Asymmetric direct aldol reaction of cyclohexanone catalyzed by (N′-benzyl-N′-D-prolyl)-trans-4-hydroxy-L-proline hydrazide

Article abstract of DOI:10.1002/cjoc.201190051

A new proline catalyst, namely (N′-benzyl-N′-D-prolyl)-trans-4- hydroxy-L-proline hydrazide, has been prepared and proved to be a superior catalyst for the asymmetric aldol reaction of cyclohexanone and aromatic aldehydes, affording up to 98:2 dr and 98%

Full text of DOI:10.1002/cjoc.201190051

NOTE
Asymmetric Direct Aldol Reaction of Cyclohexanone Catalyzed
by (N'-Benzyl-N'-D-prolyl)-trans-4-
hydroxy-L-proline Hydrazide
Cheng, Chuanling*(程传玲)
Wang, Wenliang(汪文良)
School of Food and Biological Engineering, Zhengzhou University of Light Industry,
Zhengzhou, Henan 450002, China
A new proline catalyst, namely (N'-benzyl-N'-D-prolyl)-trans-4-hydroxy-L-proline hydrazide, has been pre-
pared and proved to be a superior catalyst for the asymmetric aldol reaction of cyclohexanone and aromatic alde-
hydes, affording up to 98∶ 2 dr and 98% ee.
Keywords asymmetric aldol reaction, proline hydrazide, enantioselectivity, diastereoselectivity, cyclohexanone
Introduction
The asymmetric direct aldol reaction is one of the
most powerful C—C bond forming reactions for the
production of chiral 1,3-dioxygenated compounds.1 The
development of novel chiral organocatalyts for this
transformation has recently been the subject of intense
research2 since List, Barbas and Lehner reported that
L-proline could effectively catalyze the intermolecular
direct aldol reaction.3 A number of proline derivatives
have emerged as highly efficient and stereoselective
catalysts (for selected examples, see references 4—38).
Among them, proline hydrazides, upon protonation with
trifluoroacetic acid (TFA), behaved as highly efficient
and enantioselective catalyst in the aldol reaction of
aromatic aldehydes and ketones.19 In previous studies,
Sun et al.20 has also proved that (N'-benzyl-N'-L-prolyl)-
trans-4-hydroxy-L-proline hydrazide (1, Figure 1) was a
good catalyst for the asymmetric aldol reaction of
cyclohexanone with aromatic aldehydes, resulting in
excellent diastereoselectivity (up to 99∶1 dr) and
enantioselectivity (up to＞99% ee). In the catalysts cited
above,19,20 pyrrolidinyl groups are L-configuration. We
speculated that new catalysts with different configura-
tion of the pyrrolidinyl groups may have influence on
the output in terms of both enantioselectivity and di-
astereoselectivity during catalyzing the aldol reaction.
Herein, we report the preparation of one of the catalyst
1’s diastereoisomers, (N'-benzyl-N'-L-prolyl)-trans-4-
hydroxy-L-proline hydrazide’s counterpart—(N'-benzyl-
N'-D-prolyl)-trans-4-hydroxy-L-proline hydrazide (2,
Figure 1) and its application as a catalyst for the aldol
reaction of cyclohexanone and aromatic aldehydes. It
proved to be an excellent catalyst, affording up to 98∶2
dr and 98% ee.
Figure 1 Structures of proline 1 and 2.
Results and discussion
Preparation of organocatalysts (2, Scheme 1)19
To a solution of 2a (935 mg, 8.8 mmol) in PhCH3
(20 mL) was added benzaldehyde (935 mg, 8.8 mmol).
The reaction mixture was stirred at room temperature
for 24 h, and then concentrated under reduced pressure.
The residue was dissolved in methanol (80 mL), then
5% Pd/C (0.2 g) was added into the reaction. After stir-
ring under hydrogen (1.01×103 kPa) for 1 h, the reac-
tion mixture was filtered. The filtrate was concentrated
under reduced pressure. The residue was purified
through column chromatography on silica gel [eluent:
petroleum ether (PE)∶ethyl acetate (EtOAc)＝3∶1] to
give 2b.
To a solution of 2b (2.0 mmol) in dimethylforma-
mide (DMF, 20 mL) was added Boc-D-Pro (2.4 mmol),
N,N-diisopropylethylamine (DIEA, 700 µL) and 2-(7-
aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU, 922 mg, 2.4 mmol) at 0
℃. The reaction mixture was stirred at room tempera-
ture for 24 h, then concentrated under reduced pressure.
The residue was dissolved in EtOAc. The organic phase
was then washed with saturated aqueous NaHCO3 and
brine and dried over anhydrous Na2SO4. After removal
of solvent under reduced pressure, the residue was puri-
fied through column chromatography on silica gel (elu-
ent: PE∶EtOAc＝2∶1) to give a white solid, which
*
E-mail: chuanlingcheng@163.com; Tel.: 13253556627
Received July 18, 2010; revised September 5, 2010; accepted September 26, 2010.
196
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 196— 198

Asymmetric Direct Aldol Reaction of Cyclohexanone
was then treated with a mixture of TFA: methylene di-
chloride (DCM) (V/V＝1∶2, 20 mL). After stirring at
room temperature for 1 h, the reaction mixture was
concentrated under reduced pressure. The residue was
subjected to chromatography on a H＋－ ion-exchange
Table 1 Direct aldol reactions of aldehydes with cyclohexanone
catalyzed by 2a
1
resin column with NH3•H2O (3.0 mol•L ) as eluent to
give a crude product, which was further purified
through column chromatography on silica gel [eluent:
DCM saturated with ammonia gas∶methanol (MeOH)＝
10∶1] to give the final product 2, white solid, yield
50%; [α]2D5 ＋10.6 (c 0.246, MeOH); m.p. 128—130 ℃;
1H NMR (CD3OD, 600 MHz) δ: 1.69—1.84 (m, 4H),
2.02 (q, J ＝7.86 Hz, 2H), 2.77—2.82 (m, 2H),
2.87—2.89 (br s, 1H), 3.13—3.17 (m, 1H), 3.83 (q, J＝
9.00 Hz, 1H), 4.31 (brs, 1H), 4.65 (brs, 1H), 4.87 (brs,
1H), 7.29— 7.34 (m, 3H), 7.35—7.38 (m, 2H); 13C
NMR (CD3OD, 150 MHz) δ: 25.6, 29.9, 39.3, 46.6, 48.4,
50.5, 54.7, 57.5, 58.1, 71.8, 127.6, 128.3, 128.9, 135.3,
174.4, 175.8; ESI HRMS for calcd C17H24N4O3 [M＋H]＋
333.1921, found 333.1926.
Time/
h
drc
(anti/syn)
eed/%
(anti)
Entry
R
Yieidb/%
4-NO2Ph
3-NO2Ph
2-NO2Ph
4-CNPh
4-ClC6H4
4-BrC6H4
2-ClC6H4
Ph
1
2
3
4
5
6
7
8
9
1
3
99
99
98
95
96
98
97
82
71
58
68
68
95
97
82
98/2
96/4
95/5
97/3
97/3
98/2
95/5
90/10
95/5
95/5
96/4
94/6
94/6
98/2
98/2
97
94
96
95
95
95
98
94
93
92
93
93
95
98
97
4
Scheme 1 Preparation of proline hydrazide 2
3
50
50
24
50
72
50
50
72
0.5
3
4-MeC6H4
10 4-MeOC6H4
11 3-MeOC6H4
12 1-naphthyl
13 4-Py
14 3-Py
15 2-furfuryl
50
16
50
71
95/5
94
17e 4-NO2Ph
18f 4-NO2Ph
3
6
98
98
98/2
98/2
98
97
a Unless specified otherwise, the reaction was carried out with
b
catalyst 2 (20 mol%) and TFA (20 mol%). Isolated yield based
c
on the aldehyde. Determined by chiral HPLC analysis of the
d
mixture of the anti/syn product. For the major anti isomer, de-
termined by chiral HPLC. e In the presence of 10 mol% catalyst 2
and 10 mol% TFA. In the presence of 5 mol% catalyst 2 and 5
f
The direct aldol reaction of cyclohexanone catalyzed
by organocatalyst 2
mol% TFA.
For the purpose of comparison with catalyst 1, the
established optimal condition, namely 20 mol% catalyst
2 and 20 mol% TFA, at 0 ℃, with toluene－as solvent
dr for the anti/syn isomers) and enantioselectivity (up to
98% ee for the major anti isomer). High dr and ee val-
ues were also obtained with the relatively electron-rich
aldehydes (Entries 8—12), which, however, afforded
moderate to high yields due to their attenuated reactivi-
ties. Not unsurprisingly, the heteroaromatic aldehydes
also proved to be good substrates (Entries 13—16),
which reacted well to give the corresponding aldol
products in high diastereoselectivity and enantioselec-
tivity (up to 98/2 dr and 98% ee). Decreasing the load-
1
and the concentration of reaction 0.5 mol•L , was di-
rectly used.20 Under this condition, a range of aromatic
aldehydes were reacted with cyclohexanone in the
presence of organocatalyst 2. As shown in Table 1, the
reactions of benzaldehydes bearing electron-withdraw-
ing groups on the benzene ring proceeded smoothly to
furnish the aldol products in high yield (up to 99%, En-
tries 1—7) and excellent diastereoselectivity (up to 98/2
Chin. J. Chem. 2011, 29, 196— 198
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
197

Cheng & Wang
NOTE
9285.
ing of the catalyst to 10% or 5% merely slowed down
the reaction to some extent but did not sacrifice either
the yield or the selectivity (Entries 17—18). Notably,
catalyst 2 proved to be ineffective for aliphatic alde-
hydes. The results showed that catalyst 2 had the same
catalytic activity with catalyst 1, which further proved
that the pyrrolidinyl group closer to the hydrazide NH
(on the left) plays the central role in the enamine forma-
tion in the course of the aldol reaction, whereas the
other pyrrolidinyl group (on the right) mainly functions
as a hydrogen-bond donor. Changing the configuration
of this right-hand pyrrolidinyl group from L to D does
not affect the diastereoselectivity and enantioselectivity
of the aldol reaction.
11 Krattiger, P.; Kovasy, R.; Revell, J. D.; Ivan, S.; Wenne-
mers, H. Org. Lett. 2005, 7, 1101.
12 Chen, J.; Lu, H.; Li, X.; Cheng, L.; Wan, J.; Xiao, W. Org.
Lett. 2005, 7, 4543.
13 Samanta, S.; Liu, J.; Dodda, R.; Zhao, C. Org. Lett. 2005, 7,
5321.
14 Wang, W.; Li, H.; Wang, J. Tetrahedron Lett. 2005, 46,
5077.
15 Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J.
B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84.
16 Tang, Z.; Cun, L. F.; Cui, X.; Mi, A. Q.; Jiang, Y. Z.; Gong,
L. Z. Org. Lett. 2006, 8, 1263.
17 Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.;
Urushima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45,
958.
18 Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Ta-
naka, F.; Barbas III, C. F. J. Am. Chem. Soc. 2006, 128,
734.
19 Cheng, C.; Sun, J.; Wang, C.; Zhang, Y.; Wei, S.; Jiang, F.;
Wu, Y. D. Chem. Commun. 2006, 215.
20 Cheng, C.; Wei, S.; Sun, J. Synlett 2006, 15, 2419.
21 Raj, M.; Vishnumaya, S. K. G.; Singh, V. K. Org. Lett.
2006, 8, 4097.
22 Chen, J. R.; Li, X. Y.; Xing, X. N.; Xiao, W. J. J. Org.
Chem. 2006, 71, 8198.
23 Russo, A.; Botta, G.; Lattanzi, A. Synlett 2007, 5, 795.
24 Russo, A.; Botta, G.; Lattanzi, A. Tetrahedron 2007, 63,
11886.
25 Huang, W. P.; Chen, J. R.; Li, X. Y.; Cao, Y. J.; Xiao, W. J.
Can. J. Chem. 2007, 85, 208.
26 Puleo, G. L.; Masi, M.; Iuliano, A. Tetrahedron: Asymmetry
2007, 18, 1364.
27 Yu, G.; Ge, Z. M.; Cheng, T. M.; Li, R. T. Chin. J. Chem.
2008, 26, 911.
28 Sato, K.; Kuriyama, M.; Shimazawa, R.; Morimoto, T.;
Kakiuchi, T. K.; Shirai, R. Tetrahedron Lett. 2008, 49,
2402.
Conclusions
In summary, we have demonstrated that N'-benzyl-
N'-D-prolyl-trans-4-hydroxy-L-proline hydrazide (2) is
also a superior catalyst similar to its counterpart 120 for
the asymmetric direct aldol reaction of cyclohexanone
with aromatic aldehydes. In the presence of this catalyst,
excellent diastereoselectivities (up to 98/2 dr) and enan-
tioselectivities (98% ee) were obtained for a broad range
of aromatic aldehydes, including heteroaromatic alde-
hydes. It is worth to be noted that the results obtained
with catalyst 2 further verified the catalytic mechanism
with proline hydrazides as proposed previously.19 Fur-
ther studies focusing on the mechanistic aspects and the
full application scope of this catalyst system are cur-
rently underway and will be reported in due course.
References
1
Mahrwarld, R. Modern Aldol Reactions, Vols. 1, 2, Wiley-
VCH, Weinheim, 2004.
2
For recent reviews, see: (a) Palomo, C.; Oiarbide, M.; Gar-
cia, J. M. Chem. Soc. Rev. 2004, 33, 65.
29 Zhao, J. F.; He, L.; Jiang, J.; Tang, Z.; Cun, L. F.; Gong, L.
Z. Tetrahedron Lett. 2008, 49, 3372.
30 Chen, J. R.; An, X. L.; Zhu, X. Y.; Wang, X. F.; Xiao, W. J.
J. Org. Chem. 2008, 73, 6006.
31 Doherty, S.; Knight, J. G.; McRae, A.; Harrington, R. W.;
Clegg, W. Eur. J. Org. Chem. 2008, 73, 1759.
32 Gandhi, S.; Singh, V. K. J. Org. Chem. 2008, 73, 9411.
33 Jia, Y. N.; Wu, F. C.; Ma, X.; Zhu, G. J.; Da, C. S. Tetrahe-
dron Lett. 2009, 50, 3059.
(b) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570.
(a) List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem.
Soc. 2000, 122, 2395.
(b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C. F. J. Am.
Chem. Soc. 2001, 123, 5260.
(c) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386.
Tang, Z.; Jiang, F.; Yu, L. T.; Cui, X.; Gong, L. Z.; Mi, A.
Q.; Jiang, Y. Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125,
5262.
3
4
34 Zhang, S. P.; Fu, X. K.; Fu, S. D. Tetrahedron Lett. 2009,
50, 1173.
35 Okuyama, Y.; Nakano, H.; Watanabe, Y.; Makabe, M.;
Takeshita, M.; Uwai, K.; Kabuto, C.; Kwon, E. Tetrahedron
Lett. 2009, 50, 193.
36 Han, J.; Wu, H.; Teng, M.; Li, Z.; Wang, Y.; Wang, L.; Pan,
Y. Synlett 2009, 6, 933.
37 Urushima, T.; Yasui, Y.; Ishikawa, H.; Hayashi, Y. Org.
Lett. 2010, 12, 2966.
5
6
7
8
9
Tang, Z.; Yang, Z. H.; Cun, L. F.; Gong, L. Z.; Mi, A. Q.;
Jiang, Y. Z. Org. Lett. 2004, 6, 2285.
Mase, N.; Tanaka, F.; Barbas III, C. F. Angew. Chem., Int.
Ed. 2004, 43, 2420.
Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto,
H. Angew. Chem., Int. Ed. 2004, 43, 1983.
Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jør-
gensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790.
Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal. 2004,
346, 1141.
38 Wei, S. W.; Stingl, A. K.; Wei, K. M.; Tsogoeva, S. B.
Synlett 2010, 5, 707.
10 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,
(E1007181 Sun, H.; Dong, H.)
198
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 196— 198