Synthesis of dendrimer-supported prolinols and their application in enantioselective reduction of ketones

Article abstract of DOI:10.1055/s-2006-926253

Optically active dendritic amino alcohols were synthesized and applied to catalyze the enantioselective borane reduction of various ketones with good yield and high enantiomeric excesses. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926253

1150
LETTER
Synthesis of Dendrimer-Supported Prolinols and Their Application in
Enantioselective Reduction of Ketones
Synthesis of
Dend
u
r
imer-Suppor
a
te
d
Prolino
n
ls g-yin Wang, Xin-yuan Liu, Gang Zhao*
Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin lu, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: zhaog@mail.sioc.ac.cn
Received 31 October 2005
by their unusual fractal-like architecture.6 Due to their
unique characteristic feature they are attractive for appli-
cation in the fields of biology and materials science as
well as for use in homogeneous catalysis.7 For enantiose-
lective catalysis chiral dendrimers are required, and a
number of dendritic chiral catalysts have been described.8
Herein, we would like to report the synthesis of recover-
able prolinols anchored on dendrimers with a variety of
molecular weights and their application in enantioselec-
tive reduction of ketones with borane–dimethyl sulfide
complex.
Abstract: Optically active dendritic amino alcohols were synthe-
sized and applied to catalyze the enantioselective borane reduction
of various ketones with good yield and high enantiomeric excesses.
Key words: dendrimer-supported, asymmetric reduction, amino
alcohol
The enantioselective reduction of ketones to form optical-
ly active secondary alcohols is a focus of research field in
organic chemistry, and a large number of reducing agents
and chiral catalysts have been developed to facilitate this
reaction under a wide range of conditions.1 One of the
most successful reduction reactions involves the use of
borane in the presence of homogeneous catalysts derived
from chiral amino alcohols.2 However, the recovery and
purification of these catalysts are usually problematic. Im-
mobilization of chiral catalysts or reagents on insoluble
polymers offers a solution to the problem. The advantages
of polymer-supported catalysts are that they can be used
in excess and recovered by filtration at the end of reac-
tion.3 But the merit of these heterogeneous catalysts is al-
ways at the expense of low catalysis activity or rigor
conditions relative to their unsupported analogues due to
the polymer matrix restricting the mobility and accessibil-
ity of catalytic sites.4 A solution that combines both ad-
vantages of homogeneous and heterogeneous catalysis is
using soluble supporting matrix usually including linear
polystyrene, poly(ethylene glycol) and dendrimers.5 Of
the soluble polymers, dendrimers represent a new type of
compounds which are different from traditional polymers
The synthetic route to the chiral dendrimers is outlined in
Scheme 1. The linking of dendrimers with prolinol core
has been reported recently in another work of our group
on the enantioselective phenyl transfer reactions to alde-
hydes.9 With chiral dendrimers in hand which were pro-
tected by carbonyl group, dendrimer-supported amino
alcohols were obtained directly after hydrolysis with
potassium hydroxide in dimethyl sulfoxide.
It is well-known that solvent, temperature and amount of
catalyst profoundly affect the stereoselectivity of re-
duction. To examine these effects and determine which
catalyst was the best for the reaction, the reduction of p-
nitroacetophenone (Scheme 2) was investigated at
various reaction conditions and the results are shown in
Table 1. The reductions proceeded smoothly with both
catalysts supported by various generation dendrimers, and
excellent yields were obtained under all the reactions con-
ditions studied. The results show that the level of enantio-
meric excess is not sensitive to the reaction temperature.
1 (n = 0, para position)
2 (n = 1, para position)
3 (n = 2, para position)
4 (n = 3, para position)
5 (n = 1, meta position)
O
O
O
O
O
O
O
O
n
n
KOH, DMSO
N
N
H
HO
O
O
O
O
O
n
O
n
Scheme 1
SYNLETT 2006, No. 8, pp 1150–1154
1
5.
0
5.
2
0
0
6
Advanced online publication: 10.03.2006
DOI: 10.1055/s-2006-926253; Art ID: W30805ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Dendrimer-Supported Prolinols
1151
When the reduction was carried at room temperature (en- jected to the reduction system (entry 10), a phenomenon
try 4), the stereoselectivity did not decrease at all. Even that the ester group was also reduced was observed. The
when the temperature was decreased to 0 °C (entry 5), the fact is consistent with our previous work.10 To gain insight
stereoselectivity was still maintained at an acceptable lev- on the effect of the electron density of the aromatic ring, a
el. Although THF was more effective for the reaction, series of the aromatic ketones bearing a different sub-
Et2O and CH2Cl2 also gave satisfactory results (entries 10, stituent at para position on the phenyl group was studied
11). For each generation of dendrimer-supported catalyst, (entries 1–3). The results show that an electron-withdraw-
the C/S ratio could decrease to a level that corresponded ing group was beneficial to high enantioselectivity. For
to the small molecular catalyst with the same enantio- the aliphatic ketones (entries 4, 5), the enantiomeric ex-
selectivity and they showed no obvious difference of cess was lower than those aromatic analogues. When a
catalytic activity.
diketone was concerned (entry 11), only one diastereo-
isomer was obtained and no mesomer was observed by 1H
NMR or HPLC.
OH
Me
O
BH3·Me2S
Me
cat. 3
OH
O
THF, cat.
O2N
O2N
BH3·Me2S
RL
RS
RL
RS
Scheme 2
THF
Scheme 3
Table 1 Effect of Temperature, Solvent, and Catalyst
Entry Catalysta Amount
of catalyst
Solvent
Tempera-
ture
Yield eec
(%)b
After the reduction was complete, the dendrimer-support-
ed catalysts were precipitated by adding methanol and re-
covered by filtration. The recovered dendrimers were
reused after being dried and no loss of catalytic activity
was observed. Tests on the reduction of p-nitroacetophe-
none catalyzed by the second generation dendrimeric pro-
linol 3 (n = 2, Table 3) show that the chiral dendrimer-
supported catalyst can be recycled at least five times with
little or no loss of performance.
(mol%)
1
2
1 (n = 0)
5
THF
THF
THF
THF
THF
THF
THF
THF
Reflux
Reflux
Reflux
20 °C
98
98
93
98
88
99
98
97
92
95
99
98
98
94
96
96
96
81
97
93
90
22
92
94
95
97
2 (n = 1) 10
3
2 (n = 1)
2 (n = 1)
2 (n = 1)
3 (n = 2)
3 (n = 2)
3 (n = 2)
3 (n = 2)
3 (n = 2)
3 (n = 2)
4 (n = 3)
5 (n = 1)
5
4
5
5
5
0 °C
In summary, we have developed a new recoverable homo-
geneous dendrimer-supported catalyst for the enantiose-
lective borane reduction of prochiral ketones. And these
new types of catalysts have applicability to more sub-
strates and conditions than our previous similar works.11
6
5
Reflux
Reflux
Reflux
7
2.5
1
8
Table 3 Recycling of Chiral Dendrimer 3 (n = 2) for the Reduction
of p-Nitroacetophenone
9
5
Toluene 75 °C
10
11
12
13
5
Et2O
Reflux
Reflux
Reflux
Reflux
Run
1
Yield (%)a
ee (%)b
96.8
5
CH2Cl2
THF
99
98
97
98
96
5
2
97.0
5
THF
3
96.5
a In catalysts 1, 2, 3 and 4 (n = 0, 1, 2, 3), dendrimers were linked at
para position of the phenyl group in prolinol core, and in catalyst 5
(n = 1), dendrimers were linked at meta position.
4
96.7
5
96.3
b After column chromatography.
c Determined by HPLC using a chiral stationary phase.
a After column chromatography.
b Determined by HPLC using a chiral stationary phase.
To extend the scope of the reduction, we studied the
reduction of other ketones under the optimum reaction
conditions (Scheme 3). The results are summarized in
Table 2. In general, excellent ketone conversion was
achieved, and the corresponding optically active alcohols
were obtained in good yield (>75%). The enantioselec-
tivities were moderate to excellent (49–98%), and the
reaction was compatible to many functional groups, such
as hetero ring (entries 6, 7), sulfone (entry 8), nitrile (entry
9) and olefin (entries 12, 13). While a-keto ester was sub-
Synthesis of Catalysts 1–5
All the dendrimeric bromides and prolinol cores were prepared ac-
cording to the literature.9,12 The linking of dendrimers with prolinol
core has been reported recently in another work of our group.9 Hy-
drolysis of carbonyl group with KOH in DMSO at 80 °C for 4 h and
after purification by silica gel chromatography employing CH2Cl2–
acetone (1:1) as eluent gave the corresponding final dendrimer
supported amino alcohols 1–5.
Synlett 2006, No. 8, 1150–1154 © Thieme Stuttgart · New York

1152
G.-y. Wang et al.
LETTER
Table 2 Asymmetric Reduction of Prochiral Ketones Using Dendrimer-Supported Prolinol 3a
Entry
1
Substrate
Product
Yield (%)b
99
ee (%)c
97
Configurationd
6
R
O
Me
O2N
2
3
7
8
99
94
97
85
R
R
O
Me
O
Me
MeO
O
4
5
6
9
10
11
98
97
77
61e
68e
97
R
R
R
Me
O
Me
O
Me
N
O
7
8
12
13
14
15
16
87
99
80
94f
98
66
98
78
98
96
R
S
S
O
SO2Ph
CN
9g
10
11
R
O
O
S
CO2Me
1R,4R
Ph
O
O
Ph
12g
13g
17
18
92
77
49
66
R
R
O
Me
O
a Molar ratio of ketone:BH3·Me2S:3 = 1.0:1.1:0.05.
b After column chromatography.
c Determined by HPLC using a chiral stationary phase.
d The absolute configuration was determined by optical rotation.
e Analytical samples were converted to phenylcarbamates.
f The product was 1,2-diol.
g The reaction was carried at 0 °C.
Synlett 2006, No. 8, 1150–1154 © Thieme Stuttgart · New York

LETTER
Synthesis of Dendrimer-Supported Prolinols
1153
Catalyst 1 (n = 0)
Typical Procedure for the Asymmetric Reduction of Ketones
Catalyst 3 (0.05 mmol) was placed in a 50 mL three-necked flask,
to which was then added THF (10 mL). The solution was heated
under reflux and stirred for 0.5 h. Then a THF solution (8 mL) of
ketones (1 mmol) was added at a rate of 1.0 mL/h by a syringe
pump. After the addition was completed, the mixture was treated
with MeOH (10 mL) and filtered. The dendrimeric catalyst was
washed several times with H2O and MeOH. The resulting solution
was evaporated and purified by silica gel chromatography to give
the corresponding chiral alcohol 6–18.
Colorless oil; [a]D20 –59.58 (c 1.00, CHCl3).
IR (film): 3358, 1607, 1507, 1454, 1241 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.50–1.71 (m, 4 H), 2.85–3.02 (m,
2 H), 4.19 (t, J = 7.3 Hz, 1 H), 4.99 (s, 2 H), 5.00 (s, 2 H), 6.86–6.90
(m, 4 H, Ar), 7.23–7.46 (m, 14 H, Ar).
13C NMR (75 MHz, CDCl3): d = 25.498, 26.264, 46.735, 64.655,
69.963, 69.990, 76.577, 114.124, 114.204, 114.409, 126.641,
126.964, 127.429, 127.472, 127.542, 127.858, 127.888, 128.514,
137.129, 137.175, 138.377, 140.926, 157.254, 157.348.
MS (ESI): m/z (%) = 466.1 (100) [M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C31H32NO3: 466.23829; found:
Acknowledgment
We are grateful to the Ministry of Sciences and Technology, the
State Key Project of Basic Research (Project 973, No. G
2000048007) and National Natural Science Foundation of China for
financial support (No. 20525208, 20532040), QT program and
Shanghai Natural Science Council.
466.23767.
Catalyst 2 (n = 1)
White foam; mp 45–47 °C; [a]D20 –32.26 (c 0.93, CHCl3).
IR (KBr): 3359, 1596, 1506, 1452, 1159 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.53–1.79 (m, 5 H), 2.94–3.04 (m,
2 H), 4.19 (t, J = 6.3 Hz, 1 H), 4.95 (s, 4 H), 5.03 (s, 8 H), 6.56–6.57
(m, 2 H, Ar), 6.66–6.67 (m, 4 H, Ar), 6.86–6.93 (m, 4 H, Ar), 7.25–
7.47 (m, 24 H, Ar).
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Anal. Calcd for C59H55NO7: C, 79.62; H, 6.23; N, 1.57. Found: C,
79.58; H, 6.27; N, 1.45.
Catalyst 3 (n = 2)
White foam; mp 57–59 °C. [a]D20 –25.8 (c 1.25, CHCl3).
IR (KBr): 3353, 2872, 1596, 1506, 1452, 1157 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.52–1.69 (m, 5 H), 2.86–3.02 (m,
2 H), 4.10 (t, J = 7.5 Hz, 1 H), 4.93 (s, 12 H), 5.00 (s, 16 H), 6.51–
6.56 (m, 6 H, Ar), 6.63–6.67 (m, 12 H, Ar), 6.85–6.87 (m, 4 H, Ar),
7.29–7.41 (m, 44 H, Ar).
MALDI MS (IAA): m/z = 1720.7 [M – H2O + H]+.
Anal. Calcd for C115H103NO15: C, 79.42; H, 5.97; N, 0.81. Found: C,
79.40; H, 5.94; N, 0.76.
Catalyst 4 (n = 3)
White foam; mp 61–63 °C; [a]D20 –5.34 (c 0.8, CHCl3).
IR (KBr): 3400, 2872, 1598, 1498, 1452, 1216, cm–1.
1H NMR (300 MHz, CDCl3): d = 1.52–1.69 (m, 5 H), 2.86–3.02 (m,
2 H), 4.08 (t, J = 7.8 Hz, 1 H), 4.93 (s, 28 H), 4.99 (s, 32 H), 6.52–
6.55 (m, 14 H, Ar), 6.63–6.66 (m, 28 H, Ar), 6.82–6.85 (m, 4 H, Ar),
7.26–7.37 (m, 84 H, Ar).
MALDI MS (IAA): m/z = 3417.5 [M – H2O + H]+.
Anal. Calcd for C227H199NO31: C, 79.33; H, 5.84; N, 0.41. Found: C,
79.41; H, 5.82; N, 0.40.
Catalyst 5 (n = 1)
White foam; mp 45–46 °C; [a]D20 –22.35 (c 0.95, CHCl3).
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IR (KBr): 3358, 2871, 1596, 1496, 1451, 1156 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.19–1.73 (m, 5 H), 2.86–3.01 (m,
2 H), 4.15 (t, J = 7.6 Hz, 1 H), 4.95 (s, 4 H), 5.00 (s, 8 H), 6.55 (m,
2 H, Ar), 6.66–6.67 (m, 4 H, Ar), 6.74–6.76 (m, 2 H, Ar), 7.04–7.41
(m, 26 H, Ar).
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79.44; H, 6.29; N, 1.44.
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G.-y. Wang et al.
LETTER
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Synlett 2006, No. 8, 1150–1154 © Thieme Stuttgart · New York