Effect of long chain fatty acids on organocatalytic aqueous direct aldol reactions

Article abstract of DOI:10.1002/adsc.200900572

In an organocatalyzed, aqueous direct aldol reaction, the addition of a long chain fatty acid (1 mol%) such as stearic acid or erucic acid improved the aldol product yield and the enantioselectivity with low catalyst loading (1 mol%). The small particle s

Full text of DOI:10.1002/adsc.200900572

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DOI: 10.1002/adsc.200900572
Effect of Long Chain Fatty Acids on Organocatalytic Aqueous
Direct Aldol Reactions
Nobuyuki Mase,a,* Naoyasu Noshiro,a Asuka Mokuya,a and Kunihiko Takabea
a
Department of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu 432-8561,
Japan
Fax : (+81)-53-478-1196; e-mail: tnmase@ipc.shizuoka.ac.jp
Received: August 17, 2009; Revised: October 15, 2009; Published online: November 18, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900572.
Abstract: In an organocatalyzed, aqueous direct
aldol reaction, the addition of a long chain fatty
acid (1 mol%) such as stearic acid or erucic acid im-
proved the aldol product yield and the enantioselec-
tivity with low catalyst loading (1 mol%). The small
particle size of the emulsion (less than 1 mm) was a
key to the enhanced reactivity as shown by dynamic
light scattering (DLS) analyses.
emulsible natural compounds has been used to direct
the synthesis of novel and useful surfactants.[2]
In general, surfactant and catalyst are separately
added to the reaction mixture; however, Kobayashi
and co-workers reported an interesting “Lewis acid-
surfactant combined catalyst” named LASC in
1998.[3,4] Aldol reactions of silyl enol ethers with alde-
hydes proceeded smoothly in water in the presence of
LASCs. Recently we designed the artificial aldolase-
surfactant hybrid catalyst 3 (Figure 2) and developed
direct asymmetric cross-aldol reactions that can be
performed in bulk water without addition of organic
co-solvents. The hybrid catalyst 3 afforded the desired
aldol products in excellent yields with high enantio-
meric excesses, even when only an equal molar ratio
Keywords: aldol reaction; enantioselectivity; fatty
acids; organocatalysis; water
In living organisms, organic reactions and inorganic of the donor and acceptor was used; however,
reactions take place in an aqueous medium, whereas 10 mol% catalyst loading was required.[5,6,7] Here we
most modern organic syntheses are performed in or- report efficient, enamine-based, organocatalytic direct
ganic solvents. In aqueous environments, emulsible asymmetric aldol reactions in water with low catalyst
compounds such as bile acids (Figure 1) are required loading (1 mol%) by addition of long chain fatty acids
to facilitate organic reactions of hydrophobic organic to the reaction.
substrates. Water has advantages over organic sol-
Our artificial hybrid organocatalyst 3 formed an
vents, including cost, safety, synthetic efficiency, emulsion with the organic substrate in water and the
simple operation, environmental benefits, and new aldol reaction occurred smoothly. The catalyst 3 plays
synthetic methodologies.[1] Therefore, modeling of an important role as not only a surfactant but also a
Figure 1. Bile acids in living organisms.
Figure 2. Various organocatalysts.
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Table 1. Organocatalyzed aqueous direct aldol reactions in the presence of various surfactants.[a]
Entry
Catalyst (mol%)[b]
Surfactant
Yield [%]
anti/syn[c]
ee [%][d]
1
3 (10)
3 (1)
3 (1)
3 (1)
3 (1)
3 (1)
3 (1)
3 (1)
3 (1)
3 (1)
3 (1)
4 (1)
5 (1)
6 (1)
7 (1)
none
none
none
SDS
DODAC
TOMAC
Triton X-100
monostearin
1a
99
54
0
89/11
89/11
–
94
90
–
2
3[e]
4
54
53
62
56
47
64
61
82
0
90/10
86/14
88/12
90/10
91/9
92/8
89/11
89/11
–
90
73
71
78
84
91
94
93
–
5
6
7
8
9
10
11
12[f]
13[f]
14[f]
15[g]
2a
Stearic acid
Stearic acid
Stearic acid
Stearic acid
Stearic acid
0
52
98
–
–
81
11
88/12
67/33
[a]
Conditions: amine catalyst (0.05 mmol, 1 mol%), surfactant (0.05 mmol, 1 mol%), 8a (10 mmol), and 9a (5 mmol) in
water (5 mL).
Catalyst structures are shown in Figure 2.
Determined by H NMR of the crude product.
Determined by chiral-phase HPLC analysis for anti-product.
The reaction was carried out in DMSO.
Reactions were carried out for 72 h.
[b]
[c]
[d]
[e]
[f]
1
[g]
The reaction was carried out for 48 h.
catalyst. Therefore,
a
significant amount of
3
10a was obtained in 82% chemical yield with high di-
(10 mol%) was needed (Table 1, entry 1). Decreasing astereo- and enantioselectivities after 24 h in the pres-
the amount of catalyst 3 to 1 mol% resulted in low ence of 1 mol% stearic acid when hybrid organocata-
chemical yield but with high stereoselectivity lyst 3 was used (entry 11). Under these conditions, di-
(entry 2). In addition, no formation of the aldol 10a amine catalyst 4 and l-proline 5 did not give the aldol
was observed in a conventional organic solvent such 3 after 72 h (entries 12 and 13). Tetrazole catalyst 6
as DMSO (entry 3). To reduce catalyst usage, various afforded the aldol 10a in moderate yield with good
surfactants were evaluated. Sodium dodecyl sulphate enantioselectivity (entry 14). High yield of the aldol
(SDS, 1 mol%) is known as an efficient surfactant,[8] 10a was observed in the presence of l-prolinol 7, but
but addition of SDS did not improve the yield stereoselectivities were very low (entry 15).
(entry 4). Cationic surfactants such as dioctadecyldi-
The scope of this class of aldol reactions using
methylammonium chloride (DODAC) and trioctylme- hybrid organocatalyst 3 in water was examined with a
thylammonium chloride (TOMAC) provided better series of various carboxylic acids (Table 2). Stearic
chemical yields but decreased the stereoselectivities acid enhanced reactivity more than other carboxylic
(entry 5 and 6). In the presence of amphiphilic neutral acids tested (entry 12). In the presence of acetic acid,
surfactants, such as Triton X-100 and monostearin, reactivity and stereoselectivities were almost un-
chemical yields and stereoselectivities were low (en- changed in comparison with the reaction without car-
tries 7 and 8). We found that natural bile acids such boxylic acid (entry 1 vs. 2). Similarly, butyric acid did
as cholic acid (1a) and deoxycholic acid (2a) im- not affect the reactivity (entry 3). Carboxylic acids
proved the chemical yields up to 64% and excellent (C6 to C16) showed increased yields relative to the re-
stereoselectivities were maintained (entries 9 and 10). action without carboxylic acid (entries 4–10). Erucic
Natural bile acids are carboxylic acid derivatives acid, which is a monounsaturated fatty acid present in
bearing a hydrophobic steroid skeleton; therefore, seeds such as rapeseed and wallflower seed, gave the
simple long chain fatty acids should serve as effective aldol 10a in 81% yield with 89% ee (entry 14). Pro-
surfactants. As we expected, the desired aldol product longed reaction times afforded the aldol 10a in over
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Effect of Long Chain Fatty Acids on Organocatalytic Aqueous Aldol Reactions
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Table 2. Effect of various carboxylic acids in organocatalyzed aqueous direct aldol reactions.[a]
Entry
RCO2H
Yield [%]
anti/syn[b]
ee [%][c]
1
2
3
4
5
6
7
8
None
54
55
60
71
57
68
63
75
71
73
72
82
91
81
92
66
64
89/11
91/9
92/8
92/8
92/8
91/9
92/8
91/9
91/9
91/9
91/9
89/11
86/14
91/9
91/9
87/13
79/21
90
86
89
91
89
91
90
94
85
91
90
93
85
89
90
83
85
Acetic acid (C2)
Butyric acid (C4)
Hexanoic acid (C6)
Benzoic acid (C7)
Caprylic acid (C8)
Decanoic acid (C10)
Lauric acid (C12)
Myristic acid (C14)
Palmitic acid (C16)
Oleic acid (C18)
Stearic acid (C18)
Stearic acid (C18)
Erucic acid (C22)
Erucic acid (C22)
Decane (C10)
9
10
11
12
13[d]
14
15[d]
16
17
Eicosane (C20)
[a,b,c] See footnotes in Table 1.
[d]
The reaction was carried out for 48 h.
90% yield (entries 13 and 15). In order to confirm the ence of the most closely related fatty acids (entries 16
effect of the carboxylic acid functionality, long-chain and 17 vs. entries 12 and 14).
hydrocarbons such as decane and eicosane were ex-
The scope of this class of aldol reactions using the
amined. Chemical yields in the presence of long-chain catalyst 3 (1 mol%) in the presence of stearic acid
hydrocarbons were slightly better than that in the ab- (1 mol%) in water was examined with a series of aryl-
sence of the additive (entries 16 and 17 vs. entry 1),
ACHTUNGTRENaNUNG ldehyde acceptors 9 and ketone donors 8 (Table 3).
however, significantly lower than those in the pres- Although aldol reactions in the absence of stearic
acid afforded the aldol products in 0–54% yields,[9] in
Table 3. Aqueous direct aldol reactions of donors 8 with acceptors 9.[a]
Entry
R1
R2
-(CH2)4-
R3
Product
Time [h]
Yield [%]
anti/syn[b]
ee [%][c]
1
2
3
4
5
6
7
8
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CNC6H4
4-CO2MeC6H4
4-BrC6H4
4-ClC6H4
10a
10b
10c
10d
10e
10f
10g
10h
10i
48
48
48
96
96
96
96
96
48
96
96
91
90
75
96
65
30
44
12
99
28
93
86/14
88/12
89/11
86/14
87/13
82/18
83/17
79/21
51/49
48/52
–
85
92
94
82
85
78
82
79
70
71
38
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)3-
-(CH2)5-
Ph
9
10
11
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
10j
10k
Me
H
[a,b,c] See footnotes in Table 1.
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most cases, reactions afforded anti-aldol products 10
in reasonable yields (entries 1–8). Reactions with cy-
clopentanone (8b) afforded
a quantitative yield
(entry 9), while a low yield was observed in the reac-
tion with the less reactive cycloheptanone donor
(entry 10). The reaction of acyclic acetone donor
yielded the aldol product 10k in 93% yield with 38%
ee (entry 11).[10] These tendencies of reactivity corre-
spond with the previous data in the presence of the
catalyst 3 (10 mol%).[5]
Due to hydrophobic interactions, the liquid organic
donor 8a forms an emulsion with the catalyst 3 and
fatty acid in water. Aggregation of the organic mole-
cules excludes water from the organic phase and
drives the equilibrium toward enamine formation.
The enamine intermediate 11 is more hydrophobic
than catalyst 3, therefore the enamine intermediate
moves into organic phase from the liquid-liquid inter-
face. Carbon-carbon bond formation between the en-
amine intermediate and the aldehyde acceptor 9
occurs quickly in this highly concentrated organic
phase through a transition state 12 similar to that ob-
served in organic solvents,[11] before hydrolysis of the
enamine intermediate proceeds.
Figure 3. Proposed mechanism for organocatalyzed aqueous
direct aldol reaction.
Although the mechanism through which the fatty
acids improve yields and stereoselectivities is presum-
ably complex, we assume that the long chain fatty
acid plays two roles. One is acceleration of enamine
intermediate formation and the other is stabilization
of the emulsion. It is well known that enamine forma-
tion is effectively catalyzed by acids; indeed previous-
ly we reported that addition of carboxylic acid accel-
erates the formation of enamine intermediate derived
from isobutyraldehyde and pyrrolidine.[12] The pro-
posed mechanism for the direct aldol reaction cata-
lyzed by 3 in water in the presence of fatty acid is
shown in Figure 3.[13]
In order to confirm the properties of the emulsion,
dynamic light scattering (DLS) measurements were
performed (Figure 4).[14] A narrow distribution of di-
ameter was observed in the emulsion of water and
the donor 8a in the presence of 10 mol% catalyst 3;
the average cumulant diameter was 195 nm. This
emulsion was stable, since diameter did not signifi-
Figure 4. Dynamic light scattering (DLS) histogram analyses
of emulsions. Prior to analysis, a mixture of catalyst 3, car-
boxylic acid, water (0.5 mL), and 8a (0.1 mL) was vigorously
stirred for 10 min.
cantly change over 30 min without stirring (Figure 5). for the aqueous direct aldol reaction even when only
In contrast, a broad distribution of diameter was ob- 1 mol% of catalyst 3 was used.
served in the presence of 1 mol% catalyst 3 with an
In summary, we have shown that yields and stereo-
average cumulant diameter of 1,307 nm. Similarly, in selectivity of organocatalyzed aqueous direct asym-
the presence of 1 mol% acetic acid, a broad distribu- metric aldol reactions are enhanced by addition of
tion and a large average diameter were observed. Ad- long chain fatty acids. At 1 mol%, a long chain fatty
dition of stearic acid (1 mol%) changed these proper- acid improved reactivity at low catalyst loading
ties. The particle size distribution shifted to an aver- (1 mol%). The small particle size of the emulsion
age diameter of 600 nm. In addition, the particle sta- (less than 1 mm, as shown by DLS) was a key to the
bility was higher in the presence of stearic acid than enhanced reactivity. Further studies focusing on the
that without (Figure 5). These observations support full scope of this catalyst-aqueous media system and
our hypothesis that the emulsion is stabilized with related systems are currently under investigation and
1 mol% of long chain fatty acid providing good yields will be reported in due course.
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Effect of Long Chain Fatty Acids on Organocatalytic Aqueous Aldol Reactions
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80:20, flow rate 0.5 mLminÀ1, l=254 nm): tR =24.892 (syn
minor), 27.792 (syn major), 30.275 (anti, 2R,1’S), 39.300
(anti, 2S,1’R).
Acknowledgements
We gratefully acknowledge Dr. C. F. Barbas, III for a scientif-
ic discussion. We also wish to thank H. Suzuki and A. Sugita
for DLS and microscopy analyses. This study was supported
in part by a Grant-in-Aid from Scientific Research from the
Japan Society for the Promotion of Science and SHISEIDO
Grant for Science Research.
Figure 5. Time course of average cumulant diameter of the
emulsion. Samples were not stirred during the time course
of the analysis.
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Typical Procedure for the Aqueous Direct Aldol
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1
(hexane:ethyl acetate=70:30); H NMR (CDCl3, 300 MHz):
d=1.20–1.95 (m, 5H), 2.05–2.20 (m, 1H), 2.26–2.72 (m,
3H), 3.23 (d, J=2.4 Hz, 1H, syn-OH), 4.10 (brs, 1H, anti-
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1
[13] The enamine could not be detected by H NMR under
conditions of emulsion formation. However, the car-
boxylic acid functionality should affect the reactivity, as
even short chain carboxylic acid such as butyric acid
(C4) and hexanoic acid (C6) improve chemical yields.
[14] Optical micrograph analyses of emulsions were also
performed; however, clear differences were not ob-
served among investigated reaction conditions. See
Supporting Information.
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