silylketene acetal is easily acid catalyst, Mukaiyama aldol reaction
À
Introduction
bis-pyridino-18-crown-6[14] for asymmetric Mukaiyama
aldol reactions in aqueous ethanol (ethanol-water¼
Among the Lewis acid-catalyzed carbon-carbon bond 9:1). However, when the amount of water in the mixture
forming reactions, the aldol-type reaction of silyl enol was increased, yields and selectivities of the reaction de-
ethers with carbonyl compounds (the Mukaiyama reac- creased remarkably and, in water alone, both low yield
tion)[1] has been recognized as one of the most impor- (4%) and selectivity (ee 15%) were observed.[14] Further-
tant. In 1990 Mukaiyama[2] reported the first asymmetric more, compared to “heavier” metals, the use of ꢁlightꢀ,
aldol reaction of silyl enol ethers catalyzed by chiral di- main-group metal catalysts has environmental benefits
amine/Sn(OTf)2. Since then, several successful exam- and is more attractive. More recently, Kobayashi report-
ples of the catalytic asymmetric Mukaiyama aldol reac- ed the catalytic asymmetric hydroxymethylation of sili-
tion have been developed, including the use of p-Tol-BI- con enolates with formaldehyde in aqueous solution
NAP with AgF[3] or CuF,[4] BINOL with Zr(O-t-Bu)4[5]or with up to 90% ee by using a chiral scandium complex
Ti(O-i-Pr)4,[6] and chiral bis(oxazoline) with Cu(II)[7] or as catalyst[15] and Jankowska reported an asymmetric
Sc(III)[8] as chiral catalysts. However, most of these reac- Mukaiyama aldol reaction in aqueous media with up
tions must be conducted at low reaction temperatures in to 75% ee by using Zn-based chiral Lewis acid.[16]
aprotic anhydrous solvents. Recently, the performance
On the other hand, there are still various challenging
of organic reactions in water[9] has attracted considera- problems to face in developing catalytic asymmetric re-
ble attention, which was followed by a growing interest action in aqueous media. Will water promote or prevent
in the development of asymmetric Mukaiyama-type re- the reaction? How do we address the hydrolysis and sol-
action in aqueous media.[10] Kobayashi and co-work- ubility of the substrate in water? How do we balance the
ers[11] have reported excellent results using the combina- binding affinity of the metal with the ligand for asym-
tion of Cu(OTf)2 with a chiral bis(oxazoline) ligand,[12] metric induction and reactivity of the chiral catalyst in
Pb(OTf)2 with a chiral crown ether[13] and Ln(OTf)3 water (i.e., how to complete the catalytic cycle in water)?
[e.g., Nb(OTf)3, Ce(OTf)3 and Pr(OTf)3] with chiral Recently, Trost developed a chiral semi-crown ligand/di-
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DOI:10.1002/adsc.200505089
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Hui-Jing Li et al.
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nuclear zinc catalyst system, which has been successfully Sc(OTf)3, Nd(OTf)3, Pb(ClO4)2, Cu(OTf)2, Zn(OTf)2,
applied in catalytic enantioselective direct aldol reac- and In(OTf)3 with the chiral semi-crown ligand (S,S)-
tions,[17] nitroaldol (Henry) reactions,[18] Mannich-type 1a (Scheme 1). Although, in all cases, the reaction pro-
reactions[19] and diol-desymmetrizations.[20] As shown ceeded smoothly to give the aldol product 4a in good
by Trost, the semi-crown ligand (bearing more hydroxy yields (75–90%) and diastereoselectivities (syn:anti>
groups) has more binding sites towards metals, which 80:20), the enantioselectivities of the formed syn-4a
can meet both requirements of good affinity to metals were very poor (0–5%). Fortunately, when a catalytic
and higher catalytic activity. It appears that these com- amount of Ga(OTf)3 (20 mol %) was used under the
pounds are highly promising chiral ligands in asymmet- same reaction conditions, the ee of syn-4a was increased
ric reactions in aqueous media. Herein, we report on the remarkably to 80%. It is noteworthy to mention that al-
use of chiral gallium catalysts with chiral semi-crown li- though there are extensive reports on the use of chiral
gands for a catalytic asymmetric Mukaiyama reaction in aluminium Lewis acids in asymmetric reactions, there
aqueous media.[21]
are only few examples of chiral gallium-Lewis acid-cat-
alyzed asymmetric reactions.[21]
Subsequently, various gallium-Lewis acids prepared
by chiral semi-crown ligands (1a–g) or mono-arm-
type ligands (1h, i) with Ga(OTf)3 were examined in
Results and Discussion
According to the literature methods[16], the chiral semi- the asymmetric aldol reaction of 2a with 3a in aqueous
crown type ligands 1a–g used in our study were synthe- alcohol (C2H5OH/H2O¼9:1) (Table 1). It is seen in Ta-
sized (Figure 1) by two synthetic routes. The mono-arm ble 1 that the use of chiral ligand (S,S)-1b (R¼t-butyl)
ligand 1h was prepared similarly starting from 2-metha- provided a slightly higher enantioselectivity (87% ee)
nol-4-t-butylphenol. Treatment of various ketones with than chiral ligand (S,S)-1a (R¼methyl) (80% ee) (en-
NaH in toluene followed by reaction with chlorotrime- tries 2 vs. 1). The use of chiral ligand (S,S)-1c (R¼F) re-
thylsilane gave the corresponding (Z)-silyl enol ethers
(Z/E¼ >99:1). After establishing an optimized experi-
mental procedure and ratio of the reactants used, the
chiral Lewis acid catalysts were prepared by stirring a
mixture of the metal salt with the chiral ligand (1:1.2)
in dichloromethane at room temperature for 2 h. After
evaporation of the solvent and other volatile com-
pounds, the solid complex thus obtained was employed
as catalyst in the aldol reaction without further purifica-
tion.
At first, (Z)-1-phenyl-1-trimethylsiloxypropene (2a)
was reacted with benzaldehyde (3a) in aqueous ethanol
(C2H5OH/H2O¼9:1) in the presence of various Lewis
acid catalysts (20 mol %), which were prepared from Scheme 1.
Figure 1. Chiral semi-crown type ligands 1a–g and mono-arm-type ligands 1h, i.
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Table 1. The reaction of 2a with 3a in aqueous media.[a]
Entry
Chiral catalyst[b]
[L*þGa(OTf)3]
Reaction
time[c] [h]
Yield of 4a[d] [%]
(syn/anti)[e]
ee of syn-4a[f] [%]
Yield
of 5[d] [%]
1
2
3
4
5
6
7
8
9
1a
1b
36
36
36
24
8
80 (87/13)
89 (89/11)
61 (84/16)
76 (88/12)
81 (90/10)
84 (95/5)
–
65 (85/15)
72 (89/11)
49 (90/10)
–
80
87
78
78
87
86
5
trace
–
5
–
1bþGaCl3
1c
1d
1e
1f
1g
1h
1i
8
–
36
36
36
36
15 min
36
98
31
20
48
98
44
5
2
10
11
12
Ga(OTf)3
GaCl3
trace
–
[a]
In H2O/C2H5OH (1: 9).
[b]
[c]
[d]
[e]
[f]
Catalyst loading: 20 mol %.
Reaction temperature: 0–58C.
Yield of isolated product.
1
Determined by H NMR.
Determined by chiral HPLC.
sulted in a decrease in the enantioselectivity (78% ee, Ga(OTf)3 in H2O/C2H5OH (1:9), indicating the forma-
entry 4). The use of non-C2-symmetrical mono-prolinol tion of a 1þ1 complex. The values of the corresponding
ligands (S)-1h and (S)-1j did not provide any significant R (0.9973–0.9999) (Table 2) indicated a very good line-
enantioselectivity (entries 9 and 10).
ar relationship and also show the reliability of the plots
There are two competing reactions in the aqueous re- in extracting the association constants. The introduction
action of silyl enol ether with aldehyde: the aldol reac- of a solution of the prepared complex 1b/Ga(OTf)3 in
tion and hydrolysis of the silyl enol ether. If Ga(OTf)3 H2O/C2H5OH (1:9) to an electrospray mass spec-
(without the chiral ligand) was used alone in the aqueous trometer provided two peaks at m/e¼748.8 (calcd.
aldol reaction, silyl enol ether 2a hydrolyzed completely for C46H50GaN2O3: 748.6) and 899.8 (calcd. for
in only 15 min to give 1-phenylpropanone (5) (entry 11); C47H52F3GaN2O6S: 899.6) that correspond to Mþ1 and
whereas the use of GaCl3 alone as catalyst, although no Mþ1þHOTf, respectively. The results also demon-
hydrolyzed product 5 was obtained, resulted in only strated the formation of a 1þ1 complex in aqueous alco-
trace amounts of aldol product after stirring for 36 h (en- hol. However, no peak was observed in the electrospray
try 12). However, when the Ga-Lewis acid catalysts mass spectrum of the complex 1f/Ga(OTf)3 under the
[prepared from semi-crown ligand 1b and Ga(OTf)3 or same conditions. Based on the Benesi–Hidebrand rela-
GaCl3] were employed, the aqueous aldol reaction of tionship,[22] the association constant could be deter-
2a with 3a provided both good yield and enantioselectiv- mined by the UV-vis titration of chiral ligand with the
ity of the aldol product 4a together with a trace amount solution of Ga(OTf)3 in H2O/C2H5OH (1:9) (Table 2).
of 5 (entries 2 and 3). These results suggested that the li- As shown in Table 2, the complex of the semi-crown li-
gand played an important role in accelerating the aldol
reaction and suppressing the hydrolysis of silyl enol
ethers in aqueous media. The reaction was further accel-
erated with the use of ligands 1d and 1e, in which the
phenyl group on the chiral ligand was replaced by 2-
naphthyl and 4-biphenyl groups: the reaction time was
shortened from 24 h to 8 h with a slightly higher diaster-
eoselectivity (syn/anti¼95:5) and the same enantiose-
lectivities of syn-4a (86% ee) (entries 5 and 6).
In order to elucidate the binding ability of the semi-
crown ligands with Ga3þ in aqueous media, UV-vis titra-
tion of the chiral ligands with Ga(OTf)3 was performed.
The plotting of the change of optical density (C0/DOD)
against ODÀ1 afforded a line with linear correlation co-
efficients (R) when mixing the chiral ligands with
Table 2. Association constants of the complex in H2O/C2H5
OH (1: 9).
Complex
[ligand/Ga(OTf)3]
Association
R[b]
constant[a] [MÀ1
]
1aþGa(OTf)3
1bþGa(OTf)3
1cþGa(OTf)3
1fþGa(OTf)3
1gþGa(OTf)3
1hþGa(OTf)3
5.89ꢀ103
1.20ꢀ104
4.44ꢀ102
6.69ꢀ102
3.73ꢀ103
5.08ꢀ102
0.9973
0.9979
0.9997
0.9999
0.9998
0.9996
[a]
Measured by UV-vis titration.
Linear correlation coefficient.
[b]
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gand bearing a phenol hydroxy group and a tert-butyl case, the addition of a surfactant (SDS) did not improve
group in the phenyl ring (1b) with Ga(OTf)3 has the larg- the yield of the reaction. On the other hand, the use of
est association constant (1.20ꢀ104 MÀ1), and exhibits ethanol as solvent decreased the enantioselectivity of
the highest binding ability of the semi-crown ligand to syn-4a significantly (entry 1). In anhydrous THF, the re-
Ga3þ in aqueous media. The ligand 1f (with two alkyl hy- action offered the aldol product in a low yield (47%) to-
droxy and without a phenol hydroxy group) and mono- gether with lower diastereo- (syn/anti¼77:23) and
arm ligand 1h (with one alkyl hydroxy and one phenol enantioselectivities (44% ee of syn-4a); the addition of
hydroxy group) also have relatively low association con- a small amount of water dramatically improved the yield
stants (6.69ꢀ102 and 5.08ꢀ102, respectively), which (80%), diastereoselectivity (88:12) and enantioselectiv-
correspond to weak bonding. Thus, the Trost ligand ity (80% ee) (entries 6 and 7). Only a trace amount of
has more binding sites and can generate a stronger the aldol product was detected when dichloromethane
À
[O Ga] bond through the removal of HOTf from the re- was used as solvent under the same reaction conditions
action of OH with Ga(OTf)3. On the other hand, the (entry 8).
complex of ligand 1g (with a pyridine group) with
Subsequently, various aromatic aldehydes were em-
Ga3þ, which generates a N· · ·Ga coordination bond, ployed in the asymmetric aldol reaction in water/etha-
has a slightly lower association constant (3.73ꢀ103). nol (9:1) under the same reaction conditions catalyzed
On the basis of these results, it can be postulated that by the chiral gallium-Lewis acid [Ga(OTf)3/(S,S)-1b].
there is a dynamic equilibrium between the complex In all cases, the reactions provided good yields (77–
and the gallium species as well as the ligand in aqueous 90%), diastereoselectivities (syn/anti¼80/20–90/10)
media. For the complex (S,S)-1b/Ga(OTf)3, the equili- and enantioselectivities of syn-products (78–88% ee)
brium shifted more to the side of forming the chiral (Table 4). The presence of an electron-withdrawing
and reactive catalyst complex, leading to a higher yield group on the phenyl ring of the aldehyde (e.g., Cl) de-
of aldol product and asymmetric induction (Table 1, en- creased the enantioselectivity (entry 4). The effect is
try 2). Whereas, since the complex 1f/Ga(OTf)3 has a more prominent in the case of p-nitrobenzaldehyde
low binding ability (lower value of R) in aqueous media, (3g), generating syn-4g in 62% ee (entry 7). The abso-
the equilibrium shifted towards the side of dissociation, lute configuration of syn-4a and its analogues were de-
generating a gallium species that is inactive in catalyzing termined as 2R,3R by comparing the optical rotation
the aldol reaction and leading to hydrolysis of the silyl of syn-4a ([a]D: À11.5) and syn-4f ([a]D: À101.5) with
enol ether (Table 1, entry 7).
those of the authentic compounds (2S,3S enantiomers:
In view of the above results, the chiral catalyst [(S,S)- [a]D: þ11.7 and þ103.6, respectively).[24] The reaction
1b/Ga(OTf)3] was selected for further studies. The effect of an aliphatic aldehyde (3h) gave a lower ee (30%) (en-
of the reaction solvent on the reaction was also exam- try 8). No reaction was observed with simple ketones
ined (Table 3). Since the complex 1b/Ga(OTf)3 has the under the current conditions.
strongest binding ability in aqueous media, both diaster-
In order to investigate the relationship of the structure
eo- and enantioselectivities remained high with an in- of silyl enol ether with the enantioselectivity, various sil-
crease of the water content in the mixture-solvent and yl enol ethers 6a–e and 2a–h were synthesized and em-
with water alone as the solvent (Table 3, entries 2–5). ployed in aldol reactions with aldehydes (Scheme 2).
However, in water alone the reaction was slow and Since 6a is less stablein water, the yield of the aldol prod-
gave a lower yield of the aldol reaction product. In this uct is low (30%, Table 5, entry 1). The increase of the
Table 3. The reaction of 2a with 3a in various solvents.[a]
Entry
Solvent
Reaction time[b]
Yield of 4a[c] [%] (syn/anti)[d]
ee of syn-4a[e] [%]
1
2
3
4
5
6
7
8
C2H5OH
36 h
36 h
36 h
36 h
3 d
36 h
36 h
3 d
75 (88/12)
89 (89/11)
84 (82/18)
85 (85/15)
41 (90/10)
47 (77/23)
80 (88/12)
trace
58
87
82
85
84
44
80
H2O/C2H5OH (1: 9)
H2O/C2H5OH (1: 1)
H2O/C2H5OH (9: 1)
H2O
THF
H2O/THF (1: 4)
CH2Cl2
[a]
Catalyst: 1b/Ga(OTf)3 (20 mol %).
Reaction temperature: 0–58C.
Yield of isolated product.
Determined by H NMR.
Determined by chiral HPLC.
[b]
[c]
[d]
[e]
1
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Table 4. The reactions of 2a with various aldehydes (3a–h) in aqueous media.[a]
Entry
Aldehyde (R)
Product (R)
Yield of 4[b] [%] (syn/anti)[c]
ee of syn-4[d] [%]
1
85 (85/15)
85
3a
4a
4b
4c
2
3
89 (90/10)
80 (88/12)
88
84
3b
3c
4
5
6
77 (82/18)
90 (90/10)
87 (80/20)
78
86
82
3d
3e
4d
4e
3f
4f
7
82 (77/23)
78 (87/18)
62
30
3g
3h
4g
4h
8
[a]
In H2O/C2H5OH (9: 1), reaction temperature: 0–58C.
[b]
[c]
[d]
Yield of isolated product.
1
Determined by H NMR.
Determined by chiral HPLC.
bulkiness of substituents at the 2-position of the silyl low enantioselectivities of the syn-aldol product in gen-
enol ether affected the stereochemistry of the reaction eral, the reaction of 2h with 3d or 3i gave >90% ee (en-
strongly, and resulted in low enantioselectivities (46– tries 10 and 11). The high enantioselectivity can be at-
59% ee) (Table 5, entries 3–6).
tributed to the hydrophobic p–p stacking between the
However, variation of the aryl group at the 1-position aromatic silyl enol ether and aromatic aldehyde in aque-
of the silyl enol ethers gave very interesting results: ous media.
when 1-(4’-biphenyl)-1-trimethylsiloxy-1-propene (2h)
The silyl enol ethers (9a and 9b) prepared from ali-
was used, the diastereoselectivity of the aldol reaction phatic ketones are generally unstable in aqueous media
is syn/anti¼90:10 and the enantioselectivity of the and undergo hydrolysis readily to form ketones. In the
syn-aldol product (syn-4p) reached up to 95% ee (Ta- current reaction, an excess amount of silyl enol ethers
ble 6, entry 9); although the aldol reaction of aromatic is required (9a or 9b:3a¼3:1) and the yields of aldol
aldehydes bearing an electron-withdrawing group products are also relatively lower (Table 7, entries 1
[such as chloro (3d) and bromo (3i)] gave relatively and 2). The use of these compounds also led to lower
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Scheme 2.
Table 5. The reaction of silyl enol ether 2a, 6a–e with benzaldehyde (3a) in aqueous media.[a]
Entry
Silyl enol ether (R)
Product (R)
Yield of 7[b] [%] (syn/anti)[c]
ee of syn-7 [%][d]
1
30
66
6a
2a
6b
6c
7a
4a
7b
7c
2
3
4
5
89 (89/11)
91 (83/17)
93 (71/29)
88 (82/18)
83 (58/42)
87
46
53
59
51
6d
6e
7d
7e
6
[a]
In H2O/C2H5OH (1: 9), reaction temperature: room temperature.
Yield of isolated product.
Determined by H NMR.
[b]
[c]
[d]
1
Determined by chiral HPLC.
enantioselectivity (71–73% ee) compared with the re- metric reactions of silyl ketene thioacetal with aldehyde
action of aromatic silyl enol ethers with benzaldehyde. gave optically active b-hydroxy thioesters in 78–83% ee
Silylketene acetal 11 is even more unstable and only hy- of the syn-products, which are useful compounds for
drolysis product was isolated after stirring for 24 h. Pre- synthesizing optically pure alcohols. Because silylke-
viously, Kobayashi[14b] reported that the aqueous asym- tene thioacetals are more sensitive to water, 2,6-di-tert-
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Table 6. The reaction of aromatic silyl enol ethers with aldehydes in aqueous media.[a]
Entry
Silyl enol ether
Aldehyde
Product
Yield [%][b] (syn/anti)[c]
ee of syn-4[d] [%]
1
89 (89/11)
87
3a
2a
2b
2c
4a
4i
2
3
85 (88/12)
84 (90/10)
85
82
4j
4
5
6
87 (90/10)
93 (92/8)
87 (90/10)
77
88
86
2d
2e
4k
4l
2f
4m
7
86 (95/5)
88
2g
2h
2h
2h
2h
4n
4o
8
92 (91/9)
88 (90/10)
81 (89/11)
74 (90/10)
94
95
92
91
9
3b
3d
3i
4p
4q
4r
10
11
[a]
In H2O/C2H5OH (1: 9), reaction temperature: room temperature.
Yield of isolated product.
Determined by H NMR.
[b]
[c]
[d]
1
Determined by chiral HPLC.
butylpyridine (30 mol %) must be added in order to sup- the current reaction. By using the Trost ligand/Ga(OTf)3
press the competing hydrolysis reaction effectively. The as chiral catalyst, the reaction of silylketene thioacetal
addition of 2,6-di-tert-butylpyridine is not necessary in 12 with aldehydes in aqueous alcohol (H2O/C2H5
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Table 7. The reaction of silyl substrates with aldehydes in aqueous media.[a]
Entry Silyl substrate Aldehyde
Reaction time[b] [h] Product
Yield[c] [%] (syn/anti)[d] ee of syn-
[%][e]
1
16
66 (90/10)
73
3a
9a
10a
2
16
64 (84/16)
–
71
–
9b
10b
3
24
48
–
11
4
67 (91/9)
64 (99/1)
84
87
12
13a
13b
13c
5
72
72
12
12
3b
3c
6
69 (91/9)
88
7
8
9
72
72
72
70 (83/17)
76 (88/12)
72 (99/1)
80
90
96
12
12
12
3d
3e
13d
13e
3f
13f
[a]
[b]
[c]
[d]
[e]
In H2O/C2H5OH (1: 9).
Reaction temperature: room temperature.
Yield of isolated product.
1
Determined by H NMR.
Determined by chiral HPLC.
OH¼1:9) gave the corresponding aldol products 13a–f tR ¼16.2 (major) and 26.2 min (minor) vs. tR ¼16.2 (ma-
in the reasonable yields 64–76% and high diastereose- jor) and 25.0 min (minor).
lectivities (syn/anti¼83:17 to 99:1) (Scheme 3). When
1-naphthylaldehyde (3f) was used, the enantioselectivi-
ty of the product syn-13f reached 96% ee (entry 9). The Conclusion
configuration of the syn-b-hydroxy thioesters was de-
duced as 2R,3R by comparing the retention time of au- Chiral gallium-Lewis acids with chiral semi-crown li-
thentic compound[14b] with that of syn-13c on chiral gands (Trostꢀs ligand) have been developed for catalytic
HPLC (using the same column: Daicel Chiralcel OD): asymmetric Mukaiyama aldol reactions in aqueous me-
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Aqueous Asymmetric Mukaiyama Aldol Reaction
FULL PAPERS
31.7, 34.0, 55.0, 57.7, 71.4, 78.9, 124.0, 125.9, 126.0, 126.4,
126.6, 127.1, 128.0, 128.2, 128.8, 146.4, 147.0, 152.6; HR-MS
(FAB): m/z¼681.4066, calcd. for C46H52N2O3: 681.4066.
Synthesis of (Z)-Silyl Enol Ethers
To a suspension of sodium hydroxide (114 mg, 6 mmol) in tol-
uene (25 mL), aryl ketone (4 mmol) and trimethylchlorosilane
(0.76 mL, 6 mmol) were added dropwise, followed by refluxing
for 12 h. Upon cooling to room temperature, triethylamine
(0.83 mL, 6 mmol) was added, and the mixture was poured
into a mixture of hexane/ice water. The organic layer was sep-
arated and dried over Na2SO4. After evaporation of solvent,
the crude material was purified by flash chromatography on
silica column (eluent: hexane) to give the product. All the pre-
pared silyl enol ethers have predominantly the (Z)-configura-
tions
Scheme 3.
dia. The strong binding of Ga3þ with the semi-crown li-
gands and the ligand acceleration effect of the chiral gal-
lium catalysts exerted in the aldol reaction are responsi-
ble for the high enantioselectivities of the aqueous
asymmetric reactions. The scope and applications of
such chiral gallium catalysts in asymmetric C C bond-
forming reactions in aqueous media are under further
investigation.
(Z/E¼ >99:1) as determined by 1H NMR.
Aldol Reaction of Silyl Enolate with Aldehydes in the
Presence of a Chiral Catalyst
À
Preparation of the chiral catalyst: Asolution of the chiral ligand
(0.12 mmol) and Ga(OTf)3 (51.7 mg, 0.1 mmol) in methylene
chloride (1 mL) was stirred for 6 h at room temperature. The
solvent was evaporated to give a slightly yellow solid that
was used as the chiral catalyst directly.
Typical experimental procedure for the aldol reaction: Ben-
zaldehyde (3a; 5 mL, 0.5 mmol) and silyl enol ether 2a
(154.5 mg, 0.75 mmol) were added into a solution of the
above-prepared catalyst in a mixed solvent (H2O/C2H5OH¼
1:9) at 0–58C, followed by stirring for 36 h at 08C to room tem-
perature. The reaction was quenched with aqueous NaHCO3.
The mixture was extracted with ether (3ꢀ), 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 ether¼1:10) to give a
mixture of syn- and anti-4a. The syn/anti ratio was determined
by 1H NMR and the ee of syn-4a by chiral HPLC.
Experimental Section
General Remarks
IR spectra were recorded on a Perkin-Elmer 782 infra-red
1
spectrometer. H and 13C NMR spectra were measured with
Varian XL-300 and Bruker DMX-300 (300 MHz) spectrome-
ters in CDCl3 with tetramethylsilane as an internal standard.
Mass spectra were recorded on a Bruker APEX-2 spectrome-
ter using the FBAtechnique. Electrospray ionization mass
spectrometry (ESI-MS) analyses were performed using an
LCMS-2010 mass spectrometer (Shimadzu, JAP). The sample
solution (5 mL) was directly delivered into the ESI source with
a syringe. The mobile phase was C2H5OH:H2O (9:1, v/v).
HPLC spectra were performed on a Shimadzu CTO-
10ASVP equipped with the stated chiral columns. Optical rota-
tion was measured on a Perkin-Elmer 241 (589 nm). The UV-
vis titration was performed on a Techcomp UV-2410 spectrom-
eter. Melting points were measured using a Beijing-Taike X-4
apparatus and are uncorrected. Sample 1i is a gift kindly pro-
vided by Dr. H. Chen of Peking University.
Characterization data of compounds 1, 2, 4, and 13 can be
found in the Supporting Information.
Acknowledgements
This work was supported by the National Natural Science Foun-
dation of China, the Chinese Academy of Sciences and Ministry
of Science and Technology (No. 2002CCA03100).
Synthesis of the Chiral Ligands
Chiral ligands 1b–h were synthesized according to the litera-
ture procedure for the synthesis of (S,S)-1a.[17]
References and Notes
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