Direct enantioselective aldol reactions catalyzed by a proline-thiourea host-guest complex

Article abstract of DOI:10.1039/b817474a

Proline-thiourea host-guest complex-catalyzed direct enantioselective aldol reactions have been developed, in which the catalytic activities were evaluated in the direct asymmetric aldol reactions of various aromatic aldehydes and cyclohexanone. The Royal

Full text of DOI:10.1039/b817474a

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Direct enantioselective aldol reactions catalyzed by a proline–thiourea
host–guest complexw
¨
Omer Reis, Serkan Eymur, Barbaros Reis and Ayhan S. Demir*
Received (in Cambridge, UK) 6th October 2008, Accepted 28th November 2008
First published as an Advance Article on the web 7th January 2009
DOI: 10.1039/b817474a
Proline–thiourea host–guest complex-catalyzed direct enantio-
selective aldol reactions have been developed, in which the
catalytic activities were evaluated in the direct asymmetric aldol
reactions of various aromatic aldehydes and cyclohexanone.
reaction, where the proline and co-catalyst were proposed to
interact in a transition state assembly, in turn forming a
5
catalytic system that was ‘‘greater than the sum of its parts’’.
Recently, Clarke et al. elegantly developed an improvement in
the reactivity and selectivity of a proline-derived amide
decorated with a hydrogen bond acceptor site, which could
self-assemble with hydrogen bond donor additives, thereby
improving a poor catalyst into a very good one in a
After the discovery of a proline-catalyzed enantioselective
intramolecular aldol reaction in the 1970s, the corresponding
intermolecular enantioselective direct aldol reactions between
ketones and aldehydes were reported by Barbas et al. in
6
Michael-type addition of ketones to nitro olefins. Proline-
1a,b
2
000.
These initial reports not only provided a simple
catalyzed direct aldol reactions have been shown experimen-
tally and computationally to proceed through enamine
intermediates, in which the transition state is highly stabilized
by hydrogen bond donation from the carboxylic acid moiety
to the electrophile, with concurrent development of partial
solution to one of the most important problems in catalytic
asymmetric synthesis, but also attracted a great deal of
attention to the use of small organic molecules as catalysts
1c–e
in organic chemistry.
Although proline is a rather good catalyst, it is not without
some potential drawbacks, such as (1) a low solubility that
limits its reactivity in typical organic solvents, (2) potential side
7
iminium and carboxylate ions on the proline (Fig. 1).
Moreover, proline is known to exist as a zwitterion, forming
a highly insoluble network of hydrogen-bonded units. We
anticipated that a chemical entity that selectively and strongly
binds to the acetate functionality will (1) interact with proline
in solution, in turn altering its solution properties and
reactivity, and (2) also bind to the transition state in a stronger
fashion, thereby improving the selectivity of the reaction.
Based on this initial proposal, we decided to investigate the
use of a diarylthiourea moiety, due to its well known ability of
2
reactions and established parasitic equilibria with substrates,
and (3) low selectivities with planar aromatic aldehydes in direct
aldol reactions. Therefore, considerable effort has been directed
at the development of proline analogs in order to improve their
reactivity, selectivity and scope. Considering the practical
synthetic issues, the carboxylic acid moiety of proline has been
targeted as a site for modification. Its reactivity and selectivity is
enhanced in custom-made catalysts, even though the identifi-
cation of a good catalyst in turn requires the synthesis of
various analogs of a proposed design in order to identify the
optimum one. Moreover, the improved catalyst is usually
obtained through the modification of proline with chiral mole-
cules that have additional functionality, and are much more
8
strong and well-defined binding to carboxylates.
Herein, we report the proof-of-principle results of proline-
catalyzed direct aldol reactions between cyclic ketones and
aldehydes using (3,5-bistrifluoromethylphenyl)thiourea 4 as
the additive. We began the investigations with cyclohexanone
(
1) as the donor ketone and 4-nitrobenzaldehyde (2a) as the
3
precious than the proline itself.
‘
acceptor aldehyde. An initial screening revealed that the use of
polar solvents did not improve the proline catalysis alone.
‘To make a good asymmetric catalyst perfect’’, the role of
suitable additives, or co-catalysts, can be crucial in enhancing
the reactivity and stereoselectivity of the catalytic system. For
example, it has been shown that the addition of a small
amount of water often accelerates the reaction rate and
increases the enantioselectivity of proline-catalyzed aldol
4b–i
reactions.
Recently, Shan has shown that using chiral diols
as additives can improve the enantioselectivity of proline
catalyzed aldol reactions, probably through their involvement
in the transition state, via the formation of a hydrogen
4a
bonding network. Miller et al. showed the cooperative
effect of a co-catalyst in a proline-catalyzed Baylis–Hillmann
Department of Chemistry, Middle East Technical University, 06531
Ankara, Turkey. E-mail: asdemir@metu.edu.tr;
Tel: +90 (0)312 210 32 42
w Electronic supplementary information (ESI) available: Experimental
details, NMR spectra, and HPLC data and chromatograms. See DOI:
Fig. 1 A: The List–Houk model of the transition state of proline-
catalyzed aldol reactions. B and C: The proposed interaction of the
thiourea moiety with proline in solution and in the transition state,
respectively.
10.1039/b817474a
1
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Table 1 The enantioselective direct aldol reaction of 2a and 1 under
various conditions
Table 2 The enantioselective direct aldol reaction of aldehydes 2a–2i
and cyclohexanone (1)
a
a
Catalyst
proline :
Entry Solvent urea (%) Time/h (%)
b
c
d
Entry Aldehyde Ar Time/h Yield (%)
anti : syn
ee (%)
Conversion
anti : syn ee (%)
e
1
2
3
4
5
6
7
8
9
1
1
2a 4-NO
2a 4-NO
2b 3-NO
2b 3-NO
2
2
2
2
Ph
Ph
Ph
Ph
24
16
24
16
16
24
36
36
36
48
16
75
96
79
94
98
93
91
87
83
79
93
92 : 8
90 : 10
93 : 7
92 : 8
93 : 7
94 : 6
88 : 12
90 : 10
94 : 6
88 : 12
60 : 40
499
99
499
499
99
99
99
99
99
1
2
3
4
5
6
7
8
9
1
1
1
MeCN 20 : 20
CHCl 20 : 20
16
16
16
12
12
36
12
12
16
16
16
16
28
80
96
99
99
24
37
97
96
30
44
85
71 : 29
80 : 20
92 : 8
90 : 10
91 : 9
68 : 32
81 : 19
86 : 14
90 : 10
90 : 10
90 : 10
93 : 7
92
96
499
99
99
83
e
3
Toluene 20 : 20
Hexane 20 : 20
Hexane 20 : 5
Hexane 20 : 0
Hexane 20 : 20
Hexane 20 : 20
Hexane 10 : 10
Hexane 5 : 5
Toluene 5 : 5
2c 4-CNPh
2d 4-CF Ph
3
2e 4-ClPh
2f 4-BrPh
2g 2-ClPh
2h Ph
b
c
93
98
99
99
0
1
98
97
f
2i 4-NO
2
Ph
0
1
2
a
b
6 equiv. of cyclohexanone were used. After purification. Deter-
c
99
97
1
mined from crude NMR spectra. Determined by HPLC with
(neat)
5 : 5
d
a
b
6 equiv. of cyclohexanone were used. (S)-Tryptophan was used as
e
an appropriate chiral column. Toluene was used as the solvent.
1
the catalyst. (S)-tert-Leucine was used as the catalyst.
c
f
Cyclopentanone was used.
The reaction in DMSO, which is a typical solvent for this type
of reaction, resulted in the same level of selectivity and product
purity with or without the urea additive. When MeCN was
employed, the reaction was still sluggish and the selectivity was
low (Table 1, entry 1).
entries 1 and 3). The reactions with aldehydes bearing highly
electron-withdrawing groups proceeded smoothly, with a
good level of diastereoselectivity.
Some information about the nature of the proline–thiourea
1
species was obtained from H NMR experiments, with spectra
This was, of course, expected considering the inefficiency of
hydrogen bonding interactions in polar solvents. When we
switched to non-polar solvents, both the efficiency and
selectivity were remarkably enhanced (some selected results
are shown in Table 1). Among the non-polar solvents used,
toluene showed a slightly better selectivity, while the reaction
proceeded faster and more cleanly in hexane. This observation
is remarkable considering the solubility of proline in hexane.
We also found that the relative amount of additive could be
reduced without a loss in reactivity or selectivity (Table 1,
entry 5); however, the amount of proline was important for the
rate of the reaction without compromising the selectivity
3
being recorded in CDCl (see the ESIw). The observed results
of these experiments showed that the solubility of the proline–
thiourea mixture in chloroform was much better than each
compound alone. It was seen that following the addition of
proline, the N–H protons of the thiourea underwent a down-
field shift due to the dominant interactions that are present
in the complex via the formation of a hydrogen bonding
network, as shown in Fig. 1.
The data collected thus far indicate that a specific proline–
thiourea interaction may operate to afford an enantioselective
reaction. Exactly which intermediates and transition states
operate (Fig. 1B and C), or whether an alternative transition
state is involved, is a matter of current investigation in our
laboratory. The possibility of fine-tuning these proline–thiourea
interactions also presents a possible strategy for asymmetric
(
Table 1, entry 10). The aldol reaction performed without
solvent also furnished the product in high diastereo- and
enantioselectivities (Table 1, entry 12). When the reaction
was carried out without the thiourea additive, the reaction
was very slow, with a low stereoselectivity (Table 1, entry 6).
We also found that primary amino acids were very good
catalysts for this transformation (Table 1, entries 7 and 8),
although proline was superior. These results clearly demon-
strate the enormous effect of the thiourea on the reactivity and
selectivity, even in an unconventional non-polar reaction
medium, without the need to use low temperatures. It is also
noteworthy that the sense of stereoselection is the same as that
when proline is the sole catalyst.
9
catalyst development.
In summary, we have found that a proline–thiourea
host–guest complex can catalyze direct enantioselective aldol
reactions in non-polar solvents with high diastereo- and
enantioselectivities (up to 94 : 6 dr and 499% ee) better than
proline. These results clearly demonstrate the enormous effect
of the thiourea on the reactivity and selectivity, even in an
unconventional non-polar reaction medium, without the need
to use low temperatures. The sense of stereoselection is the
same as that when proline is the sole catalyst. More detailed
studies on the mechanism and synthetic applications of this
supramolecular catalyst for enantioselective organocatalytic
reactions are currently under investigation.
A representative selection of aldehydes was investigated to
determine the scope of this improved aldol protocol, as shown
in Table 2. Hexane was chosen as the solvent, due to the
faster reaction times and higher isolated yields compared to
those of toluene, with similar levels of selectivity (Table 2,
We gratefully acknowledge the Scientific and Techno-
¨
logical Research Council of Turkey (TUBITAK), the Turkish
This journal is ꢀc The Royal Society of Chemistry 2009
Chem. Commun., 2009, 1088–1090 | 1089

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¨
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9 The proline–thiourea-catalyzed reaction with different ureas is
under investigation.
1
090 | Chem. Commun., 2009, 1088–1090
This journal is ꢀc The Royal Society of Chemistry 2009