Asymmetric direct aldol reaction of 1,2-diketones and ketones mediated by proline derivatives

Article abstract of DOI:10.1016/j.tetlet.2006.03.085

The direct aldol reaction of 1,2-diketones and ketones mediated by proline derivatives yields the corresponding 2-hydroxy 1,4-diketones in high regioselectivity, diastereoselectivity and good enantioselectivity. This reaction provides an easy access to op

Full text of DOI:10.1016/j.tetlet.2006.03.085

Tetrahedron Letters 47 (2006) 3383–3386
Asymmetric direct aldol reaction of 1,2-diketones
and ketones mediated by proline derivatives
Sampak Samanta and Cong-Gui Zhao*
Department of Chemistry, University of Texas at San Antonio, 6900 N. Loop 1604 W., San Antonio, TX 78249-0698, USA
Received 14 December 2005; revised 13 March 2006; accepted 14 March 2006
Available online 3 April 2006
Abstract—The direct aldol reaction of 1,2-diketones and ketones mediated by proline derivatives yields the corresponding 2-hydroxy
1,4-diketones in high regioselectivity, diastereoselectivity and good enantioselectivity. This reaction provides an easy access to opti-
cally active tertiary alcohols, which are flanked by two carbonyl groups for further elaborations.
Ó 2006 Elsevier Ltd. All rights reserved.
The aldol reaction is one of the most important carbon–
carbon bond formation methods in organic synthesis.1
Due to the importance of optically active compounds
in organic synthesis, medicinal chemistry and pharma-
ceutical industry, to achieve high asymmetric inductions
in the aldol reaction has been the goal of organic chem-
ists for decades. Great progress has been achieved in the
transition-metal-catalyzed asymmetric aldol reactions.2
Due to potential environmental concerns of the metal
catalysts in general, organocatalysis has become the cur-
rent research focus.3 In this regard, proline and its deriv-
atives have risen to prominence since the early discovery
of List and Barbas III that proline can catalyze the cross
aldol reaction of ketone and aldehyde in good enantio-
selectivities.4 Many new proline derivatives have been
synthesized in an effort to improve asymmetric induc-
tions and the reactivity of the original catalyst.5 So
far, catalyst loading as low as 2 mol % and enantioselec-
tivity up to >99% ee may be achieved with some of the
most recent catalysts.6 However, even with these great
advances, a successful cross aldol reaction is usually
only possible with aldehydes as the enamine acceptors.
Although the proline-catalyzed intramolecular reaction
of two ketone carbonyls is known from the very begin-
ning of this chemistry,7 examples of cross aldol reaction
using ketone as enamine acceptor have been rare. To the
best of our knowledge, only four isolated examples are
known in the literature, all were reported most recently:
Namely the proline derivative-catalyzed cross aldol
reaction of N-alkylated isatins (a-keto lactames) with ace-
tone reported by Tomasini and co-workers;8 the proline-
catalyzed synthesis of 1,3-diketones via acyl cyanides9
and the proline-catalyzed aldol reaction of ethyl phenyl-
glyoxylate (an a-keto ester) with cyclohexanone,10 and
self-aldol of 2,2-dimethyl-1,3-dioxan-5-one.11 The reason
is probably due to the low reactivity of the ketone car-
bonyl as an enamine acceptor.
Compared with normal ketone, the carbonyl groups in a
1,2-diketone are more electrophilic since the two car-
bonyl groups are activating each other through electron
withdrawal. We speculated that this type of carbonyl is
active enough as an enamine acceptor. Such a cross
aldol reaction of 1,2-diketone and ketone should pro-
duce an optically active 2-hydroxy 1,4-diketone, a very
useful building block with multiple functional groups
for further elaborations. The cross aldol reactions of
1,2-diketones and ketones have been studied sporadi-
cally in the literature with alumina or inorganic bases
as the catalysts;12 however, no asymmetric method has
ever been developed for this reaction. Herein, we wish
to report the first asymmetric synthesis of these com-
pounds via organocatalysis.
N
N
CO2H
N
H
N
H
HN
N
Keywords: Ketone; Diketone; Aldol reaction; Asymmetric; Proline.
2
1
*
Corresponding author. Tel.: +1 210 458 5432; fax: +1 210 458
7428; e-mail: cong.zhao@utsa.edu
Figure 1. L-Proline (1) and L-proline tetrazole (2).
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.085

3384
S. Samanta, C.-G. Zhao / Tetrahedron Letters 47 (2006) 3383–3386
Table 1. Cross aldol reaction of 1-aryl-1,2-propanedione and ketonesa
X
O
O
R1 R2
Catalyst
Solvent
+
O
OH
O
X
*
*
R2
O
R1
Entry
X
H
R1
R2
Solvent
T (°C)
t (h)
Yield (%)b
ee (%)c,d
1e
2e
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
DMSO
Acetone
DMF
DMSO
DMF
rt
24
72
96
24
72
96
42
96
72
24
48
89
61
51
91
63
83
53g
43h
27i
75
59
59
64
80
50
77
83
58
80
99
84
85
À15
À15
rt
À15
À35
rt
3e
4f
5f
6f
DMF
7e
DMSO
DMSO
DMSO
DMF
8e
–(CH2)3–
–(CH2)2–
rt
rt
9e
10e
11e
NO2
CF3
H
H
H
H
À15
DMF
À15
a All the reactions were conducted with 1-aryl-1,2-propanedione (0.5 mmol), ketone (0.5 mL) and the catalyst in the specified solvent (2.0 mL), unless
otherwise specified.
b Yield of isolated product after column chromatography.
c Enantiomeric excess was determined by HPLC analysis; absolute configuration of the major enantiomer was tentatively assigned as R based on the
reaction mechanism. Determination of the absolute configuration is currently under way.
d All major isomers are levorotary.
e
L-Proline (1) as the catalyst [0.25 mmol (50 mol %)].
L-Proline tetrazole (2) as the catalyst [0.15 mmol (30 mol %)].
g Only the regioisomer as shown was obtained.
h Only one diastereomer was obtained according to 1H NMR of the crude product.
i dr P 95:5.
f
We first studied the cross aldol reaction of 1-phenyl-1,2-
propanedione and acetone, catalyzed by L-proline (1)
and L-proline tetrazole (2) (Fig. 1),5i,13 and the results
are summarized in Table 1.
H
N
CO2Me
CONH2
N
H
N
H
O
3
4
Ph
Ph
The cross aldol reaction of 1-phenyl-1,2-propanedione
with acetone in DMSO at room temperature gives a
regioselective product with an ee value of 59% when
1 was used as the catalyst (entry 1). Probably due to
steric hindrance, the reaction is pretty slow and, there-
fore, large loading (50 mol %) of the catalyst was neces-
sary to achieve good yields. The ee value may be
further improved by carrying out the reaction at sub-
ambient temperature (entries 2 and 3). Catalyst 2 leads
to similar results (entries 4 and 5). The highest ee value
of 83% was achieved when the reaction was conducted
at À35 °C in DMF (entry 6). A similar reaction with 2-
butanone produced only one regioisomer (out of four
possible regioisomers), with ee value comparable to
that of acetone (entries 1 and 7). Cyclohexanone
yielded only one diastereomer in this aldol reaction,
with an ee value of 80% for the product (entry 8).
The best enantioselectivity (99% ee) was obtained for
the aldol product of cyclopentanone (entry 9). 1-(4-
Nitrophenyl)-1,2-propanedione is a more reactive sub-
strate; it also generates slightly better ee value (84%)
than its phenyl counterpart (80%, entries 10 and 3).
Similarly, 1-(4-trifluoromethylphenyl)-1,2-propanedione
also gives excellent ee value (85%) of the aldol product
(entry 11).
Ph
NH HN
HN
Ph
O
S
O
O
O
O
NH HN
NH
NH
5
6
Figure 2. Structures of L-proline derivatives used in this study.
Symmetric benzil is a poorer substrate for this reaction.
In an effort to improve the enantioselectivity, besides 1
and 2, we also screened several proline derivatives
(Fig. 2), and the results are collected in Table 2. An ee
value of 18% was obtained for the cross aldol of benzil
and acetone when 1 was used as the catalyst (entry 1).
A slightly better (23%) enantioselectivity could be
obtained when the reaction was carried out in DMSO
instead of in acetone (entry 2). L-Prolinamide (3) is a
more reactive catalyst for this reaction, yet its asymmet-
ric induction power was poorer (entry 3). Catalyst 2
gave yields comparable to 3 and enantioselectivity
slightly better than 1 (entries 4 and 5). Dipeptide ester
catalyst 46b led to poor enantioselectivity (entry 6).
The diamine-derived catalysts 5 and 6, which are very

S. Samanta, C.-G. Zhao / Tetrahedron Letters 47 (2006) 3383–3386
Table 2. Cross aldol reaction of benzil and acetonea Table 3. Cross aldol reaction of cyclic diones and acetonea
3385
O
OH
O
Ph OH
O
O
O
O
Catalyst
Solvent
Catalyst
DMSO
Ph
Ph
+
+
*
Ph
*
O
O
O
O
7
Entry Catalyst Loading Solvent t (h) Yield (%)b ee
(mol %)
(%)c
O
O
OH
OH
O
Catalyst
DMSO
1
2
3
4
5
6
7
8
1
50
50
20
20
20
30
10
10
—
24
20
42
69
33
36
21
16
24
18e
23e
10e
23e
27e
4f
+
1d
DMSO 48
—
—
O
O
2
24
24
3
3d
DMSO 24
8
4
—
—
—
24
24
24
Yield (%)b
5
26f
33f
Entry
Dione
Catalyst
t (h)
ee (%)c
6
1
2
3
4
5
7
1
3
1
3
3
96
96
96
96
72
61
48
55
57
38
48d
66d
86d
64d
56d
a All the reactions were conducted with benzil (0.25 mmol) and the
catalyst in anhydrous acetone (0.5 mL) at room temperature, unless
otherwise specified.
b Yield of isolated product after column chromatography.
c Enantiomeric excess was determined by HPLC analysis; absolute
configuration of the major enantiomer was not determined.
d Carried out in DMSO (1.0 mL) with 5.0 mmol acetone.
e The major isomer is levorotary.
7
8e
8e
8e,f
a All the reactions were conducted with the cyclic 1,2-diketone
(0.25 mmol), acetone (0.25 mL) and the catalyst (0.125 mmol,
50 mol %) in DMSO (1.0 mL).
b Yield of isolated product after column chromatography.
c Enantiomeric excess was determined by HPLC analysis; absolute
configuration of the major enantiomer was not determined.
d The major isomer is levorotary.
f The major isomer is dextrorotary.
efficient catalysts for the cross aldol reaction of ketone
and aldehyde,6f,g produced the best ee values for the
product (entries 7 and 8), yet they are still low. It is inter-
esting to note that the major enantiomer formed in the
last three cases is dextrorotary, which is opposite to that
of the previous catalysts.
e The reaction product was dissolved in CHCl3 for 24 h to give a single
diastereomer (relative configuration is shown in Table 3).
f DMF was used as the solvent.
forms dihemiacetal in situ (Table 3). A mixture of dia-
stereomers was obtained initially; however, after treat-
ing the product with CHCl3 for 24 h, all the minor
diastereomers disappeared and a single diastereomer
was obtained (relative configuration is shown in Scheme
1, which is identical to the racemic form reported by
Linko and co-workers12g). The ee value of this diastereo-
mer was determined to be 86% (entry 3). This result
indicates that the dialdolization process is totally
diastereoselective and the additional diastereomers were
due to the hemiacetal formation, during which two
new chiral centers were generated. Catalyst 2 catalyzes
the same reaction, albeit with lower enantioselectivity
(entries 4 and 5).
If this reaction also follows the normal aldol mecha-
nism,14 benzil giving poor enantioselectivity is not sur-
prising, since the energy difference between the two
diastereomeric transition states, which leads to the two
enantiomers, is not that much (axial phenyl vs axial
benzoyl, Fig. 3). We speculated that the remote hydro-
gen bonding6 formed in the cases of catalysts 5 and 6
can overturn the steric preference so that the opposite
sense of enantioselectivity is observed (entries 5 and 6),
which is worth further study.
The cross aldol reaction of some cyclic 1,2-diones and
acetone was also studied, and the results are collected
in Table 3.
In summary, we have developed the first organocatalytic
method for the asymmetric synthesis of 2-hydroxy-1,4-
diketone compounds. Although their catalytic efficiency
is low at the moment, L-proline and L-proline tetrazole
have been identified to be good catalysts for the cross
aldol reaction of 1,2-diketones and ketones, which yields
the corresponding 2-hydroxy-1,4-diketones in a highly
regioselective and diastereoselective manner with medio-
cre to excellent enantioselectivities depending on
substrate structures. Extending this reaction to other
1,2-dicarbonyl compounds is currently under way.
L-Proline (1) catalyzes the reaction of 1,2-cyclohexane-
dione (7) and acetone and gave the product in 61% yield
and 48% ee (entry 1). A similar reaction with 2 as the
catalyst produced an ee value of 66% (entry 2). L-Pro-
line-catalyzed reaction of 9,10-phenanthrenequinone
(8) and acetone generated a dialdolized product, which
Ph
N
N
O
Ph
O
O
O
H
O
H
O
O
Acknowledgements
Ph
O
Ph
TS-S
TS-R
The generous financial support for this research from
the Welch Foundation (Grant No. AX-1593) is grate-
fully appreciated.
Figure 3. Plausible transition states (TS) of the cross aldol of benzil
and acetone.

3386
S. Samanta, C.-G. Zhao / Tetrahedron Letters 47 (2006) 3383–3386
A.; Shimomoto, A.; Fujioka, S.; Kotsuki, H. Synlett 2003,
Supplementary data
11, 1655; (f) Kofoed, J.; Nielsen, J.; Reymond, J.-L.
Bioorg. Med. Chem. Lett. 2003, 13, 2445; (g) Saito, S.;
Nakadai, M.; Yamamoto, H. Synlett 2001, 1245; (h)
Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002,
58, 8167; (i) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983; (j)
Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570;
(k) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Chen, L.; Wan, J.;
Xiao, W.-J. Org. Lett. 2005, 7, 4543.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.03.085.
References and notes
6. (a) Tang, Z.; Jiang, F.; Yu, L.-T.; Gong, L.-Z.; Mi, A.-Q.;
Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125,
5262; (b) Tang, Z.; Yang, Z.-H.; Cun, L.-F.; Gong, L.-Z.;
Mi, A.-Q.; Jiang, Y.-Z. Org. Lett. 2004, 6, 2285; (c) Tang,
Z.; Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-
Z.; Wu, Y.-D. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5755; (d) Guo, H.-M.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.;
Jiang, Y.-Z. Chem. Commun. 2005, 1450; (e) Tang, Z.;
Yang, Z.-H.; Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang,
Y.-Z.; Gong, L.-Z. J. Am. Chem. Soc. 2005, 127, 9285; (f)
Samanta, S.; Liu, J.; Dodda, R.; Zhao, C.-G. Org. Lett.
2005, 7, 5321; (g) Samanta, S.; Dodda, R.; Liu, J.; Zhao,
C.-G. Unpublished results.
7. (a) Hajos, Z. G.; Parrish, D. R. German Patent, DE
2012623, 29 July 1971; (b) Hajos, Z. G.; Parrish, D. R.
J. Org. Chem. 1974, 39, 1612; (c) Eder, U.; Sauer, G.;
Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10,
496.
8. Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.;
Broxterman, Q. B.; Tomasini, C. J. Org. Chem. 2005,
70, 7418.
1. Kim, B. M.; Williams, S. F.; Masamune, S. In Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I.,
Heathcock, C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2,
pp 229–275.
2. (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122,
12003; (b) Trost, B. M.; Ito, H.; Shilcoff, E. R. J. Am.
Chem. Soc. 2001, 123, 3367; (c) Trost, B. M.; Shin, S.;
Sclafani, J. A. J. Am. Chem. Soc. 2005, 127, 8602; (d)
Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki,
M. Angew. Chem., Int. Ed. 1997, 36, 1871; (e) Shibasaki,
M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002,
1989; (f) Kumagai, N.; Matsunaga, S.; Kinoshita, T.;
Harada, S.; Okada, S.; Sakamoto, S.; Yamaguchi, K.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 2169; (g)
Mahrwald, R. Org. Lett. 2000, 2, 4011; (h) Evans, D. A.;
Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003, 125,
8706.
3. For review, see: (a) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138; (b) Adam, W.; Saha-
Mo¨ller, C. R.; Ganeshpure, P. A. Chem. Rev. 2001, 101,
3499.
9. Shen, Z.; Li, B.; Wang, L.; Zhang, Y. Tetrahedron Lett.
2005, 46, 8785.
10. Tokuda, O.; Kano, T.; Gao, W.-G.; Ikemoto, T.; Mar-
uoka, K. Org. Lett. 2005, 7, 5103.
11. Enders, D.; Grondal, C. Angew. Chem., Int. Ed. 2005, 44,
1210.
4. (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem.
Soc. 2000, 122, 2395; (b) Notz, W.; List, B. J. Am. Chem.
Soc. 2000, 122, 7386; (c) List, B.; Pojarliev, P.; Castello, C.
Org. Lett. 2001, 3, 573; (d) Sakthivel, K.; Notz, W.; Bui,
T., ; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260;
(e) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew.
Chem., Int. Ed. 2003, 42, 2785; (f) List, B. Synlett 2001,
1675; (g) List, B. Tetrahedron 2002, 58, 5573; (h) List, B.
Acc. Chem. Res. 2004, 37, 548; (i) Martin, H. J.; List, B.
Synlett 2003, 1901; (j) Notz, W.; Tanaka, F.; Barbas, C.
F., III. Acc. Chem. Res. 2004, 37, 580; (k) Notz, W.;
Watanabe, S.-i.; Chowdari, N. S.; Zhong, G.; Betancort, J.
M.; Tanaka, F.; Barbas, C. F., III. Adv. Synth. Catal.
2004, 346, 1131.
5. (a) Kano, T.; Takai, J.; Tokuda, O.; Maruoka, K. Angew.
Chem., Int. Ed. 2005, 44, 3055; (b) Bøgevig, A.; Kumara-
gurubaran, N.; Jørgensen, K. A. Chem. Commun. 2002,
620; (c) Northrup, A. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 6798; (d) Northrup, A. B.;
Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew.
Chem., Int. Ed. 2004, 43, 2152; (e) Sekiguchi, Y.; Sasaoka,
12. (a) Allen, C. F. H. Can. J. Res. 1931, 4, 264; (b) Allen, C.
F. H.; Van Allan, J. A. J. Org. Chem. 1951, 16, 716; (c)
Magnusson, R. Acta Chem. Scand. 1958, 12, 791; (d)
Magnusson, R. Acta Chem. Scand. 1960, 14, 1643; (e)
Ried, W.; Guersan, C. Chem. Ber. 1968, 101, 2598; (f)
Strunz, G. M.; Yu, C. M. Can. J. Chem. 1988, 66, 1081; (g)
Linko, R. V.; Belsky, V. K.; Varlamov, A. V.; Zaitsev, B.
E.; Chernyshev, A. I. Russ. Chem. Bull. (Engl. Transl.)
2001, 50, 1625.
13. Cobb, A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 558.
14. (a) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J.
Am. Chem. Soc. 2003, 125, 2475; (b) Hoang, L.; Bahman-
yar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125,
16; (c) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc.
2001, 123, 12911.