Asymmetric aldol addition of α-azido ketones to ethyl pyruvate mediated by a cinchona-based bifunctional urea catalyst Dedicated to the memory of Prof. Dr. Ayhan S. Demir

Article abstract of DOI:10.1016/j.tetlet.2014.06.018

The first asymmetric synthesis of ethyl 4-aryl-3-azido-2-hydroxy-2-methyl- 4-oxobutanoates via a cinchona organocatalyst induced aldol addition of α-azido ketones to ethyl pyruvate has been developed. The coupling reaction under optimized conditions was carried out to furnish tetrafunctionalized synthons with enantioselectivities of up to 91:9 and enriched diastereoselectivities of up to 95:5 (syn:anti).

Full text of DOI:10.1016/j.tetlet.2014.06.018

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
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Asymmetric aldol addition of a-azido ketones to ethyl pyruvate
mediated by a cinchona-based bifunctional urea catalyst
z
⇑
Seda Okumusß, Cihangir Tanyeli , Ayhan S. Demir
Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
The first asymmetric synthesis of ethyl 4-aryl-3-azido-2-hydroxy-2-methyl-4-oxobutanoates via a cin-
Received 24 January 2014
Revised 26 May 2014
Accepted 5 June 2014
Available online xxxx
chona organocatalyst induced aldol addition of
a-azido ketones to ethyl pyruvate has been developed.
The coupling reaction under optimized conditions was carried out to furnish tetrafunctionalized syn-
thons with enantioselectivities of up to 91:9 and enriched diastereoselectivities of up to 95:5 (syn:anti).
Ó 2014 Elsevier Ltd. All rights reserved.
Dedicated to the memory of Prof. Dr. Ayhan
S. Demir
Keywords:
Aldol reaction
a-Azido ketone
Bifunctional urea
C–C coupling
Cinchona alkaloids
Undoubtedly, the aldol reaction is a powerful tool for the con-
struction of complex molecules with new stereogenic centers.1 In
asymmetric organocatalytic aldol reactions, stereoselective C–C
bond formation is enhanced by using a catalytic amount of a chiral
promoter in an atom economical fashion.2 Enantiomerically pure
or diastereomerically enriched chiral aldol products are important
not only for modern synthetic chemistry, but are also very impor-
tant in nature.1
prise essential components and building blocks for many bioactive
natural products.9,10
Patonay and co-worker have demonstrated trapping of the cor-
responding carbanion intermediate from
ious carbon electrophiles such as aldehydes, ketones,
aldehydes, and
-keto esters in the presence of DBU as a base.4
a-azido ketones with var-
a-oxo
a
Recently, the highly enantioselective aldol reaction between azi-
doacetone and aromatic or heteroaromatic aldehydes catalyzed
by a cooperative proline-guanidinium salt catalyst system was
reported.11 Additionally, Barbas and co-workers have obtained a
high enantiocontrol in the direct asymmetric Mannich reaction of
a-Azido ketones have highly acidic a-protons due to the anion-
stabilizing effect of the azide functionality. Their base-promoted
deprotonation leads to formation of a carbanion intermediate,
which readily reacts with an electrophilic carbonyl moiety.3
a-azido ketones in the presence of an L-proline-derived tetrazole
Aldol addition of
a
-azido ketones to ethyl pyruvate allows the
catalyst.12 Among these, the reaction of phenacyl azides with ethyl
pyruvate resulted in tetrafunctionalized ethyl 4-aryl-3-azido-2-
hydroxy-2-methyl-4-oxobutanoates, but only the 4-(4-methoxy-
phenyl) derivative could be isolated. The failure to isolate other
derivatives was attributed to a rapid retro-aldol reaction due to
the hindrance around the stereogenic methine carbon. Also, the
diastereoselectivity of the isolated derivative was low with a dia-
stereomeric ratio of 67:33 (syn:anti).4,13
synthesis of ethyl 2-azido-3-hydroxy-1,4-diones, which are valu-
able tetrafunctionalized synthons.4 The different functionalities
present in such compounds make them potential precursors for
the synthesis of a
-amino ketones,5 azido alcohols,6 1,2-amino alco-
hols,7 and 1,2,3-triazoles.8 Besides allowing many transformations,
such compounds are also important due to their having a tertiary
alcohol moiety. Chiral tertiary alcohols and a-hydroxyesters com-
In this contribution, our challenge was to overcome isolation
issues, together with enhancement of the diastereoselectivity and
enantioselectivity. For this purpose, we explored the efficiency of
cinchona alkaloids in asymmetric aldol reactions (Scheme 1).
⇑
Corresponding author. Tel.: +90 312 2103222; fax: +90 312 2103200.
E-mail address: tanyeli@metu.edu.tr (C. Tanyeli).
Deceased on June 24, 2012.
z
http://dx.doi.org/10.1016/j.tetlet.2014.06.018
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Okumußs, S.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.018

2
S. Okumußs et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Although enantiomeric excess was observed in the presence of
C2 symmetric catalysts I and II, it was relatively low compared to
bifunctional catalysts IVa, b.16 The reaction yielded aldol adduct
3a in poor conversion, but with somewhat better stereoselectivity
in the presence of bifunctional cinchona-(thio)urea catalysts IVa, b
(entries 4 and 5). The poor enantioselectivity obtained in the pres-
ence of III supports the enhancement of selective substrate binding
via the hydrogen bond donor (thio)urea moiety. Considering the
MeO
OEt
N
CF3
CF3
O
N
N
H
H
N
O
OH
O
O
catalyst IVb
N3
OEt
(2 mol%)
N3
O
O
toluene, r.t.
R
R
3a-g
1
2a-g
7 isolated derivatives
21-60% conversion
dr = 87:13 - 95:5 (syn:anti)
75:25-91:9 er
study of Barbas,12
L-proline and its combination with IVb and achi-
4 eq.
1 eq.
0.2 M
ral thiourea VI were also tested, however, these trials gave inferior
results in terms of conversion and enantioselectivity besides lead-
ing to faster retro-aldol reactions as well (entries 7–9). Choosing
IVb as the best catalyst, parameters such as the solvent, molarity,
catalyst loading, and temperature were investigated to find the
optimum conditions (entries 9–16).
a
b
c
d
e
f
g
2, 3
H
4-Me 4-MeO 4-Br 4-F 3-Br 3-MeO
R
Scheme 1. Current work.
Though polar aprotic solvents such as dichloromethane and
chloroform resulted in higher conversions, the enantioselectivity
was lower than that obtained in toluene. Toluene also led to both
higher conversions and enantiomeric ratios than when using ace-
tonitrile. Of the solvents screened, toluene proved to be the best
in terms of selectivity (entries 9–11).17
At this stage, we established that the prolonged reaction times
might have caused a decrease in the diastereomeric ratio due to
epimerization of product 3a and/or a possible retro-aldol reaction.
Cinchona alkaloids are well-known naturally occurring cata-
lysts with a Brønsted basic quinuclidine nitrogen and having a
wide range of applications in many relevant transformations.14
Inspired by the competitive use of cinchona alkaloids in various
aldol reactions,15 and the study of Barbas,12 we surveyed catalysts
I–VI in the reaction of phenacyl azide and ethyl pyruvate (Table 1,
entries 1–8).
Table 1
Screening of the catalyst and reaction conditions for the aldol reaction
catalyst
OH
OH
O
O
O
O
I-VI
OEt
OEt
OEt
N3
solvent
N3 O
O
N3 O
temperature
anti-3aa
syn-3aa
2a
1
N
N
O
O
O
O
N
N
O
N
O
OCH3
H3CO
N
N
OCH3
H3CO
N
N
N
N
II
Screened Catalysts
I
I-VI
MeO
OH
CF3
X
N
CF3
CF3
CF3
N
S
N
H
COOH
N
N
N
F3C
N
H
N
H
CF3
H
H
OMe
V
III
X= S, IVa
O, IVb
VI
IV
Entrya
Catalyst
Eq. of 1
Molarity of 2a
Solvent
Cat. loading (mol %)
Time (h)
Conversion (%)c
drc syn:anti
erd syn
1
2
3
4
5
6
7
8
I
II
III
IVa
IVb
V
V+IVa
V+VI
IVb
IVb
IVb
IVb
IVb
IVb
IVb
IVb
4
4
4
4
0.55 M
0.55 M
0.55 M
0.55 M
0.55 M
0.24 M
0.24 M
0.24 M
0.55 M
0.55 M
0.55 M
1.0 M
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CHCl3
Toluene
Toluene
Toluene
Toluene
Toluene
10
10
10
10
10
5
5+5
5+5
10
10
10
10
10
10
2
48
48
48
48
48
27
1
92
93
87
60
64
4
76:24
75:25
84:16
80:20
82:18
50:50
83:17
75:25
81:19
80:20
81:19
87:13
89:11
92:8
35:65
36:64
41:59
77:23
78:22
50:50
80:20
50:50
81:19
79:21
77:23
83:17
84:16
86:14
87:13
83:17
4
0.83
0.83
0.83
4
4
4
4
4
4
4
27
7
6
9
96
96
96
24
12
12
12
24
77
86
84
68
68
56
47
45
10
11
12
13
14
15
16b
0.6 M
0.2 M
0.2 M
0.2 M
93:7
90:10
4
2
a
b
c
Relative configuration is depicted for 3a.
Reaction performed at 0 °C.
Determined from the crude 1H NMR spectrum.
Determined by chiral HPLC.
d
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S. Okumußs et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
In this regard, the decrease in the diastereomeric ratio was con-
firmed by checking the change in the ratio and conversion of the
products at the end of specific time intervals (by 1H NMR analysis
of the crude product) in subsequent screening studies.
in accord with the results reported for the syn-adduct by Patonay
and co-workers.13 The syn-preference over the anti-isomer in the
coupling reactions of
a-azido ketones with carbon electrophiles,
reported in the work of Patonay,4 Padwa20 and Barbas,12 allowed
us to assign the diastereomers in the whole series on the basis of
the characteristic differences in their 1H NMR spectra. The stereo-
genic methine proton of the 4-MeO substituted syn-adduct, which
is in accordance with the literature,13 resonates at higher field
(d = 4.55) than its anti counterpart (d = 4.67). Likewise, the stereo-
genic methine carbon atom of the syn-isomer was observed at a
Considering entries 12–14, as the concentration of 2a decreases,
an increase in enantioselectivity was detected. Accordingly, a con-
centration of 0.2 M gave the highest er (86:14) and diastereoselec-
tivity, dr = 92:8 (syn:anti), obtained so far (entry 14).17 Among the
trials with higher and lower catalyst loadings, 2 mol % of the cata-
lyst afforded an 87:13 er, and a better diastereomeric ratio (93:7)
(entry 15). Our effort to decrease the catalyst loading to 1 mol %
for atom economy brought about a very low conversion without
any increase in the selectivity.17 Consequently, the optimum cata-
lyst loading was 2 mol %. A lower temperature was also examined
using the previously optimized conditions, but it did not enhance
the stereoselectivity (entry 16). Elevated temperatures were not
tried due to the thermally labile nature of azides.18
higher field (D
d = 1.7) than its anti counterpart in the 13C NMR
spectrum. Similarly, in the 1H NMR spectra of all the derivatives,
the stereogenic methine proton of the major diastereomers
appeared at a higher field (Dd = 0.11–0.13) than the methine pro-
ton of the minor diastereomer.17
In summary, for the first time, we have demonstrated direct
asymmetric aldol reactions of a-azido ketones and ethyl pyruvate
Despite the fact that model compound 3a could not be isolated
under the racemic conditions of Patonay’s study,4 at the end of our
optimization trials, it was found that the isolation of 3a was possi-
ble by suppressing the aforementioned retro-aldol process via the
assistance of asymmetric organocatalysts. Having established the
to afford ethyl 4-aryl-3-azido-2-hydroxy-2-methyl-4-oxobutano-
ates by controlling the rate of the retro-aldol reaction, even under
asymmetric conditions. Diastereo- and enantiocontrol was
achieved by using bifunctional cinchona-based urea catalyst IVb
as a chiral auxiliary. A significant induction of diastereoselectivity
[up to 95:5 (syn:anti) diastereomeric ratio] and enantioselectivity
of up to 91:9 were obtained using a very low (2 mol %) catalyst
loading. Further studies on increasing the stereoselectivity and
conversions are in progress.
optimum reaction conditions, a variety of a
-azido ketones 2a–g19
as aldol donors were probed and the stereocontrol on derivatives
was explored to some extent with reasonable conversions (Table 2).
p-Methoxy derivative 3c yielded the best enantioselectivity, but
the lowest conversion (entry 3). This situation can be attributed
to a decrease in the acidity of the methylene protons. On the other
hand, when the methoxy group was at the meta-position, (3g),
although the conversion was relatively high (41%), the enantiose-
lectivity was quite low (entry 7). In the case of 4-Br substituted
derivative 3d, the obtained enantiomeric ratio was 75:25. In spite
of providing almost the same conversion, 3-Br substituted adduct
3f led to an 80:20 er (entries 4 and 6, respectively). Besides its elec-
tronic effect, bromide may have a steric effect on the transition
state.
Acknowledgments
We are indebted to the Department of Chemistry (Middle East
Technical University) for financial support.
Supplementary data
Supplementary data (experimental details, chiral HPLC traces,
and copies of 1H and 13C NMR spectra for all compounds generated
in this work) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2014.06.018. These
data include MOL files and InChiKeys of the most important
compounds described in this article.
Substrate scope studies also revealed that the enantiomeric
ratio of each derivative decreases after reaching a maximum value
due to epimerization of the major enantiomer and/or a possible
retro-aldol reaction in the presence of IVb (see Supplementary
data, Graph S1).17
Among the derivatives, the major diastereomer of 3c was iso-
lated whereas other derivatives were isolated as mixtures of syn
and anti isomers. The 1H and 13C NMR spectra of isolated 3c were
References and notes
1. Mahrwald, R. Modern Aldol Reactions; Wiley-VCH: Weinheim, 2004.
2. Trost, B. M. Science 1991, 254, 1471–1477.
3. Patonay, T.; Hoffman, R. V. J. Org. Chem. 1995, 60, 2368–2377.
9
4. Juhász-Toth, È.; Patonay, T. Eur. J. Org. Chem. 2002, 3055–3064.
Table 2
Scope of the a
-azido ketones 2a-ga
5. (a) Nakajima, M.; Loeschorn, C. A.; Cimbrelo, W. E.; Anselme, J. P. Org. Prep.
Proced. Int. 1980, 12, 265–268; (b) Patonay, T.; Rákosi, M.; Litkei, G.; Bognár, R.
Liebigs Ann. Chem. 1979, 161–173; (c) Patonay, T.; Patonay-Pèli, E.; Litkei, G.;
Szilágyi, L.; Batta, G.; Dinya, Z. J. Heterocycl. Chem. 1988, 25, 343–347; (d)
Winternitz, F.; Engel, C. R. Steroids 1965, 6, 805–840.
6. (a) Moody, C. J.; Ward, J. G. J. Chem. Soc., Perkin Trans. 1 1984, 2903–2909; (b)
Benaissa, T.; Hamman, S.; Beguin, C. G. J. Fluorine Chem. 1988, 3, 163–173; (c)
Bateson, J. H.; Fell, S. C. M.; Southgate, R.; Eggleston, D. S.; Baures, P. W. J. Chem.
Soc., Perkin Trans. 1 1992, 1305–1312.
cat. IVb
O
OH
O
O
(2 mol%)
OEt
OEt
toluene, r.t.
N3
O
N3
O
R
R
3a-g
2a-g
1
syn anti)
dr= 87:13-95:5 (
:
1 eq.
4 eq.
75:25-91:9 er
0.2 M
7. (a) Brenelli, E. C. S.; Fernandes, J. L. N. Tetrahedron: Asymmetry 2003, 14, 1255–
1259; (b) Wallner, S. R.; Lavandera, I.; Mayer, S. F.; Öhrlein, R.; Hafner, A.;
Edegger, K.; Faber, K.; Kroutil, W. J. Mol. Catal. B: Enzym. 2008, 55, 126–129.
8. Kumar, D.; Reddy, V. B.; Varma, R. S. Tetrahedron Lett. 2009, 50, 2065–2068.
9. Garcia, C.; Martin, V. S. Curr. Org. Chem. 2006, 10, 1849–1889.
Entry
R
Time (h)
Conversionb (%)
drc syn:anti
erd syn
1
2
3
4
5
6
7
H (3a)
12
18
18
16
24
18
24
47 (40)
27 (23)
21 (18)
60 (55)
44 (39)
(55)
93:7
95:5
92:8
91:9
92:8
87:13
92:8
87:13
89:11
91:9
75:25
88:12
80:20
84:16
4-Me (3b)
4-MeO (3c)
4-Br (3d)
4-F (3e)
3-Br (3f)
3-MeO (3g)
10. (a) Coppola, G. M.; Schuster, H. F. a-Hydroxy Acids in Enantioselective Synthesis;
Wiley-VCH: Weinheim, 1997; (b) Marques, C. S.; Moura, N.; Burke, A. J.
Tetrahedron Lett. 2006, 47, 6049–6052.
11. Martínez-Castañeda, Á.; Ke˛dziora, K.; Lavandera, I.; Rodríguez-Solla, H.;
Concellón, C.; del Amo, V. Chem. Commun. 2014, 2598–2600.
12. Chowdari, N. S.; Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas, C. F., III Org.
Lett. 2006, 8, 2839–2842.
41 (39)
a
The reaction was performed with 1 (4 equiv),
0.2 M) and the catalyst IVb (2 mol %) in toluene. syn-3c was separated by column
chromatography.
a-azido ketone (2a-g), (1 equiv,
9
13. Patonay, T.; Jekö, J.; Juhász-Toth, È. Eur. J. Org. Chem. 2008, 1441–1448.
14. Marcelli, T. In Organocatalysis: Cinchona Catalysts; John Wiley & Sons, 2011; Vol.
1,; pp 142–152
15. Marcelli, T.; Hiemstra, H. Synthesis 2010, 1229–1279.
b
Isolated yields are in parentheses.
Determined from the crude 1H NMR spectrum.
c
d
Determined by chiral HPLC.
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4
S. Okumußs et al. / Tetrahedron Letters xxx (2014) xxx–xxx
16. Catalysts IVa and IVb were synthesized according to the literature: Vakulya, B.;
Narender, M.; Rao, K. R. Tetrahedron 2007, 63, 331–336; for 2c, see: (c) Juhász-
Toth, È.; Patonay, T. Eur. J. Org. Chem. 2002, 2, 285–295; for 2d, see: (d)
9
9
Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967–1969.
17. See Supplementary data for details and further discussions.
18. Patonay, T.; Konya, K.; Juhász-Toth, È. Chem. Soc. Rev. 2011, 40, 2797–2847.
19. For the synthesis and characterization data of 2a,e, see: (a) Patonay, T.;
Hoffman, R. V. J. Org. Chem. 1994, 59, 2902–2905; for 2b, see: (b) Reddy, M. S.;
Lourenço, N. M. T.; Afonso, C. A. M. Tetrahedron 2003, 59, 789–794; (e) see the
Supplementary data for the synthesis and characterization data of 2f, g.
20. Padwa, A.; Sá, M. M.; Weingarten, M. D. Tetrahedron 1997, 53, 2371–2386.
9
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