Highly enantioselective direct aldol reactions catalyzed by proline derivatives based on a calix[4]arene scaffold in the presence of water

Article abstract of DOI:10.1055/s-0029-1217710

A series of proline-derived organocatalysts based on a calix[4]arene scaffold have been developed to catalyze direct aldol reactions in the presence of water. Under the optimal conditions, high yields (up to>99%), good enantioselectivities (up to >99% ee)

Full text of DOI:10.1055/s-0029-1217710

2356
LETTER
Highly Enantioselective Direct Aldol Reactions Catalyzed by Proline
Derivatives Based on a Calix[4]arene Scaffold in the Presence of Water
E
nantioselective
h
Direct
A
ldo
e
l
Reaction
n
g-Yi Li,a Jia-Wen Chen,a Leyong Wang,*a Yi Pan*b
a
Key Laboratory of Mesoscopic Chemistry of Ministry of Education, School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, P. R. of China
Fax +86(25)83317761; E-mail: lywang@nju.edu.cn
State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, P. R. of China
E-mail: yipan@nju.edu.cn
b
Received 3 April 2009
Abstract: A series of proline-derived organocatalysts based on a
calix[4]arene scaffold have been developed to catalyze direct aldol
reactions in the presence of water. Under the optimal conditions,
high yields (up to >99%), good enantioselectivities (up to >99% ee)
and diastereoselectivities (up to 90:10) were obtained.
1 R = H
2 R =
3 R =
4 R =
COOH
N
H
RO
OH
O
OH
Key words: proline, calix[4]arene, organocatalyst, aldol reaction,
water
O
HN
COOH
Owing to the advantages of water over organic solvents,
reactions in aqueous media have received a great deal of
attention in recent years.1 As the aldol reaction is a syn-
thetically important carbon–carbon bond-forming reac-
tion,2 the development of enantioselective, aqueous aldol
reactions is of considerable current interest and chal-
lenge.3 So far, a great number of organocatalysts have
been designed for the asymmetric aldol reaction in the
presence of water, of which the most efficient proline-
derived catalysts had been prepared by Hayashi,4 Barbas
III,5 Armstrong,6 Singh,7 Gong,8 Benaglia,9 S. Wang,10 W.
Wang,11 Gruttadauria,12 Zhao,10,13 and Fu.14 Recently,
Armstrong and co-workers developed an asymmetric cat-
alytic system in water, mediated by sulfated b-cyclodex-
anone (b-CD), which can bind an organocatalyst of tert-
butyl-phenoxyproline to catalyze stoichiometric direct al-
dol reactions of cyclohexanone and aryl aldehydes with
excellent enantioselectivity and diastereoselectivity.6
Calixarenes with hydrophobic cavities and hydrophilic
phenolic hydroxyls such as b-CD have been used as in-
verse phase-transfer catalysts in many aqueous reac-
tions.15 Meanwhile, calix[4]arene-based organocatalysts
have been developed for a direct aldol reaction under sol-
vent-free conditions by Chen.16 Herein, we wish to de-
scribe the design and use of novel organocatalysts
possessing both an L-proline catalytic center and a
calix[4]arene skeleton for the direct aqueous aldol reac-
tion. The structures of the L-proline derivatives based on
the calix[4]arene scaffold 1–4 are shown in Scheme 1.
The hydrophobicity, reactivity, and selectivity can be ap-
propriately tuned by ligating additional functions to the
narrow (lower) rim of calix[4]arene via ether or ester link-
Scheme 1 Chemical structures of catalysts 1–4
ages. Moreover, compared to 1, catalyst 2 has two proline
moieties which might act cooperatively in the catalytic
process.
Catalysts 1–4, with L-Proline based on calix[4]arene scaf-
folds, were prepared from 4-tert-butylcalix[4]arene 917
and Cbz-L-proline derivative 10 in two or three steps
(Scheme 2). First, Mitsunobu reactions of 9 and different
loadings of 10 were carried out utilizing triphenylphos-
phine and diisopropyl azodicarboxylate (DIAD) in tolu-
ene at 70 °C, according to a literature procedure, to
smoothly give a range of proline-containing calixarene
derivatives.18 The Cbz and Bn groups were deprotected in
methanol with Pd/C and H2. For the preparation of 3 and
4, prior to the deprotection, alkylation with 1-bromobu-
tane in the presence of potassium carbonate in refluxing
acetonitrile, or esterification with octanoyl chloride in py-
ridine was performed, respectively. The structures of 1–
1
419–22 were confirmed by H and 13C NMR spectra, ESI-
MS spectrometry, and elemental analyses.
The catalytic activities of 1–4 for the asymmetric direct
aldol reaction were evaluated by performing a model re-
action between 4-nitrobenzaldehyde and cyclohexanone
in the presence of water at room temperature. As a com-
parison, the catalytic properties of L-proline 5 and L-hy-
droxyproline 6 were also investigated. The results are
summarized in Table 1. Catalyst 1 afforded the aldol ad-
ducts with higher diastereo- and enantioselectivities than
catalysts 2–4 (Table 1, entries 1 vs 2–4), which might be
attributed to their differing hydrophobicities.1f L-Proline 5
or L-hydroxyproline 6 without the calix[4]arene platform
hardly catalyzed the aldol reaction in water at all4e,5a,6
(Table 1, entries 5 and 6), which demonstrated the signif-
icance of the calix[4]arene skeletons in 1–4. Therefore,
SYNLETT 2009, No. 14, pp 2356–2360
x
x
.x
x
.2
0
0
9
Advanced online publication: 31.07.2009
DOI: 10.1055/s-0029-1217710; Art ID: W05109ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioselective Direct Aldol Reactions
2357
a
1
HO
b
2
e
+
COOBn
a
a
c
N
3
4
Cbz
d
HO
OH
OH
OH
9
10
Scheme 2 Synthesis of catalysts 1–4. Reagents and conditions: (a) 10 (1.1 equiv), Ph3P, DIAD, toluene, 70 °C, 47%; (b) 10 (2.2 equiv), Ph3P,
DIAD, toluene, 70 °C, 78%; (c) 1-Bromobutane, K2CO3, MeCN, reflux, 96%; (d) Octanoyl chloride, pyridine, r.t., 75%; (e) Pd/C, H2, MeOH,
r.t., >99%. DIAD = diisopropyl azodicarboxylate.
catalyst 1 was chosen for further studies to determine the activity of organic catalysis on water.1f,g,12 Moreover, it is
optimal conditions. The solvent effects on the reaction well-known that the yield, diastereo- and enantioselectiv-
were then studied for catalyst 1. The reactions in DMSO ities could be significantly influenced by the loading of
or under solvent-free conditions resulted in lower enantio- substrates and water.4 Thus, different amount of 4-ni-
selectivities and yields than in water (Table 1, entries 7 trobenzaldehyde, cyclohexanone and water were em-
and 8 vs 1), which indicated that water was indispensable ployed in order to further evaluate the catalytic efficiency
for the high enantioselectivity and yield. As depicted in of 1 (Table 1, entries 1 and 9–14). In these cases, increas-
Figure 1, a hydrophobic region and a hydrophilic region ing the amount of cyclohexanone could promote the yield,
can be formed by the formation of hydrogen bonds be- while the appropriate loading of water induced higher
tween free OH groups of interfacial water molecules and diastereo- and enantioselectivities because of solvation
OH and COOH groups of catalyst 1, which enhances the effect (Table 1, entries 13 vs 12 and 14). To our delight,
Table 1 Screening of Organocatalysts and Optimizing the Reaction Conditions for the Direct Asymmetric Aldol Reaction of Cyclohexanone
with 4-Nitrobenzaldehydea
O
OH
syn
O
OH
O
cat. (2 mol%)
r.t.
+
+
CHO
O2N
NO2
NO2
anti
Entry
Catalyst
Cyclohexanone
(equiv)
Water
(equiv)
Yield
(%)b
dr
ee
(anti/syn)c
(%, anti)c
1
2
1
2
3
4
5
6
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
–
1
1
1
3
3
3
28
28
28
28
28
28
–
68
60:40
59:41
50:50
50:50
–
93
85
65
69
–
48
3
70
4
94
5
trace
trace
40
6
–
–
7d
8e
9
60:40
57:43
76:24
78:22
65:35
75:25
90:10
70:30
56
38
90
94
94
97
98
96
–
32
18
8
48
10
11
12
13
14
48
1
48
28
18
8
73
73
73
a Reagents and conditions: catalyst (2 mol%), 4-nitrobenzaldehyde (1 mmol), and cyclohexanone (1 or 3 mmol), water, r.t., 48 h.
b Combined yield of isolated diastereomers.
c Determined by HPLC analysis on a chiral phase.
d The reaction was performed in DMSO (0.5 mL).
e The reaction was performed in neat cyclohexanone (0.5 mL).
Synlett 2009, No. 14, 2356–2360 © Thieme Stuttgart · New York

2358
Z.-Y. Li et al.
LETTER
catalyst 1 could smoothly catalyze the aldol reaction in corresponding aldol adducts were obtained in moderate to
73% yield with high diastereoselectivity (90:10, anti/syn) good yields (up to >99%) with up to >99% ee and up to
and enantioselectivity (98% ee) when 4-nitrobenzalde- 90:10 dr. As shown in Table 2, the electronic effects of the
hyde (1 mmol), cyclohexanone (3 mmol), and water (18 aromatic rings have a significant influence on the diaste-
mmol) were employed (Table 1, entries 13).
reo- and enantioselectivities. Aromatic aldehydes with
electron-withdrawing groups afforded predominantly
anti-products with excellent enantioselectivities (94 to
>99% ee; Table 2, entries 1–4). In contrast, electron-rich
2-methoxybenzaldehyde gave more syn-product with
83% ee (Table 2, entry 9). In the case of neutral aromatic
aldehydes, 3-chlorobenzaldehyde and benzaldehyde gave
slight excesses of the anti-products, while good enantiose-
lectivities (syn-95% ee and anti-81% ee) without diastere-
oselectivity were observed when 4-bromobenzaldehyde
was employed (Table 2, entries 6–8). Moreover, moderate
results were obtained when the fused-ring 2-naphthalde-
hyde was adopted (Table 2, entry 5). The catalytic system
also worked for the challenging substrate cyclopentanone
(Scheme 3). In this instance, the aldol process proceeded
smoothly in high yield (>99%) with excellent enantio-
selectivity [99% ee syn- and >99% ee anti] and gave pre-
dominantly the syn-product (32:68, anti/syn). Different
ketone substrates might lead to opposite diastereoselectiv-
ity in certain circumstance.25
With the optimized conditions in hand, the substrate scope
of the reaction was probed (Table 2 and Scheme 3). The
H
H
O
hydrophilic
region
O
H
O
H
O
O
H
H
O
O
H2O
hydrophobic
region
O
HN
H
O
H
O
H
O
Figure 1 Proposed structure of catalyst 1 in the presence of water
Table 2 Aldol Reactions of Different Aromatic Aldehydes with
Cyclohexanone Catalyzed by 1a
O
OH
O
O
OH
In conclusion, a series of novel organocatalysts containing
proline on calix[4]arene scaffolds have been synthesized
and applied to the direct aldol reactions of aromatic alde-
hydes with cyclohexanone or cyclopentanone in the pres-
ence of water. Under the optimal conditions, high yields
(up to >99%), enantioselectivities (up to >99% ee), and
diastereoselectivities (up to 90:10) were obtained. The
diastereoselectivities can be tuned by adjusting the elec-
tronic effects of the aromatic rings. Further studies on the
mechanism, generality of substrates, other applications of
these catalysts, and the design of more efficient catalysts
for the asymmetric reactions in water are underway.
1 (2 mol%)
Ar
Ar
Ar CHO
+
+
H2O, r.t., 48 h
syn-7
anti-7
Entry Ar
Product Yield dr
ee
ee
(%)b
73
63
59
54
63
50
37
71
23
(anti/syn)c (%, anti)c(%, syn)c
1
2
3
4
5
6
7
8
9d
4-O2NC6H4
2-O2NC6H4
3-O2NC6H4
4- F3CC6H4
2-naphthyl
3-ClC6H4
C6H5
7a
7b
7c
7d
7e
7f
90:10
89:11
66:34
67:33
68:32
55:45
54:46
50:50
12:88
98
>99
94
96
74
97
63
81
–
–
–
–
–
–
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
–
7g
7h
7i
–
Acknowledgment
4-BrC6H4
2-MeOC6H4
95
83
We gratefully acknowledge financial support from the Natural Sci-
ence Foundation of China (No. 20602017), National Basic Re-
search Program of China (2007CB925103), and Program for New
Century Excellent Talents in University (NCET-07-0425). This
work was also partially supported by research funds from the ‘Qing-
Lan Program’ of Jiangsu Province. The referees are acknowledged
for helpful comments.
a Reagents and conditions: 1 (2 mol%), aromatic aldehyde (1 mmol),
ketone (3 mmol), H2O (324 mL, 18 mmol), r.t., 48 h.23
b Combined yield of isolated diastereomers.
c Determined by HPLC analysis on a chiral phase.24
d The reaction was carried out for 96 h.
O
O
O
OH
OH
1 (2 mol%)
+
CHO
+
O2N
H2O, r.t., 48 h
>99% yield
NO2
NO2
syn-8
anti-8
anti/syn: 32:68
anti: >99% ee
syn: 99% ee
Scheme 3 Direct asymmetric aldol reaction of cyclopentanone with 4-nitrobenzaldehyde catalyzed by 1 in the presence of water
Synlett 2009, No. 14, 2356–2360 © Thieme Stuttgart · New York

LETTER
Enantioselective Direct Aldol Reactions
2359
Hz, 2H, CH2), 3.40–3.47 (m, 4H, ArCH2Ar), 3.34 (d,
References and Notes
J = 12.3 Hz, 2H, NCH2), 4.03–4.09 (m, 4H, ArCH2Ar),
4.37–4.43 (m, 2H, NCHCO + OCH), 4.59 (s, 1H, NH), 6.98–
7.22 (m, 8H, ArH). 13C NMR (75 MHz, DMSO-d6): d = 31.4,
31.7, 32.6, 34.1, 34.3, 36.4, 51.0, 60.5, 84.1, 125.2, 126.1,
126.5, 128.2, 128.4, 130.2, 130.4, 133.6, 133.8, 143.0,
146.4, 148.3, 148.6, 148.9, 150.8, 171.8. IR (KBr): 3440,
2959, 2869, 1629, 1485, 1364, 1299, 1262, 1204, 1031, 909,
874, 802 cm–1. Anal. Calcd for C49H63NO6: C, 77.23; H,
8.33; N, 1.84. Found: C, 77.52; H, 8.06; N, 1.65. ESI-MS:
m/z (%) = 762 (8) [M + 1]+, 784 (100) [M + Na]+.
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(20) Analytical data for compound 2: Yield: 78%. White solid,
mp 261–263 °C. [a]D26 +43.0 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CD3OD): d = 1.07 [s, 18H, 2 × C(CH3)3], 1.24 [s,
18H, 2 × C(CH3)3], 2.72 (m, 2H, CH2), 2.84–2.90 (m, 2H,
CH2), 3.35–3.48 (m, 4H, ArCH2Ar), 3.68–3.74 (m, 2H,
NCH2), 4.17–4.38 (m, 8H, NCH2 + ArCH2Ar + OCH), 4.65–
4.69 (m, 2H, NCHCO), 5.08 (s, 2H, NH), 7.05–7.16 (m, 8H,
ArH). 13C NMR (75 MHz, CDCl3): d = 30.8, 31.5, 33.7,
51.2, 60.0, 85.1, 124.8, 124.9, 125.5, 125.9, 127.9, 128.0,
128.5, 131.0, 131.1, 131.7, 141.9, 146.5, 149.9, 173.6,
173.7. IR (KBr): 3448, 2961, 2868, 1632, 1485, 1393, 1362,
1300, 1203, 1124, 1035, 979, 873 cm–1. Anal. Calcd for
C54H70N2O8: C, 74.11; H, 8.06; N, 3.20. Found: C, 74.32; H,
7.86; N, 3.45. ESI-MS: m/z (%) = 898 (100) [M + Na]+.
(21) Analytical data for compound 3: Yield: 96%. White solid,
mp 137–139 °C. [a]D27 –6.7 (c = 8.5, CHCl3). 1H NMR (300
MHz, CDCl3): d = 0.82 [s, 9H, C(CH3)3], 0.94 [s, 9H,
C(CH3)3], 1.06 (t, J = 7.2 Hz, 3H, CH3), 1.25 [s, 9H,
C(CH3)3], 1.31 [s, 9H, C(CH3)3], 1.58–1.72 (m, 2H, CH2),
1.81–1.98 (m, 2H, CH2), 2.43–2.52 (m, 1H, CH2), 2.65–2.82
(m, 1H, CH2), 3.21–3.34 (m, 4H, ArCH2Ar), 3.58 (br s, 2H,
ArOCH2), 3.91–3.96 (m, 2H, NCH2), 4.01–4.28 (m, 4H,
ArCH2Ar), 4.39–4.51 (m, 2H, OCH + NCHCOO), 6.53–
6.81 (m, 4H, ArH), 6.98–7.06 (m, 4H, ArH). 13C NMR (75
MHz, CDCl3): d = 14.0, 19.3, 33.7, 33.8, 34.9, 59.7, 84.0,
124.8, 125.1, 125.3, 125.7, 125.8, 127.0, 127.3, 128.2,
128.4, 131.5, 132.1, 132.2, 141.4, 146.3, 146.8, 149.3,
149.4, 150.2, 173.1. IR (KBr): 3441, 2960, 2870, 1717,
1635, 1485, 1392, 1362, 1300, 1201, 1123, 1026, 872 cm–1.
Anal. Calcd for C53H71NO6: C, 77.81; H, 8.75; N, 1.71.
Found: C, 77.42; H, 8.96; N, 1.45. ESI-MS: m/z (%) = 818
(23) [M + 1]+, 840 (100) [M + Na]+.
(22) Analytical data for compound 4: Yield: 75%. White solid,
mp 157–159 °C. [a]D27 –31.3 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 0.84 [s, 9H, C(CH3)3], 0.87 [s, 9H,
C(CH3)3], 0.91 (t, J = 7.2 Hz, 3H, CH3), 1.27 [s, 9H,
C(CH3)3], 1.29–1.31 (m, 5H, CH2), 1.32 [s, 9H, C(CH3)3],
1.46–1.51 (m, 2H, CH2), 1.60–1.65 (m, 1H, CH2), 1.80–1.94
(m, 2H, CH2), 2.33 (t, J = 7.5 Hz, 2H, OOCCH2), 2.71–2.93
(m, 2H, CH2), 3.23–3.39 (m, 4H, ArCH2Ar), 3.76 (d,
J = 13.5 Hz, 2H, NCH2), 3.99–4.16 (m, 4H, ArCH2Ar),
4.01–4.48 (m, 2H, OCH + NCHCOO), 5.50 (s, 1H, OH),
5.63 (s, 1H, OH), 6.57–7.08 (m, 8H, ArH). 13C NMR (75
MHz, CDCl3): d = 14.1, 22.5, 24.9, 29.0, 29.1, 30.7, 30.8,
31.3, 31.4, 31.6, 33.8, 35.5, 49.0, 59.9, 84.3, 124.8, 125.0,
125.3, 126.0, 126.9, 127.3, 127.6, 127.7, 129.0, 130.7,
131.0, 131.4, 132.0, 141.8, 142.0, 142.2, 147.0, 148.0,
148.3, 149.7, 149.9, 172.0, 173.3, 178.0. IR (KBr): 3520,
2957, 2868, 1761, 1634, 1485, 1363, 1301, 1204, 1139,
1122, 1037, 873 cm–1. Anal. Calcd for C57H77NO7: C, 77.08;
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m/z (%) = 888 (26) [M + 1]+, 910 (100) [M + Na]+.
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(17) Gutsche, C. D.; Iqbal, M. Org. Synth. 1990, 68, 234.
(18) Dondoni, A.; Marra, A.; Scherrmann, M.-C.; Casnati, A.;
Sansone, F.; Ungaro, R. Chem. Eur. J. 1997, 3, 1774.
(19) Analytical data for compound 1: Yield: 47%. White solid,
mp 233–235 °C. [a]D26 +21.6 (c = 1.0, CHCl3). 1H NMR
(300 MHz, DMSO-d6): d = 1.11 [s, 9H, C(CH3)3], 1.16 [s,
18H, 2 × C(CH3)3], 1.17 [s, 9H, C(CH3)3], 3.34 (d, J = 8.1
(23) General procedure for asymmetric aldol reactions: Catalyst
1 (2 mol%) was added to a suspension of aldehyde (1.0
mmol) and ketone (3.0 mmol) in water (324 mL, 18 mmol) at
room temperature. The mixture was allowed to stir for the
Synlett 2009, No. 14, 2356–2360 © Thieme Stuttgart · New York

2360
Z.-Y. Li et al.
LETTER
Hexane, 5:95; flow rate 1.0 mL/min; l = 254 nm; 20 °C.
anti-Diastereomer: tR(major) = 60.2 min and
tR(minor) = 43.5 min; 98% ee. For further data on 7 and
HPLC spectra, see Supporting Information.
given time, then ethyl acetate (10 mL) and anhydrous
MgSO4 (0.6 g) were added. After filtration, the solvent was
evaporated under vacuum and the crude products were
purified by flash chromatography (hexane–EtOAc). The
anti/syn ratio (diastereoselectivity) and enantiomeric excess
(enantioselectivity) were determined by chiral HPLC
analysis (see ref 24).
(25) (a) Paradowska, J.; Stodulski, M.; Mlynarski, J. Adv. Synth.
Catal. 2007, 349, 1041. (b) Ma, G.-N.; Zhang, Y.-P.; Shi,
M. Synthesis 2007, 197.
(24) Compound 7a: Yield: 73%; Ratio anti/syn = 90:10. HPLC
conditions: Daicel Chiralpak AD-H column; i-PrOH–
Synlett 2009, No. 14, 2356–2360 © Thieme Stuttgart · New York