Aqueous solutions of facial amphiphilic carbohydrates as sustainable media for organocatalyzed direct aldol reactions

Article abstract of DOI:10.1039/c1gc16326d

The organocatalyzed direct aldol reaction was efficiently performed in aqueous solutions of facial amphiphilic carbohydrates with high diastereoselectivity and yield. Such sustainable media in addition with the use of 2% catalyst loading paves the way for

Full text of DOI:10.1039/c1gc16326d

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Volume 14 | Number 2 | February 2012 | Pages 235–530
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COVER ARTICLE
Daniellou and Plusquellec et al.
Aqueous solutions of facial amphiphilic carbohydrates as sustainable
media for organocatalyzed direct aldol reactions

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COMMUNICATION
Aqueous solutions of facial amphiphilic carbohydrates as sustainable media
for organocatalyzed direct aldol reactions†
Ana Bellomo,a,b Richard Daniellou*‡a,b and Daniel Plusquellec*a,b
Received 25th October 2011, Accepted 17th November 2011
DOI: 10.1039/c1gc16326d
The organocatalyzed direct aldol reaction was efficiently
performed in aqueous solutions of facial amphiphilic car-
bohydrates with high diastereoselectivity and yield. Such
sustainable media in addition with the use of 2% catalyst
loading paves the way for the development of original
ecofriendly procedures through non-covalent induction.
a hydrophilic face and a hydrophobic region (Fig. 1), have
already demonstrated their potency in selectively promoting
reductions, epoxidations and indium-promoted allylations.7
Faster reactions as well as better solubility of the organic
reactants were also observed. Thus, such original media may
constitute alternative solvents for the development of sustainable
chemistry.
Introduction
The aldol reaction is one of the most powerful methods of
forming carbon–carbon bonds and has tremendous synthetic
applications.1 Biological systems have perfected this stereospe-
cific transformation by using enzymes: type I aldolases function
via the formation of an enamine intermediate with a lysine
residue whereas type II aldolases activate substrates by forming
a zinc enolate. Despite their lack of large-scale compatibility
and their narrow substrate specificity, aldolases represent a
great source of inspiration for the development of catalysts. For
example, catalytic antibodies have already been demonstrated
to be useful tools in organic chemistry.2 Seminal works of List,
Lerner and Barbas have also proved that small molecules like
L-proline are able to act as enamine-based aldol catalysts whose
simplicity contrast with the complex machinery of enzymes.3
However, even if these asymmetric reactions are efficiently
performed using both metal- and organocatalysts in organic
solvents, similar transformations in water generally require the
use of additives or co-solvents, or are just impossible to perform.4
As an alternative to the de novo design of water-compatible
catalysts,5 we wish to develop environmentally friendly, efficient
and stereoselective protocols based on aqueous solutions of sus-
tainable natural products. Especially, inexpensive carbohydrates
like sucrose 1 or alkyl b-D-fructopyranosides 26 exhibiting facial
amphiphilic characters, i.e. their pyranoside ring displaying both
Fig. 1 Structure and hydrophobic areas of facial amphiphilic carbohy-
drates 1–2.
Herein we wish to report our findings concerning the mild
and stereoselective direct aldol reaction of cyclic ketones in
aqueous carbohydrate solutions. Small organic catalysts were
selected considering the formation of an enamine intermediate,
resembling the mechanistic pathway followed by L-proline and
its analogues.8 It is noteworthy that as previous experiments
have shown the low potency of carbohydrates to orientate
cyclic ketones in water,7c we envisioned that sugars may still
be involved in the transition state, diminishing contacts with
bulk water9 and allowing the orientation of the assumed
enamine-incoming aldehyde intermediate, thus influencing the
stereochemical outcome of the reaction.
aEcole Nationale Supe´rieure de Chimie de Rennes, CNRS, UMR 6226,
Avenue du Ge´ne´ral Leclerc, CS 50837, 35708, Rennes Cedex 7, France.
E-mail: richard.daniellou@univ-orleans.fr, daniel.plusquellec@ensc-
rennes.fr; Fax: (+)33-2-23-23-80-46;
Results and discussion
The direct aldol reaction of cyclohexanone (5 equiv.) and m-
nitrobenzaldehyde (1 equiv.) in 1 M aqueous solution of ethyl
b-D-fructopyranoside 2b was chosen as a model (Table 1).
Initial screenings were focused on the catalytic efficiency of
commercially available bases and their influence on the diastere-
oselectivity. Furthermore, fixed catalyst loadings of 2 mol%
Tel: (+)33-2-23-23-80-96
bUniversite´ Europe´enne de Bretagne,
† Electronic supplementary information (ESI) available: See DOI:
10.1039/c1gc16326d
‡ Present address: ICOA–Universite´ d’Orle´ans–CNRS UMR 6005, rue
de Chartres, BP 6759, 45067 Orle´ans cedex 2, France.
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The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 281–284 | 281
©

Table 1 Screening of organocatalysts for the direct aldol reaction of cyclohexanone
Entry
1
Organocatalyst
Additive
—
Time (h)
96
Yield (%)a
anti/syn
eeb (%)
No reaction
—
—
2
3
—
2b
36
36
90
87
1.1 : 1
1.4 : 1
<5
<5
4
5
—
2b
1.5
1.0
85
86
1 : 1.3
1.9 : 1
<5
<5
6
7
—
2b
72
72
77
65
3 : 1
2.6 : 1
<5
<5
8
9
—
2b
2.5
1.5
88
73
3 : 1
9 : 1
<5
<5
10
11
12
—
2b
1
4
3
2.5
90
91
88
3 : 1
13.3 : 1
7.3 : 1
<5
<5
<5
a Combined yield of isolated diastereoisomers. b Determined through 1H NMR experiments in the presence of Eu.
were used. As expected, L-proline was completely inefficient
for catalysing aldolisation in water (entry 1).10 Ethanolamine,
a mimic of the lysine side chain, afforded compound 3 in
nearly 90% yield (entries 2–3) but with long reaction times and
expected poor selectivities. The use of pyrrolidine as catalyst
showed better results (entries 4–5), enabling the completion
of the reaction in about 1 h. For the first time, 2b was able
to influence significantly the syn/anti ratio, which increased
to 1.9 : 1. L-Prolinol (entries 6–7) exhibited low reactivity and
similar 3 : 1 diastereoselectivities whether the sugar additive was
present or not. The existence of steric hindrance at position
2 of the pyrrolidine, thus slowing down the formation of the
enamine intermediate, easily explained these observations. 3-
Hydroxy-pyrrolidine systems showed improved catalytic effects
(entries 8–12). rac-3-Pyrrolidinol was a good catalyst (entries
8–9) generating the aldol product 3 in around 2 h and good
yields. In this case, the presence of 2b unambiguously influenced
the stereochemical outcome of the reaction as the anti/syn ratio
was increased three times (entry 9 compared to 8). The system
(R)-3-pyrrolidinol/2b was the best as compound 3 was obtained
in 91% yield, after just 3 h of reaction and with the best 13.3 : 1
observed diastereoselectivity (entry 11), 4.4 times greater than
without the sugar additive. Under these conditions, we were
able to decrease the amount of cyclohexanone to 1.5 equiv.
without compromising the yield and reaction time (87%, 3.5 h).
Sucrose, a naturally occurring raw material, rendered 3 in
short time and 88% yield but, with an anti/syn ratio of 7.3 : 1,
demonstrating a slightly lower impact on diastereoselectivity
(entry 12). Finally, it is also noteworthy that the racemic or
enantiopure pyrrolidinol as well as the other organocatalysts
tested in this study demonstrated no effect on the enantiose-
lectivity. Still, our results clearly showed that the presence of a
polar substituent on the pyrrolidine was crucial i) to generate
sufficient facial amphiphilicity in the enamine intermediate, ii)
to favour its orientation in the media, and iii) to increase the
diastereoselectivity.
The scope of the organocatalytic system was then evaluated
with racemic cyclohexanones. As depicted in Table 2, the current
method allowed us to obtain aldol products 4–7 via the forma-
tion of the less substituted or sterically encumbered enamine.
Substituted ketone at position 2 (entries 1–2) rendered 4 with low
yields and no selectivity, due to its poor reactivity as emphasized
by the recovery of 30% of unreacted aldehyde and the long
◦
reaction times, even at 65 C. 3- And 4-methylcyclohexanones
were also able to serve as donors (entries 3–6) leading to
compounds 5 and 6 in around 90% yields. Moreover, it is of
utmost interest that in the presence of 2b, faster reactions as
well as better diastereoselectivities up to 5 : 1 were also observed
(entry 4 compared to 3 and 6 to 5). Finally, the 2,2-dimethyl-
(S)-3-hydroxy-cyclohexanone despite good yields showed no
improvement on the ratio of the anti/syn aldol product 7 (entry
8 compared to 7). However, in these latter cases, a temperature
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Table 2 Organocatalyzed direct aldol reaction of substituted cyclohexanones in water
Entry
R1
Product
Additive
Time (h)
Yield (%)a
anti/syn
eec (%)
1
2
3
4
5
6
7
8
2-OMeb
4
5
6
7
—
2b
—
2b
—
2b
—
2b
72
72
18
12
24
6
55
30
93
95
82
90
75
93
1.1 : 1
1 : 1.1
1.3 : 1
5.7 : 1
1.4 : 1
4.3 : 1
1 : 1.3
1 : 1.3
<5
<5
<5
<5
<5
<5
<5
<5
3-Me
4-Me
2,2-Me-(S)-3-OHb
24
18
a Combined yield of isolated diastereoisomers. b Reactions performed at 65 ◦C. c Determined by 1H NMR experiments in the presence of Eu.
Table 3 Influence of the carbohydrate
Entry
Additive
Time (h)
Yield (%)a
anti/syn
anti ratio
syn ratio
1
2
3
4
5
2a
2b
2c
2d
2e
20
6
10
18
8
50
90
70
90
84
2.6 : 1
4.3 : 1
2.7 : 1
1.9 : 1
4 : 1
4.9 : 1
9 : 1
7.3 : 1
4 : 1
1 : 2.6
nd
nd
1 : 2.7
1 : 2.1
5.7 : 1
a Combined yield of isolated diastereoisomers.
of 65 ◦C was needed for the reaction to occur. Once again,
these results demonstrated that the reaction is very sensitive to
hindered substrates at position 2, which might slow down the
formation of the enamine intermediate.
The rationalization of the observed selectivity in correlation
with the type of glycosidic chains is tenuous but might be the
consequence of hydrophobic interactions in the transition state.
1H NMR experiments were performed in order to demonstrate
the presence of these latter (see ESI†). The addition of increased
amounts of cyclohexanone to the allyl sugar derivative 2d caused
a significant perturbation of the signals corresponding to the
allyl group that was more pronounced in the presence of the
catalyst. Thus, the facial amphiphilic carbohydrate seems to
interact more with the transient enamine-incoming aldehyde
intermediate (Fig. 2) and favour the anti aldol product.
Finally, we turned our attention to the study of the influence
of the nature of the sugar additive on the aldolisation using 4-
methyl-cyclohexanone (Table 3). Interestingly, all of them were
able to induce diastereoselectivity but at different levels. As
expected, methyl b-D-fructopyranoside 2a (entry 1), displaying
the lowest facial amphiphilicity, was found to form 6 in only
moderate yield as well as long reaction time. The best result was
obtained in the presence of 2b (entry 2) with 90% of yield in
6 h and an anti/syn ratio of 4.3 : 1. The n-pentenyl derivative 2e
(entry 5) showed similar properties with a ratio of 4 : 1 for the anti
aldol products. The reaction with propyl derivative 2c and allyl
sugar additive 2d (entries 3 and 4) proceeded with satisfactory
yields but with decreased diastereoselectivity. In addition, in all
cases, syn ratios of diastereoisomers were similar as opposed to
anti ratios for which diastereoselectivity depends on the sugar
additive and follows the same trend as for the syn/anti ratio (two
last columns in Table 3). Finally, it should be pointed that higher
yields and improved anti/syn ratio were obtained with respect
to the decrease in reaction time.
Conclusion
In summary, the direct aldol reaction of m-nitrobenzaldehyde
with various cyclohexanones has been accomplished by
organocatalysis, using only 2 mol% of (R)-3-pyrrolidinol in
aqueous solutions of alkyl b-D-fructopyranosides with excellent
yields, short reaction times and improved diastereoselectivities
up to 13 : 1. It represents a “green” alternative to previously
described diastereoselective procedures implied in natural prod-
uct synthesis.11 Therefore, such sugar additives turn out to be
a promising approach to control the selectivity, probably by
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©

several times. The combined organic layers were dried with
MgSO4, concentrated, and the residue was purified by flash
chromatography on silica gel (cyclohexane/ethyl acetate: 3/1)
to give the aldol products (3–7) as yellow oils.
Notes and references
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Hoffmann, S. Gramatikova, R. Bjornestedt, B. List, J. Anderson,
E. A. Stura, I. A. Wilson and R. A. Lerner, Science, 1997, 278, 2085–
2092.
3 B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc., 2000,
122, 2395–2396.
4 N. Mase and I. I. I. C. F. Barbas III, Org. Biomol. Chem., 2010, 8,
4043–4050.
5 (a) J. Paradowska, M. Stodulski and J. Mlynarski, Angew. Chem.,
Int. Ed., 2009, 48, 4288–4297; (b) A. Chanda and V. V. Fokin, Chem.
Rev., 2009, 109, 725–748; (c) Y. Hayashi, T. Sumiya, J. Takahashi, H.
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6 V. Ferrie`res, T. Benvegnu, M. Lefeuvre, D. Plusquellec, G. Mackenzie,
M. J. Watson, J. A. Haley, J. W. Goodby, R. Pindak and M. K. Durbin,
J. Chem. Soc., Perkin Trans. 2, 1999, 951–959.
Fig. 2 Proposed intermediate for the direct aldol reaction in the
presence of an aqueous solution of amphiphilic carbohydrate 2.
7 (a) C. Denis, B. Laignel, D. Plusquellec, J.-Y. Le Marouille and A.
Botrel, Tetrahedron Lett., 1996, 37, 53–56; (b) C. Denis, K. Misbahi,
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mimicking an enzyme’s sequestration of intermediates away
from bulk water. Such sustainable media pave the way to
the further development of organic reactions by non-covalent
induction in water and will benefit from a better understanding
of the hydrophobic interactions.12 Works towards the generation
of amphiphilic sugar additives able to induce enantioselectivity
are actually under progress.
9 J. Huang, X. Zhang and D. Armstrong, Angew. Chem., Int. Ed., 2007,
46, 9073–9077.
General procedure
10 N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka and
C. F. Barbas III, J. Am. Chem. Soc., 2006, 128, 734–735.
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2703–2708; (b) N. P. Mulholland, G. Pattenden and I. A. Walters,
Org. Biomol. Chem., 2008, 6, 2782–2789.
A mixture of 3-nitrobenzaldehyde (75.8 mg, 0.50 mmol), ketone
(2.50 mmol), the catalyst (2 mol%) with or without the sugar
derivative (1.0 M) was stirred vigorously at RT in water (1.0
mL). Then, the reaction mixture was quenched by adding
saturated aqueous NH4Cl solution, and extracted with CH2Cl2
12 M. Rueping and T. Theissmann, Chem. Sci., 2010, 1, 473–476.
284 | Green Chem., 2012, 14, 281–284
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