Organocatalytic asymmetric syn-aldol reactions of aldehydes with long-chain aliphatic ketones on Water and with dihydroxyacetone in organic solvents

Article abstract of DOI:10.1002/adsc.200800105

An on-water, asymmetric, and direct synaldol reaction of aliphatic ketones with aromatic aldehydes catalyzed by a primary amino acid-based organocatalyst afforded the syn-aldol adducts in high yields with excellent diastereo- and enantioselectivities (up

Full text of DOI:10.1002/adsc.200800105

FULL PAPERS
DOI: 10.1002/adsc.200800105
Organocatalytic Asymmetric syn-Aldol Reactions of Aldehydes
with Long-Chain Aliphatic Ketones on Water and with
Dihydroxyacetone in Organic Solvents
Ming-Kui Zhu,a,c Xiao-Ying Xu,a and Liu-Zhu Gonga,b,*
a
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, Peopleꢀs Republic of China
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science
b
and Technology of China, Hefei 230026, Peopleꢀs Republic of China
Fax : (+86)-551-360-6266; e-mail: gonglz@ustc.edu.cn
Graduate School of Chinese Academy of Sciences, Beijing, Peopleꢀs Republic of China
c
Received: February 15, 2008; Revised: March 23, 2008; Published online: May 16, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An on-water, asymmetric, and direct syn- from the hydrogen bond formed between a pendant
aldol reaction of aliphatic ketones with aromatic al- hydroxy group of surface water molecules at the hy-
dehydes catalyzed by a primary amino acid-based or- drophobic interface with the amide oxygen of the or-
ganocatalyst afforded the syn-aldol adducts in high ganocatalyst, which increases the acidity of the
yields with excellent diastereo- and enantioselectivi- amide NH and thereby strengthens the related hy-
ties (up to > 20/1 dr, >99% ee), and a highly enan- drogen bond formed with the aldehyde.
tioselective syn-aldol reaction of dihydroxyacetone
with a variety of aldehydes in THF proceeded with
14/1 to >20/1 dr and 92 to >99% ee. Water not only Keywords: aldol reaction; aqueous-phase catalysis;
accelerated the reaction, but also enhanced the enan- asymmetric catalysis; carbohydrates; hydrogen
tioselectivity. This positive water effect might arise bonds; organic catalysis
Introduction
and co-workers.[3] Of the diastereo- and enantioselec-
tive organocatalytic direct aldol reactions, anti-selec-
Since the pioneering reports of the proline-catalyzed tive variants have been readily available with impres-
asymmetric direct aldol reaction,[1] numerous organo- sive results by using secondary amine-based organoca-
catalysts have been designed and the stereochemistry talysts.[1,2] Recently, a limited number of syn-selective
of these newer reagents has been significantly im- asymmetric direct aldol reactions catalyzed by a pri-
proved in comparison with the initial organocata- mary amine have been reported.[3,4] Those aldol reac-
lysts.[2] b-Hydroxy carbonyl and polyoxygenated com- tions employing protected dihydroxyacetone as donor
pounds have found widespread applications in organic provided an important pathway to access carbohy-
synthesis. The organocatalytic direct aldol reaction, drates and have also received much attention, leading
which straightforwardly generates b-hydroxy carbonyl to the discovery of some organocatalytic asymmetric
and/or polyoxygenated compounds, has been the sub- procedures with excellent levels of stereoselectivity.[5]
ject of increasing research interest and is viewed as a An even more efficient method for the construction
revolutionary innovation in modern asymmetric orga- of carbohydrates is undoubtedly the direct aldol reac-
nocatalysis.[2] Despite the important advances, some tion of unprotected dihyhydroxyacetone. However,
limitations still exist and await a solution. For exam- these reactions have not been well established until
ple, among these studies, simple ketones such as ace- very recently with a few primary amine-based organo-
tone, cyclohexanone, and cyclopentanone have been catalysts that appeared to afford the direct aldol reac-
most commonly used as aldol donors, while organoca- tion of dihydroxyacetone with aldehydes with high
talytic direct aldol reactions using long-chain aliphatic stereoselectivity.[6] The development of highly stereo-
ketones have been less investigated. Just recently, a selective organocatalysts for direct aldol reactions
single example of an aldol reaction using linear ali- with dihydroxyacetone remains an important goal. In
phatic ketones has been reported by Luo and Cheng this paper, we report a highly enantioselective syn-se-
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Organocatalytic Asymmetric syn-Aldol Reactions of Aldehydes
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Table 1. Optimization of reaction conditions and screening of organocatalysts.[a]
Entry
Solvent
Additive
Catalyst
Time [h]
Yield [%][b]
dr (syn/anti)[c]
ee [%][d]
1
2
3
4
5
6
7
8
none
H2O
none
none
none
4-NO2C6H4CO2H
CH3CO2H
3a
3a
3a
3a
3a
3a
3b
4
48
72
72
36
48
48
60
36
60
60
60
82
81
87
93
35
54
95
90
47
62
35
4/1
6/1
6/1
6/1
6/1
2/1
4/1
6/1
6/1
6/1
4/1
80
91
91
98
80
94
95
96
83
90
77
brine
brine
brine
brine
brine
brine
brine
brine
brine
CF3CO2H
4-NO2C6H4CO2H
4-NO2C6H4CO2H
4-NO2C6H4CO2H
4-NO2C6H4CO2H
4-NO2C6H4CO2H
9
10
11
5a
5b
5c
[a]
The reaction of 2a (0.30 mmol) with 1a (3.0 mmol) in the presence of the organocatalysts 3–5 (0.06 mmol) and additive
(0.06 mmol) at 258C.
[b]
[c]
[d]
Isolated overall yield of syn and anti-diastereomers.
1
Determined by H NMR spectroscopy.
Measured by chiral HPLC.
lective direct aldol reaction of aldehydes with aliphat- zoic acid could apparently enhance both the reaction
ic ketones on water[7] and with 1,3-dihydroxyacetone rate and the enantioselectivity (entry 4). The subse-
in organic solvents, affording excellent levels of ste- quent investigation into the effect of acid additives re-
reoselectivities (up to 7/1 dr, 97% ee for unfunctional- vealed that para-nitrobenzoic acid served as the best
ized aliphatic ketones and 14/1 to >20/1 dr, 92 to additive, which was able to improve the enantioselec-
>99% ee for dihydroxyacetone). The finding that tivity from 91% ee to 98% ee, along with a high con-
water could not only accelerate the reaction, but also version within a comparably short reaction time (en-
enhance the enantioselectivity will also be presented tries 4–6). Under the optimized conditions, organoca-
and clarified.
talysts 3a, b, 4, and 5 were screened for the aldol reac-
tion and 3a was revealed to exhibit the highest level
of enantioselectivity (entries 7–11).
Results and Discussion
In recent years, we have designed a family of organo-
catalysts on the basis of an “enamine double hydro-
gen-bonding activation” strategy, which promote
direct aldol reactions with high stereoselectivities.[8,9]
Of these organocatalysts, primary amino acid-based
organic molecules such as 3a and 3b provided highly
diastereo- and enantioselectivities for syn-aldol reac-
tions of aldehydes with hydroxyacetone.[9] However,
an aldol reaction of meta-nitrobenzaldehyde in neat
3-pentanone catalyzed by 20 mol% of 3a afforded the
syn-product with an unsatisfactory enantioselectivity
of 80% ee, albeit in a high yield (Table 1, entry 1).[9]
Strikingly, the use of water to replace the organic sol-
vent significantly enhanced the enantio- and diaste-
reoselectivities with
a
maintained conversion
The on-water acceleration observed above was
(entry 2).[10] Further improvement was achieved in the more accurately demonstrated by kinetic studies
conversion by performing the reaction on brine[11] (Figure 1). In the presence of 20 mol% 3a and para-
without a deleterious effect on the stereoselectivity nitrobenzoic acid, the model aldol reaction was con-
(entry 3). The presence of 20 mol% of para-nitroben- ducted in neat 3-pentanone, on water, and on brine,
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Figure 1. The effect of reaction solvents on the kinetic parameters of the aldol reaction of 2a with 1a in the presence of 20
mol% of 3a and para-nitrobenzoic acid.
respectively (Figure 1). Surprisingly, a linear correla- However, electron-rich aromatic aldehydes such as
tion between conversion Y (Ca/C0) and reaction time tolualdehydes and anisaldehydes were much less reac-
was observed and indicated a pseudo zero order reac- tive and therefore unable to undergo the aldol reac-
tion that has not previously been observed in organo- tion.
catalyzed aldol reactions. Such a trend suggests that
Aliphatic linear ketones that differ in their length
the rate-determining step in the reaction cycle is not were next examined in reactions with m- and p-nitro-
the addition of enamine to aldehyde that normally benzaldehydes, respectively (Table 3). Interestingly,
leads to a pseudo first order reaction. As butanone the diastereo- and enantioselectivities are independ-
was used in a large excess and the on-water aldol re- ent of the size of the ketone in the reaction using m-
action occurred in “solvent-free” conditions, the con- nitrobenzaldehyde as the aldol acceptor (entries 1–4)
centration of butanone could be considered a constant while in the cases involving p-nitrobenzaldehyde as
in the course of reaction. Thus, the pseudo zero order an aldol acceptor, the enantioselectivity gradually
reaction implied that the formation of enamine from drops as the ketone lengthens and thereby becomes
the catalyst and ketone might be the rate-limiting more hydrophobic (entries 5–8).
step. The water displayed a significant rate enhance-
The success of 3a in catalyzing syn-aldol reactions
ment. Accordingly, the aldol reaction on brine is 5 prompted us to apply the conditions to dihydroxyace-
times faster than that under neat conditions, but has a tone, which would allow an efficient synthesis of car-
comparable rate with that conducted on pure water.
bohydrates.[5] However, no reaction was observed
The optimized conditions were then expanded to under the aqueous conditions, probably because the
the direct aldol reactions of 3-pentanone with a range dihydroxyacetone was dissolved in the aqueous phase
of substituted benzaldehydes (Table 2). As observed and was thereby isolated from the organocatalyst 3a,
previously,[8] the electron-withdrawing substitutent fa- which remained suspended in the water, thus prevent-
cilitated the direct aldol reaction. Accordingly, high ing the formation of the enamine. In contrast, in THF,
yields were obtained with excellent enantioselectivi- the aldol reactions of aromatic aldehydes 2 with 1,3-
ties for aldehydes bearing a highly electron-withdraw- dihydroxyacetone (8) proceeded smoothly under the
ing substituent at the 4-position (entries 1–3). Halo- influence of the combined catalysis of 3a (20 mol%)
gen-substituted benzaldehydes also delivered high and p-nitrobenzoic acid (20 mol%) to afford the syn-
yields and enantioselectivities regardless of either the aldol products in high yields and with excellent ste-
position or number of the substituents (entries 4–11). reoselectivities (Table 4). As Barbas and co-workers
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Organocatalytic Asymmetric syn-Aldol Reactions of Aldehydes
Table 2. syn-Aldol reactions of benzaldehydes with 3-pentanone.[a]
FULL PAPERS
Entry
6
R
Time [h]
Yield [%][b]
dr (syn/anti)[c]
ee [%][d]
1
2
3
4
5
6
7
8
6b
6c
6d
6e
6f
6g
6h
6i
4-NO2C6H4
4-MeO2CC6H4
4-CF3C6H4
2-BrC6H4
2-FC6H4
2-ClC6H4
3-BrC6H4
3-ClC6H4
2,3-Cl2C6H3
2,3,4-F3C6H2
3,4,5-F3C6H2
30
48
48
72
48
72
72
72
48
48
48
98
95
92
81
83
82
98
98
78
83
88
5/1
5/1
3/1
3/1
4/1
4/1
4/1
4/1
4/1
6/1
7/1
95
93
92
95
95
95
94
91
97
84
94
9
10
11
6j
6k
6l
[a]
The reaction of 2 (0.30 mmol) with 1a (3.0 mmol) in the presence of the organocatalysts 3a (0.06 mmol) and para-nitro-
benzoic acid (0.06 mmol) was performed in brine (0.5 mL) at 258C.
[b]
[c]
[d]
Isolated overall yield of syn and anti-diastereomers.
1
Determined by HNMR spectroscopy.
Measured by chiral HPLC.
Table 3. syn-Aldol reactions of m- and p-nitrobenzaldehydes with various aliphatic ketones.[a]
Entry
7
R1
R2
Time [h]
Yield [%][b]
dr (syn/anti)[c]
ee [%][d]
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
CH3
CH2CH3
AHCTREUNG
AHCTREUNG
CH3
CH2CH3
AHCTREUNG
AHCTREUNG
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
48
48
60
60
48
48
60
60
84
86
93
85
81
84
95
92
5/1
5/1
5/1
5/1
5/1
4/1
4/1
4/1
93
94
91
94
92
92
84
73
[a]
The reaction of 2 (0.30 mmol) with 1a (3.0 mmol) in the presence of the organocatalysts 3a (0.06 mmol) and para-nitro-
benzoic acid (0.06 mmol) was performed on brine (0.5 mL) at 258C.
[b]
[c]
[d]
Isolated overall yield of syn and anti-diastereomers.
1
Determined by H NMR spectroscopy.
Measured by chiral HPLC.
did,[6a] we converted the triols into the corresponding steric or electronic features of aldehydes,[6a] 3a provid-
peracetylated compounds 9 by exposure to a mixture ed generally high diastereo- and enantioselectivities
of acetyl anhydride and pyridine for measurement of that seemed less dependent on the substituent of the
the stereoselectivity. Catalyst 3a offered high diaster- benzaldehydes.
eo- and enantioselectivities (14/1 to >20/1 dr, 92 to
>99% ee) for a wide range of aromatic aldehydes
(Table 4), and these values are mostly greater than Transition State Considerations
those obtained from similar reactions catalyzed by
primary amino acids.[6a] Importantly, unlike amino In our previous work,[9] we proposed a transition state
acid catalysis, which commonly provided the aldol ad- for the syn-selective aldol reaction catalyzed by the
ducts with stereoselectivities highly dependent on the primary amino acid-derived amino alcohol amides 3–
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Table 4. syn-Selective aldol reactions of dihydroxyacetone catalyzed by 3a.[a]
Entry
9
R
Time [h]
Yield [%][b]
dr (syn/anti)[c]
ee [%][d]
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
4-NO2C6H4
4-CF3C6H4
4-MeO2CC6H4
4-CNC6H4
4-BrC6H4
3-CF3C6H4
3-NO2C6H4
3-FC6H4
3-BrC6H4
3-ClC6H4
2-NO2C6H4
2-CF3C6H4
2-FC6H4
40
40
72
60
120
48
40
78
75
86
90
81
82
85
83
65
70
90
89
86
72
89
74
14/1
95
96
98
>99
96
98
98
99
92
99
>99
98
94
98
>20/1
>20/1
19/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
17/1
>20/1
>20/1
>20/1
>20/1
>20/1
60
9
108
120
60
72
48
108
72
96
10
11
12
13
14
15
16
2-BrC6H4
2,3-Cl2C6H3
1-BrC10H6
98
99
[a]
The reaction of 2 (0.30 mmol) with dihydroxyacetone (0.6 mmol) in the presence of the organocatalyst 3a (0.06 mmol)
and 4-nitrobenzoic acid (0.06 mmol) in THF was performed at room temperature.
Overall yield of syn and anti.
Determined by H NMR spectroscopy.
Measured by chiral HPLC.
[b]
[c]
[d]
1
5 in an organic solvent, in which the aldehyde was ac-
tivated by double hydrogen bonds formed with the
amide and the hydroxy group of the organocatalyst.
Basically, water breaks the hydrogen bond required
for activation of the substrates. As neither the reac-
tants nor the organocatalyst is soluble in the water,
we surmised that the organocatalytic aldol reaction
might take place in a concentrated organic phase en-
vironment, suspended in the water. The hydrophobic
substituents of the organocatalyst 3a surrounding the
hydrogen-bonding site and the enamine may provide
a protective environment for the enamine and the hy-
drogen bonds that activate the aldehyde, thereby se-
questering them from water. Thus, a transition state
similar to that proposed for the syn-aldol reaction in
organic solvent is still possible, that is, the Z-enamine
and double hydrogen bonds exist in the transition and the double hydrogen bonds that are critical to the
state of the on-water aldol reaction.[11] To further catalysis are not interrupted either by water or by the
demonstrate the possibility of the double hydrogen carboxylic acid additive.
bonds used for the activation of the aldehyde, we in-
The fact that the most concentrated reaction,
vestigated the model reaction [Eq. (1)] in the pres- namely a neat reaction, proceeded more slowly and
ence of 20 mol% of organocatalyst 10, which differs afforded much less enantioselective syn-aldol adduct
from 3a by the absence of one hydrogen donor. How- than the on-water reactions implied that water partici-
ever, very little conversion (<5%) was observed by pates in the control of enantioselectivity of the on-
1H NMR measurement after the reaction was con- water aldol reaction. However, the experimental ob-
ducted for 48 h. This result clearly showed that the servation that the compound 10 is unable to catalyze
hydroxy formed hydrogen bond with the aldehyde the aldol reaction indicated that water and the car-
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boxylic acid additive have very little effect on the lized by a hydrogen bond, which favors transition
transition state. The conflict between the conclusions state TS-2b over TS-2a, and leads to the predominant
drawn from these experiments leads to an interesting formation of syn-aldol adducts.
and important question: how does the water influence
the 3a-catalyzed on-water aldol reaction? Elegant
studies on the hydrophobic surface structure of Conclusions
water[12] and on the on-water organic reactions[13]
have shown that the dangling hydroxy groups of sur- We have disclosed an on-water, organocatalytic syn-
face molecules at the hydrophobic interface can hy- aldol reaction of acyclic aliphatic ketones with aro-
drogen bond with the carbonyl of the reactants of the matic aldehydes, providing highly diastereo- and
on-water reactions.[13a] In the 3a-catalyzed aldol reac- enantioselectivities. The aldol reaction on-water pro-
tion, the dangling OH might form a hydrogen bond vided much higher enantioselectivity than the reac-
with the amide oxygen, but not with either NH or tion conducted in organic solvents. The enhancement
OH of the catalyst due to the hydrophobic substitu- of water in the enantioselectivity might stem from the
ents, leading to TS-1b, which differs from TS-1a in hydrogen bond formed between a dangling hydroxy
that the syn-aldol reaction proceeds in the organic group of surface water molecules at the hydrophobic
phase by forming an additional hydrogen bond with interface with the amide oxygen of the organocatalyst,
water (Figure 2). In this transition state, the hydrogen which increases the acidity of the amide NH and
thereby strengthens the related hydrogen bond
formed with the aldehyde. In organic solvents, syn-
aldol reactions of dihydroxyacetone with aldehydes
afforded triols with 14/1–>20/1 dr and 92–99% ee.
Experimental Section
General Procedure for the Aldol Reaction on-Water
After a suspension of an aldehyde (0.3 mmol), catalyst 3a
(20 mol%), 4-nitrobenzoic acid (20 mol%), and a ketone
(3 mmol) in brine (0.5 mL) had been stirred at room tem-
perature for 30–120 h, the reaction was quenched with satu-
rated aqueous ammonium chloride. The aqueous layer was
extracted with ethyl acetate (3”15 mL). The combined or-
Figure 2. Rationale for the effect of water on the enantiose-
lectivity.
ganic layers were washed with brine (1”10 mL) and dried
over anhydrous Na2SO4. After removal of the solvent under
the reduced pressure, the residue was purified by flash
column chromatography on silica gel to give the desired
aldol product.
bond between the dangling OH and the amide oxy-
gen[8e] makes the NH of amide group more acidic and
thereby strengthens the hydrogen bond formed be-
tween the NH and the aldehyde. The stronger hydro-
gen bond is able to improve both the catalytic effi-
ciency and the enantioselectivity, as we indicated pre-
viously.[8b,c]
General Procedure for the Aldol Reaction of
The plausible transition state shown in Figure 3
could explain the highly stereoselective syn-aldol re-
action of dihydroxyacetone with aldehydes in THF.
The aldehyde was activated by double hydrogen
bonds formed with NH and OH of the catalyst on the
basis of the previous studies.[8,9] As Barbas and co-
workers indicated,[6a] the Z-enamine in TS-2b is stabi-
Dihydroxyacetone with Aldehydes Catalyzed by 3a
To a solution of aldehyde (0.3 mmol) in anhydrous THF
(1.0 mL) was added dihydroxyacetone dimer (0.3 mmol) fol-
lowed by catalyst 3a (0.06 mmol), and 4-nitrobenzoic acid
(0.06 mmol) at room temperature. The reaction solution was
stirred at room temperature until the aldehyde was con-
sumed (monitored by TLC). The mixture was purified (with-
Figure 3. Proposed transition state of the syn-aldol reaction of dihydroxyacetone with aldehydes.
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Ming-Kui Zhu et al.
FULL PAPERS
out work-up) through flash column chromatography (mix-
tures of hexanes/ethyl acetate) to give the aldol product.
The resultant aldol product was dissolved in anhydrous
CH2Cl2 (2 mL) and pyridine (0.5 mL) and acetic anhydride
(0.3 mL) were added to the solution at room temperature.
After stirring for 4 h at the same temperature, the mixture
was diluted with CH2Cl2 (2 mL) and washed with 1N HCl.
The aqueous layer was extracted with CH2Cl2. The organic
layers were combined, washed with saturated NaHCO3 and
brine, and dried over Na2SO4. After concentration under re-
duced pressure, the residue was purified by flash column
chromatography on silica gel to give the acetylated aldol
product.
1738; c) P. Diner, M. Amedjkouh, Org. Biomol. Chem.
2006, 4, 2091; d) N. Utsumi, M. Imai, F. Tanaka, S. S. V.
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[5] For an excellent review, see: M. Markert, R. Mahrwald,
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[6] a) S. S. V. Ramasastry, K. Albertshofer, N. Utsumi, F.
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Li, J.-P. Cheng, Org. Lett. 2008, 10, 653.
[7] For the concept of the “on-water” reaction, see: S. Nar-
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K. B. Sharpless, Angew. Chem. 2005, 117, 3339; Angew.
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Supporting Information
Experimental details and characterization data of new com-
pounds are given in the Supporting Information.
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Acknowledgements
We are grateful for financial support from the National Natu-
ral Science Foundation of China (grants 20732006 and
20325211) and CAS.
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