Table 1 Addition of cyclopentadiene to nonyl acrylate in water containing
surfactant 1
drawn due to the chirality present. Alignment of nonyl acrylate
with the underside of 1 results in the cyclopentadiene having to
approach from below the acrylate. As shown in Scheme 2 (for
the reaction under neutral conditions), the carbonyl moiety can
complex to the nitrogen and hydrogen bond to the O–H group
with the alkene beneath the isopropyl group in A, with
subsequent approach of cyclopentadiene beneath the complex
leading to the formation of the R-isomer. However, in B,
reaction with the diene would generate the S-isomer. Since A is
complexed more favourably (with possible hydrogen bonding
and carbonyl complexation) as well as having the polar
carbonyl moiety directed towards the Stern layer, the R-isomer
would be expected to be more prevalent. Future work will shed
more light on this model.
In summary, we have performed the first Diels–Alder
reaction in aqueous chiral micellar media, obtaining selectivi-
ties comparable with the best reported for other non-enzymic
aqueous Diels–Alder reactions. We established that the R
enantiomer in the endo isomer was formed preferentially in this
system and have rationalised these results.
Entry
[Surfactant]/g l21
Yielda (%)
N/X
Eeb (%) (R)
1
2
3
4
5
0.011
0.022
0.006
0.011c
0.011d
55
72
43
29
75
2.1
2.1
2.0
2.1
2.2
10
12
7
13
15
a
b
c
d
Isolated yields. Determined by chiral HPLC. pH 3. pH 3 with
LiCl.
In view of the initial uncertainty in the optimum surfactant
concentration for use in such applications, the concentration of
1 was varied and the effects on enantioselectivities and yield
were noted,§ see summarised results in Table 1. For comparison
purposes, the reaction in water alone under identical conditions,
gave a yield of 70% and an N/X selectivity of 1.7.
At the starting point, an ee of 10% was observed (entry 1),
rising slightly (entry 2) as surfactant concentration was
increased then falling as the concentration was decreased (entry
3) together with a lowering of the yield, which could be due to
the presence of non-micellar aggregates. Previously, we had
seen the greatest yields and N/X selectivities in acrylate systems
in the absence of surfactant when operating at pH 3.5 In this
instance, we found that when the solution was at pH 3 the
enantioselectivity increased, although the yield of cycloadduct
that was isolated was poor (entry 4). In determining how to
increase the yield in this system, we reasoned that a salting-out
agent would tend to remove the reactants from the aqueous
pseudo-phase, increasing the complexation of the substrates to
the micelles. Further, it is known that an increased concentra-
tion of chloride counterions can cause a shrinkage in the Stern
layer, leading to a concentration of reactants1 which, in our
system, could translate to greater pre-orientation and enhanced
yield and ees. In view of these factors, we added lithium
chloride (4.86 m) to the reaction at pH 3, thence obtaining both
the highest yield (75%) and the greatest ee (15%). This result
compares well with the results quoted for Diels–Alder reactions
in cyclodextrins in which maximum enantioselectivities of 21%
are reported.3
Subsidiary results include a further confirmation of the fact
that the selection of the surfactant concentration is an important
but elusive parameter in organic synthesis and that the pH is
significant in chiral micellar catalysis. Finally, we have seen
that lithium chloride may prove to be useful in such systems.
This work is part of a series of ongoing projects. We are
aiming at further enhancing selectivity in Diels–Alder reactions
by investigating a range of substrates with the aim of reducing
the effects of the competing reaction in the water phase. We are
also investigating the use of chiral surfactants in other classes of
reaction as well as exploring the effect of more conformation-
ally constrained surfactants.
We are grateful to University College London (Access Funds
for M. J. D.-C.), Bush Boake Allen, Central Research Fund
University of London, The Royal Society, and The Nuffield
Foundation for funding. We thank Dr P. Sandor for running
NOE experiments.
Notes and References
† E-mail: h.c.hailes@ucl.ac.uk
‡ Chiralcel OD column, 0.5% propan-2-ol–hexane, 1 ml min21. Retention
times: 2 7.0 min; 3 4.8 min. Optical rotations were: 3 via TiCl4 catalysis,
[a]D +8.1 (c 1.00, in CH2Cl2, 20 °C), 2 and 3 via micellar catalysis [a]D
+5.0 (c 1.03, in CH2Cl2, 20 °C).
A number of conformations of the surfactant 1 could be
considered (since surfactants are dynamic in nature) and a
representative one, consistent with NOE difference experiments
is shown below in Scheme 2, in an attempt to provide a tentative
simplistic model which nevertheless helps to visualise the
observed preferences. All possible conformations have the
common feature of a more hindered top face of the molecule as
§ Reactions were repeated a minimum of three times, giving enantio-
selectivities consistent to ± 0.5%. Cyclopentadiene (3.8 mmol) was reacted
with nonyl acrylate (1.9 mmol) in water (25 ml) containing surfactant 1 for
20 h. Acidity adjusted with HCl. Chiralcel OD column, 0.1% propan-2-ol–
hexane, 0.75 ml min21. Retention times: exo, 6.7 and 6.9 min; endo, 7.9 and
9.0 min.
A
B
1 T. Tascioglu, Tetrahedron, 1996, 52, 11113.
2 Y. M. Zhang, W. Fan, P. Lu and W. Wang, Synth. Commun., 1988, 18,
1495; Y. M. Zhang and W. Li, Synth. Commun., 1988, 18, 1685;
Y. M. Zhang, S. Qu and W. Bao, Synth. Commun., 1994, 24, 2437;
Y. M. Zhang and W. D. Wu, Tetrahedron: Asymmetry, 1997, 8, 3573;
Y. M. Zhang and W. D. Wu, Tetrahedron: Asymmetry, 1997, 8, 2723.
3 H.-J. Schneider and N. K. Sangwan, Angew. Chem., Int. Ed. Engl., 1987,
26, 896.
H
H
H
H
O
H
Cl-
O
O
micelle
interior
micelle
interior
O
N+
N+
O
H
Cl-
O
4 M. J. Diego-Castro, H. C. Hailes and M. J. Lawrence, unpublished
results.
H
25C12
H25C12
C8H17
C8H17
5 M. J. Diego-Castro and H. C. Hailes, Tetrahedron Lett., 1988, 39,
2211.
6 M. J. Diego-Castro, H. C. Hailes, M. J. Lawrence and D. J. Barlow,
unpublished results.
7 B. Lindman and H. Wennerstrom, Top. Curr. Chem., 1981, 87, 1.
8 M. Vanderwalle, J. Van der Eyeken, W. Oppolzer and C. Vullioud,
Tetrahedron, 1986, 42, 4035.
H
H
CO2C9H19
CO2C9H19
R
S
Scheme 2 Positioning of the acrylate with respect to the surfactant head
group
Received in Liverpool, UK, 15th April 1998; 8/02825G
1550
Chem. Commun., 1998