Aldol reactions in water using a β-cyclodextrin-binding proline derivative

Article abstract of DOI:10.1055/s-2007-985569

The aldol reaction of various aromatic aldehydes with cyclohexanone is catalyzed by the inclusion complex of a proline derivative and β-cyclodextrin in water, yielding hydroxyketones with anti/syn ratio of up to 99:1 and ee values well above 90%. Georg Th

Full text of DOI:10.1055/s-2007-985569

2298
LETTER
Aldol Reactions in Water Using a b-Cyclodextrin-Binding Proline Derivative
A
ldol Reactionsin
e
W
ate
r
gang Liu, Daniel Häussinger, Wolf-D. Woggon*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax +41(61)2671102; E-mail: wolf-d.woggon@unibas.ch
Received 16 June 2007
H2N
Abstract: The aldol reaction of various aromatic aldehydes with
a
O
O
cyclohexanone is catalyzed by the inclusion complex of a proline
derivative and b-cyclodextrin in water, yielding hydroxyketones
with anti/syn ratio of up to 99:1 and ee values well above 90%.
+
COCl
N
CBz
OBn
HN
O
4
5
6
Key words: adamantane, aldol reaction, b-cyclodextrin, proline,
organocatalysis
N
CBz
OBn
b
secondary face
Enantioselective organocatalysis1 has experienced a re-
naissance in catalytic asymmetric reactions, especially for
the aldol reaction, one of the most efficient carbon–carbon
bond-forming reactions in organic synthesis.2 Several
asymmetrical methodologies for this reaction using orga-
nocatalysts have been developed,3 but most of the reac-
tions are pursued in organic solvents, such as DMSO,
DMF, or CHCl3. In contrast, enzymes and antibodies can
catalyze aldol reactions in water,4,5 but substrate scope
limits their practical application. Recently, some research
groups reported highly diastereo- and enantioselective
aldol reactions in water,6 using for example amphiphilic
dendritic catalysts and polystyrene-supported proline
derivatives 6d,e and hence it has been debated whether the
term ‘in water’ is justified.7 Herein, we describe the syn-
thesis and application of a simple proline derivative which
forms inclusion complexes with b-cyclodextrin and hence
is completely soluble in water catalyzing aldol reations
under neutral conditions with high diastereo- and enantio-
selectivity.
O
O
2
HN
HN
O
O
N
H
N
H
OH
OH
1
3
primary face
Scheme 1 Synthesis and structure of organocatalyst 1 and its b-cy-
clodextrin inclusion complex 3. Reagents and conditions: a) DIPEA,
CH2Cl2, r.t., 93%; b) H2, 10%Pd/C, MeOH, 100%.
The concept involves the attachment of an adamantyl sub-
unit to proline, see 1. The target structure 1 was conve-
niently prepared in two steps from commercially available
4 and 58 and subsequent hydrogenolysis of 6.9,10 Accord-
1
ing to H NMR spectroscopy the adamantane amide 1
binds to b-cyclodextrin 2 yielding the 1:1 complex 3
(Scheme 1).11 A characteristic upfield shift of the triplet of
H at C3¢ (3.94 ppm) of the glucose unit indicates the in-
clusion of the adamantane into the cavity of 2. NMR-con-
trolled titration of b-cyclodextrin 2 with aliquots of the
organocatalyst 1 led to a continuous shift of this triplet
from which the binding constant Kass = 1.4·104 mol–1 was
determined.12
The orientation of the adamantane unit as shown in
Scheme 1 was deduced from the NOSY spectrum of 3
(Figure 1).The significant cross peaks indicate the
Figure 1 The orientation of 1 within the cavity of b-cyclodextrin 2;
1H shifts and NOE contacts between 1 and 2 are indicated in the car-
toon above. Region of the NOESY spectrum of an equimolar mixture
of 1 and 2 (D2O, 298 K, 600 MHz) is shown below.
SYNLETT 2007, No. 14, pp 2298–2300
Advanced online publication: 13.08.2007
DOI: 10.1055/s-2007-985569; Art ID: G18807ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.0
9
.2
0
0
7

LETTER
Aldol Reactions in Water
2299
proximity of H at C-3¢ of glucose to H at C2 of adaman- Table 1 Asymmetric Aldol Reaction in Water Catalyzed by 3
tane and the interaction of H at C5¢ and H at C4. The pro-
OH
O
O
ton at C-3 of adamantane is close to both protons at C3¢
and at C5¢ of glucose. It follows that the adamantane
amide protrudes beyond the secondary face of b-cyclo-
dextrin.13
O
R
3
R
H
H2O, r.t.
7
8
9
A representative set of aldehydes was examined in detail
using catalyst 3 and cyclohexanone. The reactions pro-
ceeded smoothly in excellent diastereoselectivities (up to
99:1) and enantioselectivities (up to >99% ee) to furnish
the aldol adducts 9a–n, see Table 1.14,15
Entry Ra
Product Time Yield anti/sync ee (%,
(h)
72
72
72
72
72
72
96
48
72
96
96
72
3
(%)b
88
80
94
90
48
84
60
97
50
28
31
62
98
90
86
90
92
anti)d
1
2
7a 4-NO2C6H4
7b 2-NO2C6H4
7c 4-CF3C6H4
7d 4-NCC6H4
7e 4-ClC6H4
7f 2-ClC6H4
7g 4-FC6H4
9a
9b
9c
9d
9e
9f
90:10
96:4
91
96
The reactions of cyclohexanone 8 with benzaldehydes
bearing electron-withdrawing groups (entries 1–8) gave
moderate to excellent yields (48–97%). In contrast, the
yields of the reactions with p-tolylaldehyde 7j and 1-
naphthaldehyde 7k were somewhat lower (entries 10 and
11). Interestingly, the reactions of 8 with the pyridine al-
dehydes 7m and 7n (entries 13 and 14), were very fast and
high yields were observed, but the distereoselectivities
were disappointingly low. However, except for one case
(entry 14), the enantioselectivities are well above 90%ee.
A further advantage of the system is the facile recovery of
the catalyst. After completion of the reaction and sub-
sequent extraction of the product with dichloromethane
the catalyst remaining in the aqueous layer can be reused
in subsequent reactions, entries 15–17 show that 3 can be
recycled up to four times without changes in reactivity
and enantioselectivity.
3
92:8
99
4
90:10
92:8
94
5
98
6
94:6
>99
97
7
9g
87:13
>99:1
92:8
8
7h 2,6-diClC6H3 9h
97
9
7i Ph
9i
97
10
11
12
13
14
15
16
17
7j 4-MeC6H4
7k 1-Naphthyl
7l 2-Furyl
9j
86:14
92:8
95
9k
9l
94
81:19
60:40
69:31
92:8
96
7m 2-Pyridyl
7n 4-Pyridyl
7c 2nd Cycle
7c 3rd Cycle
7c 4th Cycle
9m
9n
9c
9c
9c
92
In conlusion, the easy access and recycling of the catalyst
and the high enantio- and diastereoselectivity of the
reaction makes this procedure an attractive alternative to
existing methods 6 for the synthesis of b-hydroxy ketones
in water.
3
39
80
72
72
99
92:8
99
92:8
99
a The reaction was performed with aldehyde 7 (0.2 mmol), ketone 8
(0.8 mmol), 3 (0.02 mmol), and H2O (0.2 mL) at r.t.
b Combined yields of isolated diastereoisomers.
Acknowledgment
Financial support by the Swiss National Science Foundation is
gratefully acknowledged.
c Determined by 1H NMR of the crude product.
d Determined by chiral-phase HPLC of the anti product.
References and Notes
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Synlett 2007, No. 14, 2298–2300 © Thieme Stuttgart · New York

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K. Liu et al.
LETTER
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b trans to Ha), 2.18 (s, 3 H, H-3), 1.91 (s, 6 H, H-2), 1.78 (s,
6 H, H-4). 1H NMR (600 MHz, H2O): d = 7.37 (d, 1 H,
NHC=O). 13C NMR (151 MHz, D2O): d = 180.7 (NHC=O),
174.3 (COOH), 102.7 (C-1¢), 81.9 (C-4¢), 73.5 (C-3¢), 72.4
(C-2¢), 72.3 (C-5¢), 60.6 (C-a), 60.5 (C-6¢), 50.4 (C-d), 49.2
(C-g), 40.9 (C-1), 38.9 (C-2), 36.8 (C-4), 34.8 (C-b), 27.8
(C-3).
(12) Hwang, T. L.; Shaka, A. J. J. Magn. Reson., Ser. A 1995,
112, 275.
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Chem. Int. Ed. 2006, 45, 8100. (b) Hayashi, Y. Angew.
Chem. Int. Ed. 2006, 45, 8103. (c) Blackmond, D. G.;
Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem. Int.
Ed. 2007, 46, 2.
(8) Calderón, F.; Ferández, R.; Sánchez, F.; Fernández-
Mayoralas, A. Adv. Synth. Catal. 2005, 347, 1395.
(9) Synthesis of 6
(13) The NOESY spectrum was acquired on an equimolar
mixture of 1 and 2 in D2O using a mixing time of 500 ms and
512 (142 ms) and 2048 (285 ms) points (acquisition times)
in the F1 and the F2 dimension. Assignment of the
resonances of this complex was accomplished using
standard COSY, HMQC, and HMBC pulse sequences. NMR
data were processed using Bruker XWINNMR software.
(14) General Procedure for the Aldol Reaction Catalyzed by
the Inclusion Complex of 1 and b-Cyclodextrin 2
To a suspension of the proline derivative 1 (5.84 mg, 0.02
mmol) in H2O (0.2 mL) was added b-cyclodextrin 2 (22.7
mg, 0.02 mmol) and stirred for 10 min at r.t. until a clear
solution was obtained; then cyclohexanone (80 mL, 0.8
mmol) was added. The reaction mixture was stirred at r.t. for
further 10 min and subsequently aldehyde 7 (0.2 mol) was
added. The reaction mixture was stirred for 3–96 h (TLC
monitoring the consumption of aldehyde). The reaction was
quenched with aq NH4Cl and extracted with EtOAc. The
combined organic layers were washed with H2O and brine,
dried over Na2SO4. Purification by flash chromatography
(silica gel, hexane–EtOAc, 2:1) gave the pure aldol products
for further analysis.
To a solution of 5 (70.8 mg, 0.2 mmol) in CH2Cl2 (1 mL) was
added solid 1-adamantane carboxylic acid chloride 4 (44 mg,
0.22 mmol) at 0 °C, followed by addition of DIPEA (52 mg,
0.4 mmol). The reaction mixture was stirred for 4 h at r.t. and
finally diluted with CH2Cl2 (5 mL). The organic phase was
washed consecutively with 1 N HCl, H2O, brine and dried
over Na2SO4.The solvent was removed under reduced
pressure. Purification of the residue by flash chromatog-
raphy using hexane–EtOAc (2:1) affords 6 as an oil (96 mg,
93%); [a]D25 –32.1 (c 0.88, CHCl3). 1H NMR (400 MHz,
CDCl3): d = 7.23–7.37 (m, 10 H), 6.65 (d, 1 H, J = 9.2 Hz),
4.95–5.34 (m, 4 H), 4.69 (m, 1 H), 4.41–4.50 (m, 1 H), 3.51–
3.71 (m, 2 H), 2.41–2.50 (m, 1 H), 2.00 (m, 3 H), 1.91 (m,
1 H), 1.63–1.73 (m, 12 H). 13C NMR (100 MHz, CDCl3):
d = 177.86, 177.78, 174.45, 155.16, 154.52, 136.65, 136.57,
135.68, 135.44, 129.06, 128.98, 128.94, 128.89, 128.57,
128.52, 128.44, 128.38, 128.23, 67.82, 67.73, 58.66, 58.20,
54.41, 54.12, 48.70, 47.72, 40.87, 40.86, 39.27, 39.26,
37.39, 36.87, 36.32, 28.47. ESI-MS: m/z = 539.2 [M + Na]+,
555.1 [M + K]+. Anal. Calcd (%) for C31H36N2O5: C, 72.07;
H, 7.02; N, 5.42. Found: C, 71.27; H, 7.09; N, 5.20.
(10) Synthesis of 1
For Recycle Case
After the completion of reaction, the reaction mixture was
directly extracted with CH2Cl2 for three times. The aqueous-
phase-containing catalyst was reused again for next time
after removing a little amount of CH2Cl2 under reduced
pressure.
(15) Absolute configuration of the aldol products anti-9 were
determined by optical rotation in comparison to reported
values6 except compound 9h.
To a solution of compound 6 (96 mg, 0.186 mmol) in MeOH
(2 mL) was added 10% Pd/C (30 mg). The reaction mixture
was stirred for 5 h under hydrogen, subsequently filtered
through Celite and the catalyst was washed with MeOH
three times. The combined organic solutions were
concentrated under reduced pressure to afford the proline
derivative 1 as a colorless solid (54 mg, 100%); mp 230–
232 °C; [a]D25 –32.9 (c 0.5, MeOH). 1H NMR (400 MHz,
DMSO-d6): d = 7.60 (d, 1 H, J = 6.8 Hz), 4.34 (m, 1 H), 4.15
(t, 1 H, J = 8.4 Hz), 3.28 (dd, 1 H, J = 11.2, 7.2 Hz), 3.10 (dd,
1 H, J = 11.2, 6.0 Hz), 2.46 (m, 1 H), 1.91 (m, 4 H), 1.58–
1.72 (m, 12 H). 13C NMR (100 MHz, DMSO-d6):
The following are the analytical data of 2-hydroxy-
methylene-(2¢,6¢-dichlorophenyl) cyclohexanone (9h):
anti-9h: 1H NMR (400 MHz, CDCl3): d = 7.29 (m, 2 H), 7.13
(m, 1 H), 5.82 (dd, 1 H, J = 9.6, 4.4 Hz), 3.67 (d, 1 H, J = 4.4
Hz), 3.46–3.49 (m, 1 H), 2.35–2.52 (m, 2 H), 2.05–2.09 (m,
1 H), 1.78–1.82 (m, 1 H), 1.62–1.69 (m, 2 H), 1.49–1.53 (m,
1 H), 1.34–1.41 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 214.85, 136.08, 135.10,
129.92, 70.97, 54.04, 42.85, 30.26, 28.04, 25.10. ESI-MS:
m/z (%) = 295.3 (100) [M + Na]+. The ee of anti-9h (97%)
was determined by HPLC with a Chiralpak AD-H column
(heptane–2-PrOH, 90:10), 20 °C, 210 nm, 0.5 mL/min;
major enantiomer tR = 24.2 min, minor enantiomer tR = 30.9
min.
d = 177.93, 170.99, 58.99, 49.98, 48.50, 39.30, 36.94, 34.67,
28.43. ESI-MS: m/z = 293.4 [M + 1]+. Anal. Calcd (%) for
C16H24N2O3: C, 65.73; H, 8.27; N, 9.58. Found: C, 65.66; H,
8.18; N, 9.44.
syn-9h: 1H NMR(400 MHz, CDCl3): d = 7.08–7.31 (m, 3 H),
5.73 (t, 1 H, J = 7.6 Hz), 3.27–3.33 (m, 1 H), 2.84 (d, 1 H,
J = 7.6 Hz), 1.17–2.40 (m, 8 H). The ee was determined by
HPLC with a Chiralpak AD-H column (heptane–2-PrOH,
90:10), 20 °C, 210 nm, 0.5 mL/min, one enantiomer
tR = 20.2 min, another enantiomer tR = 22.1 min.
(11) Spectroscopic Data of Inclusion Complex 3
1H NMR (600 MHz, D2O): d = 5.04 (d, 7 H, H-1¢), 4.55 (m,
1 H, H-g), 4.22 (dd, 1 H, H-a), 3.89 (m, 7 H, H-6¢¢), 3.87 (m,
7 H, H-3¢), 3.84 (m, 7 H, H-6¢), 3.75 (m, 7 H, H-5¢), 3.64 (dd,
7 H, H-2¢), 3.60 (dd, 1 H, H-d cis), 3.56 (dd, 7 H, H-4¢), 3.46
(dd, 1 H, H-d trans), 2.66 (m, 1 H, H-b cis), 2.20 (m, 1 H, H-
Synlett 2007, No. 14, 2298–2300 © Thieme Stuttgart · New York

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