Direct asymmetric aldol reactions catalyzed by l-proline-2,4,6-trinitroanilide

Article abstract of DOI:10.1016/j.tetlet.2008.02.066

Direct aldol reactions of several aromatic aldehydes with ketones using l-proline-2,4,6-trinitroanilide catalyst 2d were conducted. Under optimized conditions, high enantioselectivity (99% ee), regioselectivity (up to 95:5), and diastereoselectivity (up to 98:2) were achieved.

Full text of DOI:10.1016/j.tetlet.2008.02.066

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Tetrahedron Letters 49 (2008) 2402–2406
Direct asymmetric aldol reactions catalyzed
by L-proline-2,4,6-trinitroanilide
Kosuke Sato a, Masami Kuriyama b, Rumiko Shimazawa b, Tsumoru Morimoto a,
Kiyomi Kakiuchi a, Ryuichi Shirai a,b,
*
a Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), Nara 630-0192, Japan
b Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kyoto 610-0395, Japan
Received 15 December 2007; revised 7 February 2008; accepted 12 February 2008
Available online 14 February 2008
Abstract
Direct aldol reactions of several aromatic aldehydes with ketones using L-proline-2,4,6-trinitroanilide catalyst 2d were conducted.
Under optimized conditions, high enantioselectivity (99% ee), regioselectivity (up to 95:5), and diastereoselectivity (up to 98:2) were
achieved.
Ó 2008 Elsevier Ltd. All rights reserved.
Asymmetric aldol reactions are one of the most valuable
fundamental C–C bond forming reactions because they
give synthetically useful chiral building blocks.1 Although
first reported in the 1970s that the L-proline (1) catalyzed
intramolecular aldol reactions,2 L-proline remained undev-
eloped for the next 30 years. After List and Barbas adopted
1 for intermolecular aldol reactions,3 it has been reevalu-
ated in asymmetric aldol reactions.4 List’s work4f,g on the
mechanism of intermolecular aldol reactions proposed that
the enamine formed rigid transition states where the chiral-
ity was regulated through hydrogen-bonding with the car-
bonyl group of the aldehyde (Scheme 1). Recently, new
additions are continuously being made to the list of organ-
ocatalysts that can yield high enantioselectivity through the
transition state related to the above: L-proline aliphatic
amides,5 L-proline aromatic amides,6 chiral pyrrolidines
with tetrazole,7 chiral pyrrolidines with sulfonamide,8 4-
substituted L-prolines,9 chiral diamine-protonic acids,10
and axially chiral amino acids.11 Gong disclosed that when
L-prolineanilide analogs were used in asymmetric aldol
reactions, ee of aldol adducts increased as the electron-
withdrawing ability of 4-substituent of anilide increased.5b
However, L-proline-4-nitroanilide (2b), which had strong
electron-withdrawing group12 on the aromatic ring, gave
low enantioselectivity.5b In this Letter, we report asymmet-
ric direct aldol reactions catalyzed by novel L-proline-2,4,6-
trinitroanilide (2d), which possesses a strong acidic N–H
moiety caused by three electron-withdrawing nitro groups
(see Fig. 1).
Reaction of 2a13 with fuming nitric acid (6 equiv) and
sulfuric acid in chloroform gave 2d in high yield (Scheme
2).14 The optical purity of 2d was confirmed to be pure
(>99% ee) in comparison with the DL-2d by chiral HPLC.15
The aldol reactions of acetone with 4-nitrobenzaldehyde
(4a) are shown in Table 1.16 When using catalyst 2d and
HMPA as a solvent, ee was highest (85% ee) among the
solvents investigated; however, the yield of the adduct
was only 20% (entry 6). This is due to the formation of
*
Corresponding author. Tel./fax: +81 774 65 8510.
Fig. 1. L-Proline and its nitroanilide analogs.
E-mail address: rshirai@dwc.doshisha.ac.jp (R. Shirai).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.066

K. Sato et al. / Tetrahedron Letters 49 (2008) 2402–2406
2403
Scheme 1. Proposed mechanism for asymmetric direct aldol reaction
catalyzed by L-proline (1).
Fig. 2. Structures of L-prolineanilide analogs 2a–d, 3a–f.
the yield was not improved even in the presence of weak
acids (entries 10 and 11). At best, the aldol adduct was
obtained in 90% yield and 85% ee when 4a (1 equiv) was
reacted with acetone (20 equiv) in HMPA (3 mL) and
water (30 equiv) for 4 d (entry 12). In the reactions using
several L-proline-nitroanilide catalysts 2a–d,17 ee of aldol
adducts increased as the number of nitro group of catalysts
increased (entries 12–15). Similarly, ee of aldol adducts
increased as the electron-withdrawing ability of 2,6-substit-
uents of the catalysts 3a–e18 increased (entries 16–20), and
the reaction using 3f18 gave 5a with 88% yield and 87% ee.
Scheme 2. Synthesis of L-proline-2,4,6-trinitroanilide 2d.
dehydration and double aldol reaction products. To
improve catalytic turnover, water and weak acid5o were
added (entries 7–11). The formation of byproducts was
suppressed without the loss of enantioselectivity when
30 equiv of water was added (entries 8 and 9). However,
Table 1
Direct asymmetric aldol reactions of 4-nitrobenzaldehyde 4a with acetone
Entrya
Acetone
Solvent H2O
Weak acid
Catalyst
5a
6 Yieldb (%) 7d Yieldb (%) 4a Recoveryb (%)
Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
9
10
11
12e
13e
14e
15e
16e
17e
18e
19e
20e
21e
a
10 equiv
10 equiv
10 equiv
10 equiv
10 equiv
10 equiv
10 equiv
10 equiv
20 equiv
20 equiv
20 equiv
20 equiv
20 equiv
20 equiv
20 equiv
20 equiv
20 equiv
20 equiv
20 equiv
20 equiv
20 equiv
None
CH2Cl2 0 equiv
THF
DMF
DMSO 0 equiv
HMPA 0 equiv
HMPA 5 equiv
HMPA 30 equiv None
HMPA 30 equiv None
0 equiv
None
None
None
None
None
None
None
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
79
65
58
41
33
20
53
42
56
49
55
90
88
80
90
18
89
80
72
96
88
20
ꢀ17
20
61
76
85
87
85
84
84
83
85
8
Trace
9
9
11
18
Trace
Trace
7
13
5
18
11
7
6
6
19
9
54
0 equiv
0 equiv
12
7
12
7
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
18
Trace
Trace
Trace
7
41
47
41
HMPA 30 equiv HOAc (0.2 equiv)
HMPA 30 equiv PhCOOH (0.2 equiv) 2d
HMPA 30 equiv None
HMPA 30 equiv None
HMPA 30 equiv None
HMPA 30 equiv None
HMPA 30 equiv None
HMPA 30 equiv None
HMPA 30 equiv None
HMPA 30 equiv None
HMPA 30 equiv None
HMPA 30 equiv None
2d
2a
2b
2c
3a
3b
3c
3d
3e
3f
Trace
Trace
Trace
Trace
70
Trace
Trace
Trace
Trace
Trace
54
82
4
9
18
50
63
87
18
Trace
Trace
The reaction of 4a (0.3 mmol, 1 equiv) with acetone was conducted in the indicated solvent (3 mL) and H2O in the presence of catalyst (0.06 mmol,
0.2 equiv) at room temperature for 1 d.
b
Isolated yield.
c
Optical purity was determined by chiral HPLC (CHIRALPAK AS-H). Absolute configuration of the major enantiomer was determined by comparing
the measured optical rotation.4j
d
Relative and absolute configuration were unclear.
The reaction was conducted for 4 d.
e

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K. Sato et al. / Tetrahedron Letters 49 (2008) 2402–2406
Table 2
from 78% ee to 89% ee (entries 1–5). The chemical yield
of the adducts increased as the strength of the electron-
withdrawing property increased. Reactions of aromatic
aldehyde with no electron-withdrawing group were very
slow, and the reactions did not complete even after 4 days
(entries 2 and 3). When 4d was used as a substrate, the
aldol adducts 5d were obtained in 65% yield and 88% ee,
but dehydrated byproducts were obtained in 30% yield
(entry 4). Reaction of heteroaromatic aldehyde 4g gave
5g with 48% yield and 82% ee (entry 6). The reactivity of
aliphatic aldehyde 4f was very low to give trace amount
of 5g (entry 7).
Next, aldol reactions between 4a and several ketones
catalyzed by 2d were investigated (Table 3). The reactivity
of sterically hindered ketones was low (entries 4–6). Reac-
tion of cyclopentanone with 4a gave 5l with high ee (96%
ee), but diastereoselectivity (anti:syn) was moderate
(71:29) (entry 7). Reaction of 2-butanone with 4-nitrobenz-
aldehyde gave anti-5h with 56% yield and 99% ee (entry 3).
In this case, diastereoselectivity was very high (98:2), but
regioselectivity (5:8) was low (62:38). When chloroacetone
was used as a substrate, the aldol adducts 5m were obtained
in 90% yield and 98% ee (anti) with high diastereo-
selectivity (94:6) and regioselectivity (92:8) (entry 9).
In conclusion, we synthesized novel organocatalyst L-
proline-2,4,6-trinitroanilide (2d), and applied it for direct
asymmetric aldol reactions. Under optimized conditions,
high enantioselectivity (up to 99% ee), regioselectivity (up
to 95:5), and diastereoselectivity (up to 98:2) were achieved.
Further mechanical study as well as the application of 2d to
the other reactions is currently underway.
Direct asymmetric aldol reaction of aromatic aldehyde with acetone
catalyzed by 2d
Entrya
Aldehyde
R
Yieldb (%)
eec (%)
1
2
3
4d
5
6
7
a
4a
4b
4c
4d
4e
4f
4-NO2Ph
Ph
5a
5b
5c
5d
5e
5f
90
8
Trace
65
85
78
n.d.
88
89
4-OMePh
4-ClPh
2-NO2Ph
2-Pyridyl
C6H11
87
48e
Trace
82
n.d.
4g
5g
The reaction of aldehyde (0.3 mmol, 1 equiv) with acetone (6.0 mmol,
20 equiv) was conducted in HMPA (3 mL) and H2O (9.0 mmol, 30 equiv)
in the presence of 2d (0.06 mmol, 0.2 equiv) at room temperature for 4 d.
b
Isolated yield.
c
Optical purity was determined by chiral HPLC (CHIRALPAK AS-H).
Absolute configuration of the major enantiomer was determined by
comparing the measured optical rotation.4j
d
The reaction was conducted for 12 d in the presence of H2O (15 equiv).
Although the reaction proceeded in good conversion, the isolation
e
procedure was not optimized due to high hydrophilicity of 5f.
It is demonstrated that the inductive electron-withdrawing
groups on the aromatic ring are also effective for high ee
(see Fig. 2).
The generality of the substrates of the aldol reactions
was elucidated (Table 2). In the reactions of acetone with
several aldehyde catalyzed by 2d, ee of aldol adducts was
Table 3
Direct asymmetric aldol reaction of 4-nitrobenzaldehyde 5a with ketones catalyzed by 2d
Entrya
Ketone
R2
5
rrc (5:8)
8
R1
Yieldb (%)
drc (anti:syn)
eed (%) anti; (syn)
Yieldb (%)
eed (%)
1
2
3e
4
5
6
7
8
9f
a
H
Me
Me
Me
Me
Et
90 (5a)
—
85
—
—
—
87
93
n.d.
—
—
—
n.d.
80
Me
Me
Et
Me
H
23 (anti-5h), Trace (syn-5h)
56 (anti-5h), Trace (syn-5h)
Trace (5i)
None (5j)
None (5k)
87 (anti-5l + syn-5l)
44 (anti-5m + syn-5m)
90 (anti-5m + syn-5m)
98:2
98:2
n.d.
—
98; (n.d.)
99; (n.d.)
n.d.
—
—
96; (54)
95; (21)
98; (21)
63:37
62:38
n.d.
—
13 (8h)
34 (8h)
Trace
—
—
—
Ph
—
—
Cyclopentanone
Cl
Cl
71:29
93:7
94:6
Me
Me
95:5
92:8
Trace
7 (8m)
The reaction of 4a (0.3 mmol, 1 equiv) with ketone (6.0 mmol, 20 equiv) in HMPA (3 mL) and H2O (9.0 mmol, 30 equiv) was conducted in the presence
of 2d (0.06 mmol, 0.2 equiv) at room temperature for 4 d.
b
Isolated yield.
c
Diastereoisomeric and regioisomeric ratios were obtained by 1H NMR of the crude mixture.
d
Optical purity was determined by chiral HPLC (CHIRALPAK AS-H or AD-H). Absolute configuration of the major enantiomer was determined by
comparing the measured optical rotation and the retention times with the reported data.4j,5d,8b,19
e
The reaction was conducted for 12 d in the presence of H2O (15 equiv).
In the presence of H2O (15 equiv) and 2d (0.5 equiv).
f

K. Sato et al. / Tetrahedron Letters 49 (2008) 2402–2406
2405
Tetrahedron: Asymmetry 2006, 17, 1493; (d) Guizzetti, S.; Benaglia,
M.; Pignataro, L.; Puglisi, A. Tetrahedron: Asymmetry 2006, 17, 2754;
(e) Fu, Y.-Q.; Li, Z.-C.; Ding, L.-N.; Tao, J.-C.; Zhang, S.-H.; Tang,
M.-S. Tetrahedron: Asymmetry 2006, 17, 3351; (f) Ma, G.-N.; Zhang,
Y.-P.; Shi, M. Synthesis 2007, 197; (g) Guizzetti, S.; Benaglia, M.;
Raimondi, L.; Celentano, G. Org. Lett. 2007, 9, 1247; (h) Guillena,
G.; Hita, M. C.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 1272;
(i) Wang, C.; Jiang, Y.; Zhang, X.-X.; Huang, Y.; Li, B.-G.; Zhang,
G.-L. Tetrahedron Lett. 2007, 48, 4281; (j) Russo, A.; Botta, G.;
Lattanzi, A. Tetrahedron 2007, 63, 11886; (k) Kikuchi, M.; Inagaki,
T.; Nishiyama, H. Synlett 2007, 1075.
Acknowledgments
This work was supported by Grant-in-Aid for Scientific
Research (C) (No. 18590023) from the Japan Society for
the Promotion of Science, Grant-in-Aid for Scientific
Research on Priority Areas ‘Advanced Molecular Trans-
formations of Carbon Resources’ from MEXT, and by
Kyoto-Advanced Nanotechnology Network. We are grate-
ful to Professor Gong for the helpful information of the
aldol reactions using chloroacetone. We also thank Mr.
Asanoma for elemental analysis, and Ms. Nishikawa for
the measurement of HRMS.
7. (a) Hartikka, A.; Arvidsson, P.-I. Tetrahedron: Asymmetry 2004, 15,
1831; (b) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto,
H. Angew. Chem., Int. Ed. 2004, 43, 1983; (c) Saito, S.; Yamamoto, H.
Acc. Chem. Res. 2004, 37, 570.
8. (a) Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal. 2004, 346, 1141;
(b) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8,
4417.
References and notes
9. (a) Bellis, E.; Kokotos, G. Tetrahedron 2005, 61, 8669; (b) Hayashi,
Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M.
Angew. Chem., Int. Ed. 2006, 45, 958; (c) Tang, X.; Liegault, B.;
Renaud, J.-L.; Bruneau, C. Tetrahedron: Asymmetry 2006, 17,
2187.
10. (a) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245; (b)
Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002, 58, 8167; (c)
Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734.
1. (a) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000,
39, 1352; (b) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc. Rev.
2004, 33, 65; (c) Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron:
Asymmetry 2007, 18, 2249; (d) Mukherjee, S.; Yang, J. W.; Hoffmann,
S.; List, B. Chem. Rev. 2007, 107, 5471.
2. (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
1971, 10, 496; (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39,
1615.
3. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395.
11. (a) Kano, T.; Takai, J.; Tokuda, O.; Maruoka, K. Angew. Chem., Int.
Ed. 2005, 44, 3055; (b) Kano, T.; Tokuda, O.; Maruoka, K.
Tetrahedron Lett. 2006, 47, 7423; (c) Kano, T.; Yamaguchi, Y.;
Tanaka, Y.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 1738.
12. Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96.
4. (a) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386; (b)
Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc.
2001, 123, 5260; (c) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001,
3, 573; (d) Cordova, A.; Notz, W.; Barbas, C. F., III. Chem. Commun.
2002, 3024; (e) Northrup, A. B.; Macmillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 6798; (f) Hoang, L.; Bahmanyar, S.; Houk, K. N.;
List, B. J. Am. Chem. Soc. 2003, 125, 16; (g) Bahmanyar, S.; Houk, K.
N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475; (h) List,
B.; Hoang, L.; Martin, H. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5839; (i) Northrup, A. B.; Mangion, I. K.; Hettche, F.; Macmillan, D.
W. C. Angew. Chem., Int. Ed. 2004, 43, 2152; (j) Zhou, Y.; Shan, Z.
Tetrahedron: Asymmetry 2006, 17, 1671.
5. (a) 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; (b) 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; (c) Tang, Z.; Yang, Z.-
H.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org. Lett. 2004,
6, 2285; (d) 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; (e)
Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.; Xiao, W.-J.
Org. Lett. 2005, 7, 4543; (f) Samanta, S.; Liu, J.; Dodda, R.; Zhao,
C.-G. Org. Lett. 2005, 7, 5321; (g) He, L.; Tang, Z.; Cun, L.-F.; Mi,
A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Tetrahedron 2006, 62, 346; (h)
Chimni, S. S.; Mahajan, D. Tetrahedron: Asymmetry 2006, 17, 2108;
(i) Vishnumaya, M. R.; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006,
8, 4097; (j) Chen, J.-R.; Li, X.-Y.; Xing, X.-N.; Xiao, W.-J. J. Org.
Chem. 2006, 71, 8198; (k) Zheng, J.-F.; Li, Y.-X.; Zhang, S.-Q.; Yang,
S.-T.; Wang, X.-M.; Wang, Y.-Z.; Liu, F.-A. Tetrahedron Lett. 2006,
47, 7793; (l) Xu, X.-Y.; Wang, Y.-Z.; Cun, L.-F.; Gong, L.-Z.
Tetrahedron: Asymmetry 2007, 18, 237; (m) Lei, M.; Shi, L.; Li, G.;
Chen, S.; Fang, W.; Ge, Z.; Cheng, T.; Li, R. Tetrahedron 2007, 63,
7892; (n) Chen, X.-H.; Luo, S.-W.; Tang, Z.; Cun, L.-F.; Mi, A.-Q.;
Jiang, Y.-Z.; Gong, L.-Z. Chem. Eur. J. 2007, 13, 689; (o) Huang, W.-
P.; Chen, J.-R.; Li, X.-Y.; Cao, Y.-J.; Xiao, W.-J. Can. J. Chem. 2007,
85, 208.
13. O’Brien, P.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1996,
2117.
14. Procedure for the synthesis of L-proline-2,4,6-trinitroanilide (2d): To a
solution of an L-prolineanilide (2a) (2.00 g, 10.5 mmol) in chloroform
(40 mL) and sulfuric acid (8 mL), fuming nitric acid (2.6 mL,
63.5 mmol) was added at 0 °C. After being stirred at room temper-
ature for 12 h, the reaction was quenched with saturated NaHCO3
(500 mL). The resulting mixture was extracted with ethyl acetate
(400 mL ꢁ 3) and the organic layers were dried over anhydrous
Mg2SO4, and the solvent was removed in vacuo. The residue was
recrystallized by acetonitrile to give 2d as a yellow prism 2.79 g
(8.6 mmol, 82%). Analytical data for 2d: mp 174–178 °C. 1H NMR
(500 MHz, DMSO-d6) 9.00 (1H, br), 8.66 (2H, s), 8.35 (1H, br), 4.05
(1H, dd, J = 7.6, 7.0 Hz), 3.23 (1H, dt, J = 11.0, 6.5 Hz), 3.11 (1H, dt,
J = 11.0, 7.3 Hz), 2.16 (1H, m), 2.06 (1H, m), 1.85 (2H, m). 13C NMR
(125 MHz, DMSO-d6) 170.7, 144.5, 144.4, 135.1, 122.7, 61.7, 45.7,
18:0
28.8, 23.5: ½aꢂD ꢀ155.2 (c 1.00, DMSO); IR (KBr, cmꢀ1) 3487, 3090,
2989, 2760, 2548, 1622, 1589, 1560, 1532, 1466, 1405, 1338, 1169,
1086, 1044, 975, 943, 922, 863, 779, 756, 738, 720, 617, 578, 526: Anal.
Calcd for C11H11N5O7: C, 40.62; H, 3.41; N, 21.53. Found: C, 40.59;
H, 3.36; N, 21.68.
15. Ee of 2d was determined (>99% ee) by HPLC (SHISEIDO Chiral
CD-Ph, 0.1 mol/L aq KPF6:CH3CN = 55:45) UV 254 nm, flow rate
0.5 mL/min, tD = 15.3 min, tL-2d = 16.5 min.
-2d
16. General procedure for the aldol reactions with 2d: To a solution of
4-nitrobenzaldehyde 4a (47.75 mg, 0.3 mmol) and catalyst 2d
(19.57 mg, 0.06 mmol) in anhydrous HMPA (3 mL), water (0.162 mL,
9.0 mmol) and acetone (0.44 mL, 6.0 mmol) were added. After being
stirred at room temperature for 4 d, the reaction was quenched with
1 N HCl (1 mL). The resulting mixture was extracted with ethyl
acetate (50 mL) and organic layer was washed with brine (50 mL ꢁ 4).
The organic layers were dried over anhydrous Na2SO4, and the
solvent was removed in vacuo. The residue was purified by PTLC20
(diethyl ether:n-hexane = 3:1) to give the aldol adducts 5a, 56.2 mg
(0.27 mmol, 90% yield).
6. (a) Guillena, G.; Hita, M. C.; Najera, C. Tetrahedron: Asymmetry
2006, 17, 729; (b) Guillena, G.; Hita, M. C.; Najera, C. Tetrahedron:
Asymmetry 2006, 17, 1027; (c) Guillena, G.; Hita, M. C.; Najera, C.

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K. Sato et al. / Tetrahedron Letters 49 (2008) 2402–2406
17. Compounds 2a13 and 2b5b are known compounds. Compound 2c was
prepared from 2a with fuming nitric acid (2.3 equiv) and sulfuric acid
in chloroform.
18. Compounds 3b,c are known compounds.6k Compounds 3a,d–f were
prepared in the same manner as described in literature.6k
19. Maggiotti, V.; Wong, J.-B.; Razet, R.; Cowley, A. R.; Gouverneur, V.
Tetrahedron: Asymmetry 2002, 13, 1789.
20. In the case of the aldol reactions using chloroacetone, we used ODS
silica gel column chromatography (pentane:ethyl acetate = 70:1)
instead of PTLC to avoid syn/anti isomerization of 5m.