Highly enantio- and diastereoselective organocatalytic desymmetrization of prochiral cyclohexanones by simple direct aldol reaction catalyzed by proline

Article abstract of DOI:10.1002/chem.200900488

A straightforward, efficient and highly enantio- and diastereoselective desymmetrization of 4-substituted cyclohexanones using proline as catalyst was investigated. Once a suitable catalyst system was obtained for the desymmetrization of 4-methylcyclohexanone (1a) by aldol addition, the reaction of different 4-substituted cyclohexanones with 4-nitrobenzaldehyde was studied. The final aldol adduct in excellent enantioselectivities and in good to excellent yields and diastereoselectivities was obtained. Both the UV and fluorescence spectra of the additive 4 f with different amounts of proline was used to investigate the stoichiometry between additives and proline in CHCl₃. The UV spectrum of compound 4 f showed a slight blue-shift to 360 nm, an absorbance increase at 360 nm and an isosbestic point around 310 nm with increasing concentration of proline. It was demonstrated that the use of simple hydrogen-bond donors as additives increases dramatically the efficiency of the process.

Full text of DOI:10.1002/chem.200900488

DOI: 10.1002/chem.200900488
Highly Enantio- and Diastereoselective Organocatalytic Desymmetrization
of Prochiral Cyclohexanones by Simple Direct Aldol Reaction Catalyzed by
Proline
Xavier Companyꢀ,[a] Guillem Valero,[a] Luis Crovetto,[b] Albert Moyano,*[a] and
Ramon Rios*[a, c, d]
The use of desymmetrization reactions in organic chemis-
try is one of the most common and powerful methods for
the stereocontrolled preparation of chiral molecules.
the organocatalytic aldol reaction has become one of the
cornerstones of organocatalysis. A huge effort has been de-
voted to the optimization of conditions, catalysts and addi-
tives that allow us to achieve high levels of enantio- and dia-
stereoselectivities. Surprisingly, although the aldol reaction
of simple cyclohexanones has received much attention, the
use of aldol reaction in the desymmetrization of 4-substitut-
ed cyclohexanones remains almost unexplored.[6] Only in
2007, Gong and co-workers described a nice desymmetriza-
tion of 4-substituted cyclohexanones catalyzed by 4-hydroxy-
prolinamide derivatives (Scheme 1), providing the resulting
compounds in good diastereo- and enantioselectivities and
with moderate to good yields.[7] However, the use of 4-hy-
droxyprolinamides derived from b-aminoalcohols (which are
much more precious than proline) and the use of low tem-
peratures in order to achieve high enantioselectivities make
this method not very useful from a practical point of view.
Soon after, Bolm and co-workers reported a few examples
of desymmetrization of ketones using proline in ball mills as
catalyst.[8]
Enzymatic transformation strategies are, to the best of
our knowledge, the most usual type of desymmetrization.
For example, Reetz and co-workers developed a new cyclo-
hexanone monooxygenase by directed evolution that
showed high levels of enantioselectivity in Baeyer–Villiger
reactions of prochiral cyclohexanones.[1] However, there are
few examples of desymmetrizations using well established
chemical organic transformations. In 2005, Shibasaki and co-
workers described an elegant desymmetrization of meso-N-
acylaziridines with TMSCN, achieving high levels of enan-
tioselectivity.[2] In the realm of organocatalysis, there are
few examples of desymmetrization reactions. In 2008, Song
and Connon almost simultaneously reported a very efficient
desymmetrization of anhydrides.[3] In 2005, Barbas et al. re-
ported an elegant desymmetrization of meso compounds by
a direct amino acid-catalyzed aminoxylation.[4]
Since the rediscovery of proline-catalyzed intermolecular
enantioselective direct aldol reactions between ketones and
aldehydes reported by List, Barbas and Lerner in 2000,[5]
Based in our previous work, we thought that proline
could be a suitable catalyst for the desymmetrization of pro-
chiral ketones.[9] However, proline itself presents some po-
tential drawbacks, such as poor performance in aldol reac-
tions with aromatic aldehydes, poor solubility in non-polar
organic solvents, and potential parasitic reactions that make
[a] X. Companyꢀ, G. Valero, Prof. Dr. A. Moyano, Dr. R. Rios
Departament de Quꢁmica Orgꢂnica, Universitat de Barcelona
Martꢁ i Franquꢃs 1-11, 08028 Barcelona (Spain)
Fax : (+34)933397878
E-mail: riosramon@icrea.cat
amoyano@ub.edu
[b] Dr. L. Crovetto
Departamento de Quꢁmica Fꢁsica, Facultad de Farmacia
Universidad de Granada, 18071 Granada (Spain)
[c] Dr. R. Rios
ICREA Researcher at UB.
[d] Dr. R. Rios
ICC Researcher at UB.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900488.
Scheme 1. Reaction reported by Gong and co-workers.[7]
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COMMUNICATION
Table 1. Screening of cocatalysts.[a]
necessary the use of high catalyst loadings to achieve good
conversions.
In the area of organocatalytic aldol reaction, several re-
search groups have been working in order to overcome
these drawbacks. For example, Pericꢂs and co-workers re-
ported recently an interesting polymer-bound 4-hydroxypro-
line catalyst with excellent results.[10] On the other hand, sev-
eral groups described the use of additives such as acids or
hydrogen-bond donors in order to enhance the catalytic
properties of proline. For example, Shan and co-workers
showed that the use of chiral diols as additives in aldol reac-
tions improved the enantioselectivity of proline, probably by
hydrogen-bonding interaction in the transition state.[11] In
2009, Demir et al. described the use of Schreiner thiourea as
suitable additive to enhance the catalytic activity of proline
in the direct aldol reaction.[12]
Entry Cocatalyst
Conversion d.r.[c]
[%][b]
ee[d]
1
2
3
–
0
–
–
50
14:1:0:0 87
traces
–
–
–
4
traces
57
Clearly inspired by the original work of Demir et al. and
based on those previous reports, we envisioned an easy
entry for the desymmetrization of 4-substituted-cyclohexa-
nones catalyzed by proline, using as cocatalyst different hy-
drogen-bonding donors. As proper additives,[13] we chose thi-
oureas,[14] squaramides[15] and different diamines as hydrogen
bond donors.
5
70
4:1:0:0
7:1:0:0
94
99
To our delight, when a toluene solution of 4-methyl-cyclo-
hexanone was reacted with 4-nitrobenzaldehyde using pro-
line as organocatalyst in the presence of 4a, the reaction
took place in moderate conversion after 120 h, and with
good enantioselectivity and with excellent diastereoselectiv-
ity (entry 2, Table 1). In contrast, when only proline was
used as organocatalyst no reaction was observed (entry 1).
Surprisingly, when BINOL (4b) or squaramides (4c) were
used as cocatalysts no reaction was observed after 120 h.
Next, we studied the aldol reaction using as cocatalyst the 2-
aminobenzoimidazole (4d). We were pleased to observe
that the enantioselectivity of the reaction rose to 94%
(entry 5). When different thioureas were used as additives
the enhancement of the diastereo- and enantioselectivity
was evident (entries 6, 7 and 8; Table 1). We obtained the
best results when 3,5-dimethylphenyl 3,5-bistrifluoromethyl-
phenyl thiourea (4 f) was used, affording aldol adduct in
99% ee and 10:1:0:0 diastereomeric ratio (entry 7). It
should be noticed that Schreiner thiourea 4e showed also a
very good enantio- and diastereoselectivity, but lower con-
versions than previously reported (entry 6). This result can
be easily explained by parasitic reactions of proline cata-
lyzed by thioureas (Scheme 2).
6
7
8
75
90
53
10:1:0:0 99
5:1:0:0
99
[a] See Supporting Information for conditions. [b] Determined by NMR
spectroscopy. [c] Determined by NMR spectroscopy. [d] Determined by
chiral HPLC analysis.
When 1 equiv of proline and 2 equiv of 4-nitrobenzalde-
hyde in toluene were added to a catalytic amount of thiour-
eas 4e–g (10 mol%), the parasitic reaction[16] took place.
Schreiner thiourea 4e catalyzed this reaction faster than 3,5-
dimethylphenyl-3,5-bistrifluoromethylphenyl thiourea (4 f)
or 2,6-diisopropylphenyl-3,4-bistrifluoromethylphenyl thio-
urea (4g), as shown in Scheme 2.
Once we obtained a suitable catalyst system for the de-
symmetrization of 4-methylcyclohexanone (1a) by aldol ad-
dition, we studied the reaction of different 4-substituted cy-
clohexanones with 4-nitrobenzaldehyde (Table 2). To our
Scheme 2. Parasitic reaction of proline.
delight, in all the entries we obtained the final aldol adduct
in excellent enantioselectivities and in good to excellent
yields and diastereoselectivities. For example, 4-phenylcyclo-
hexanone (3e) reacted with 4-nitrobenzaldehyde (2a) to fur-
nish the diastereopure aldol adduct in 83% yield, isolated
from a 11:2:0:0 diastereomeric mixture and with 97% enan-
tiomeric excess (entry 5; Table 2).
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R. Rios, A. Moyano et al.
Table 2. Ketone scope.[a]
Table 3. Aldehyde scope.[a]
Entry
Ketone
Product
3a
Yield
[%][b[
d.r.[c]
ee [%][d]
Entry
Aldehyde
Product
3a
Yield
[%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
85
65
80
69
83
10:1:0:0
11:2:0:0
4:1:0:0
7:2:1:0
11:2:0:0
99
94
96
97
97
1
2
3
85
68
86
10:1:0:0
7:2:0:0
24:3:1:0
99
99
99
3b
3 f
3c
3g
3d
4
5
6
3h
3i
74
86
87
5:1:0:0
95
97
96
3e
12:1:0:0
[a] See Supporting Information for conditions. [b] Isolated yield of dia-
stereopure aldol adduct. [c] Determined by NMR spectroscopy. [d] De-
termined by chiral HPLC analysis.
[e]
3j
Next, we decided to study the scope of the reaction using
different benzaldehydes with 4-methylcyclohexanone 1a
(Table 3). When electron-withdrawing groups such as nitro
or cyano were present in the benzaldehyde, the reaction
took place in reasonable reaction times and gave excellent
enantio- and diastereoselectivities. It is noteworthy that
when 2,6-dichlorobenzaldehyde was used, only one diaste-
reomer was observed by NMR spectroscopy, with good
enantioselectivities (entry 6).
To investigate the stoichiometry between additives and
proline in CHCl3, we recorded both the UV and fluores-
cence spectra of the additive 4 f with different amounts of
proline. As shown in Figure 1 (top), the UV spectrum of
compound 4 f showed a slight blue-shift to 360 nm, an ab-
sorbance increase at 360 nm and an isosbestic point around
310 nm with increasing concentration of proline. These spec-
tral features suggest a ground-state complex between thiour-
ea and proline. Since the UV spectra did not show large
enough differences to calculate the stoichiometry of the
complex, fluorescence spectroscopy was used to evaluate
this interaction. Addition of increasing amounts of proline
to a solution of 4 f led to a decrease of the fluorescence
signal at 360 nm and to an increase at 445 nm (Figure 1,
middle). A Job plot[17] with these two l indicated the forma-
tion of a stable 1:1 complex between proline and compound
4 f (Figure 1, bottom). On the other hand, when BINOL was
used the ratio between proline and BINOL in the complex
was 1.4:1 (see the Supporting Information).
[a] See Supporting Information for conditions. [b] Isolated yield of dia-
stereopure aldol adduct. [c] Determined by NMR spectroscopy. [d] De-
termined by chiral HPLC analysis. [e] Only one diastereomer detected
by NMR spectroscopy.
The absolute configuration of the products was ascer-
tained from comparison with data reported by Gong and co-
workers[7] and Bolm and co-workers,[8] and by conversion of
product 3a to dihydroxyester 6a (Scheme 3), which shows
spectral data identical with those reported in the litera-
ture.[7]
The general stereochemical outcome of the reaction can
be explained by the following mechanism: As shown by
Houk et al.[18] and the original work by Demir et al.,[12] the
proline mediated aldol reaction takes place through a Zim-
merman–Traxler transition state. Since the spectroscopic
studies described above show the formation of a stable 1:1
complex between thiourea and proline, we propose a hydro-
gen bond between the NH hydrogens of the thiourea and
the carboxyl moiety of proline. This interaction will increase
the acidity of the carboxylic hydrogen of proline and at the
same time stabilize the “chair” transition state. Accordingly,
we can draw two possible transition states with the prochiral
ketones (Scheme 4). In TS I, the interactions between 4-sub-
stituent of the ketone and the aldehyde will make this tran-
sition state more unstable than TS II. This is in accordance
with the stereoselectivity observed in the reaction.
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Organocatalytic Desymmetrization of Prochiral Cyclohexanones
COMMUNICATION
Scheme 4. Transition states proposed.
of this transformation, as well as the development of enan-
tioselective reactions based on this new concept are ongoing
in our laboratories and will be reported in due course.
Experimental Section
To a stirred solution of proline (11.5 mg, 0.10 mmol, 20 mol%, 0.2 equiv)
in toluene (2.0 mL), cocatalyst 4 f (40 mg, 0.10 mmol, 20 mol%,
0.2 equiv) and 4-methylcyclohexanone 1a (560.0 mg, 5 mmol, 10 equiv)
were added. The reaction was stirred at room temperature for 30 min,
and then 4-nitrobenzaldehyde 2a (75.5 mg, 0.50 mmol, 1 equiv) was
added. The reaction was vigorously stirred at room temperature for
120 h. Next, the crude product was purified by silica gel chromatography
(hexane/EtOAc mixtures) to give the corresponding diastereopure aldol
product 3a (111.8 mg, 85% yield). The NMR data matched with the pre-
viously reported in the literature.[7] 1H NMR (400 MHz, CDCl3, TMSint):
d=1.05 (d, J=6.9 Hz, 3H), 1.31–1.35 (m, 1H), 1.54–1.60 (m, 1H), 1.78–
1.81 (m, 1H), 1.89–1.93 (m, 1H), 2.07–2.09 (m, 1H), 2.38–2.43 (m, 1H),
2.48–2.50 (m, 1H), 2.72–2.78 (m, 1H), 3.82–3.89 (brs, 1H), 4.92 (d, J=
8.6 Hz, 1H), 7.47–7.52 (m, 2H), 8.18–8.23 ppm (m, 2H).
Figure 1. Top: UV spectra; middle: fluorescence spectra for proline/4 f
Acknowledgements
~
&
mixtures; bottom: Job plot at l=360 nm ( ) and 445 nm ( ).
We thank the Spanish Ministry of Sci-
ence and Innovation for financial sup-
port (Project AYA2006-15648-C02-
01).
Keywords: aldol reaction
desymmetrization hydrogen
organocatalysis ·
·
·
Scheme 3. Synthesis of compound 6a.
bonds
·
proline
In summary, we have developed a straightforward, effi-
cient and highly enantio- and diastereoselective desymmetri-
zation of 4-substituted cyclohexanones using proline as cata-
lyst. We have shown that the use of simple hydrogen-bond
donors as additives increases dramatically the efficiency of
the process. Mechanistic studies and synthetic applications
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Received: February 22, 2009
Published online: April 29, 2009
Please note: Minor changes have been made to this manuscript since its
publication in Chemistry–A European Journal Early View. The Editor.
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