A highly efficient and practical new PEG-bound bi-cinchona alkaloid ligand for the catalytic asymmetric aminohydroxylation of alkenes

Article abstract of DOI:10.1016/j.tetasy.2004.05.007

A new recyclable PEG-bound bi-cinchona alkaloid ligand has been developed for homogeneous catalytic asymmetric aminohydroxylation; it can be easily recovered by precipitation and reused more than five times without any significant loss in its catalytic efficiency.

Full text of DOI:10.1016/j.tetasy.2004.05.007

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1915–1918
A highly efficient and practical new PEG-bound bi-cinchona
alkaloid ligand for the catalytic asymmetric aminohydroxylation
of alkenes
Xi-Wen Yang, Han-Quan Liu, Ming-Hua Xu* and Guo-Qiang Lin*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 2 April 2004; accepted 6 May 2004
Abstract—A new recyclable PEG-bound bi-cinchona alkaloid ligand has been developed for homogeneous catalytic asymmetric
aminohydroxylation; it can be easily recovered by precipitation and reused more than five times without any significant loss in its
catalytic efficiency.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The Sharpless asymmetric aminohydroxylation (AA)
reaction is one of the most efficient methods for the
preparation of chiral vicinal aminoalcohols.1 It offers
the advantages of direct addition of the two heteroatom
substitutes to an olefin with excellent enantioselectivities
in good yields. The catalytic system based on cinchona
alkaloids, K2OsO2(OH)4 and various nitrogen sources
has received a great deal of interest.1;2 However, the
toxicity and high cost of osmium tetroxide and cinchona
alkaloids has limited its application on a large scale. To
address these drawbacks, efforts have been made for
developing immobilized catalysts which may provide an
efficient recycling and subsequent reuse.3 Although the
use of solid-supported catalysts in the asymmetric
dihydroxylation (AD) has gained much attention,4 only
a few examples of polymer-supported chiral catalysts
used in the heterogeneous AA have been reported to
date.5
Poly(ethylene glycol) (HO–PEG–OH) is very useful as a
soluble support for catalyst immobilization.6 The new
PEG-bound bi-cinchona alkaloid ligand 4 was designed
to contain two DHQ–PHAL structures linked with PEG
(Scheme 1). Unlike other immobilized cinchona alkaloid
ligands that contain only one catalytic site, this ligand
can have two catalytic sites (DHQ–PHAL) on each
N
N
Cl
N
Cl
N
N
N
2
O
Cl
OH
H
H
H3CO
H3CO
K2CO3/KOH
THF, reflux
N
N
3
1
nBuLi, THF
HO-PEG-OH
Herein, we report our recent development of a
novel soluble PEG-bound bi-cinchona alkaloid ligand
for the enantioselective AA reaction. To the best of
our knowledge, this is the first example of an immo-
bilized chiral catalyst for the homogeneous AA
reaction.
N
OCH3
N
N
N
H
O
O-PEG-O
O
H
N
N
N
H3CO
N
4a HO-PEG-OH MW ca. 4000
4b HO-PEG-OH MW ca. 6000
4c HO-PEG-OH MW ca. 8000
* Corresponding authors. E-mail addresses: xumh@mail.sioc.ac.cn;
lingq@mail.sioc.ac.cn
Scheme 1.
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.05.007

1916
X.-W. Yang et al. / Tetrahedron: Asymmetry 15 (2004) 1915–1918
molecule. We envisioned that the introduction of two
DHQ–PHAL structures could potentially increase the
efficiency of the ligand for asymmetric catalysis. Also,
the soluble polymer backbone (PEG) would provide
easily accessible reaction sites in solution. Thus, the
combination features of more catalytic sites and the
higher solubility of this polymer-supported ligand might
make it comparable to the corresponding nonimmobi-
lized ligand (DHQ)2PHAL.
ligand to afford 6 in good yield and enantioselectivity.
Less satisfactory results were obtained with a reduced
amount of ligand loading (5 and 10 mol %) (compare
entries 5 and 6 with 7). When the reaction was carried
out with 10 mol % of ligand, a much lower yield was
observed although the enantioselectivity still remained
high (entries 6 and 7). In studies on the effects of the R2
group (R2 ¼ Me, Et, iPr, Bn), iso-propyl was found to be
the best, leading to greatly improved regioselectivity
(>20:1) and enantioselectivity (97%) (entries 1, 2, 7, and
8). To examine the effect of changing the molecular
weight of poly(ethylene glycol), we investigated ligands
4a,b, and 4c in the reaction of 5c. As shown in entries 3,
4 and 7, similar chemical yields (85–93%) and ees (95–
97%) were observed, suggesting that changing the
molecular weight of PEG did not have any apparent
influence on the asymmetric induction of the reaction.8
With the optimized conditions, other iso-propyl trans-
cinnamate derivatives containing electron-donating or
electron-withdrawing substituents at the para-position
were successfully employed with very good enantiomeric
excesses (91–97%) being achieved (entries 9–11).
The synthesis of the ligand is shown in Scheme 1. The
mono-substituted chlorophthalazine 3 was prepared by
coupling of dihydroquinine 1 with 1 equiv of 1,4-di-
chlorophthalazine 2. The reaction of the obtained mono-
substituted chlorophthalazine
3
(2.5 equiv) with
poly(ethylene glycol) (1 equiv) in THF in the presence of
nBuLi followed by precipitation from ethyl ether afford-
ed 4 as a white solid in good yield. Poly(ethylene glycol)
with different molecular weights (MW ca. 4000, 6000,
and 8000) was used in the preparation.7 As we expected,
the obtained ligands 4a, 4b, and 4c were all soluble in
tBuOH, acetone and other common organic solvents
such as CHCl3 and THF.
The polymeric ligand could be easily recovered by sim-
ple precipitation (ether), filtration, washing, and drying
after the catalytic reaction. To further test the efficiency
of the recovered catalyst, we reused it in the amino-
hydroxylation of iso-propyl trans-cinnamate with the
reaction results summarized in Table 2. As can be seen,
the recovered catalyst can be recycled more than five
times without any significant loss of its activity. Excel-
lent yields and enantioselectivities were also observed in
all five runs under the same reaction conditions. It is
interesting to note that excellent enantioselectivities can
also be achieved by using a somewhat lower amount
(2.8 mol %) of the expensive osmium oxidant in the
recycling process; however, the reaction takes a longer
time and gives a slightly lower yield. Thus, the C-13
Taxol side chain precursor 6 (R1 ¼ H) could be prepared
in a single step in a large scale with high enantioselec-
tivities and yields but low costs by using the recyclable
immobilized bi-cinchona alkaloid ligand 4.
We have studied the AA reaction of trans-cinnamate
derivatives with K2OsO2(OH)4 using AcNHBr as the
nitrogen source under conventional Sharpless condi-
tions (Scheme 2) with the results summarized in Table 1.
The reaction proceeded smoothly with 20 mol % of
AcHN
O
O
Ligand 4
AcNHBr, LiOH
OR2
OR2
K2OsO2(OH)4
Solvent
OH
R1
R1
5
6
a R1 = H, R2 = Me
b R1 = H, R2 = Et
c R1 = H, R2 = iPr
d R1 = H, R2 = Bn
e R1 = CH3, R2 = iPr
f R1 = OCH3, R2 = iPr
g R1 = NO2, R2 = iPr
Scheme 2.
Table 1. The homogeneous asymmetric AA reaction using PEG-bound bi-cinchona alkaloid ligand 4a
Entry
Substrate
Solventb
Ligand
Time (h)
Yield (%)
Regioselectivity (%)c
Ee (%)d
1
5a
5b
5c
5c
5c
5c
5c
5d
5e
5f
Acetone–H2O
tBuOH–H2O
tBuOH–H2O
tBuOH–H2O
tBuOH–H2O
tBuOH–H2O
tBuOH–H2O
Acetone–H2O
tBuOH–H2O
tBuOH–H2O
tBuOH–H2O
4c
4c
4a
4b
4ce
4cf
4c
4c
4c
4c
4c
12
12
12
12
14
14
12
14
12
12
18
75
80
85
90
45
60
93
85
75
86
65
ꢀ10:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
ꢀ10:1
>20:1
>20:1
>20:1
74
84
97
95
76
98
97
79
91
99
97
2
3
4
5
6
7
8
9
10
11
5g
a K2OsO2(OH)4 (4 mol %), polymeric ligand 4 (20 mol %), AcNHBr (1 equiv), and LiOHÆH2O (1 equiv) were used unless otherwise noted.
b In the cases of substrates 5a and 5d, acetone–H2O was used due to their solubility.
c Determined by 1H NMR spectroscopy.
d Determined by chiral HPLC analysis on a chiralcel AD column (detected at 254 nm).
e Compound 4c (5 mol %) was used.
f Compound 4c (10 mol %) was used.

X.-W. Yang et al. / Tetrahedron: Asymmetry 15 (2004) 1915–1918
1917
Table 2. The asymmetric aminohydroxylation of isopropyl trans-cin-
namate with recycled PEG-bound bi-cinchona alkaloid ligand 4c in the
homogeneous phasea
(t, J ¼ 7:2 Hz, 3H), 1.25–1.60 (m, 5H), 1.77–1.93 (m,
4H), 2.46 (m, 1H), 2.73 (m, 1H), 3.13 (m, 1H), 3.32 (m,
1H), 3.57 (m, 1H), 4.02 (s, 3H), 7.37 (dd, J1 ¼ 2:7 Hz,
J2 ¼ 8:7 Hz, 1H), 7.44 (d, J ¼ 4:5 Hz, 1H), 7.66 (d,
J ¼ 2:4 Hz, 1H), 7.98–8.04 (m, 3H), 8.19–8.22 (m, 1H),
8.39–8.42 (m, 1H), 8.65 (d, J ¼ 4:5 Hz, 1H); EIMS (m=z,
%): 488 (Mþ), 309 (100%).
Run
Time (h)
Yield (%)
Ee (%)b
1
2
3
4
5
15
18
20
18
14
90
92
91
84
88
99
99
97
98
95
a Reaction performed on a 3.3 mmol (630 mg) scale at 5 °C using
4 mol% of K2Os2O2(OH)4, 20 mol % of polymeric ligand 4c, AcNHBr
4.2. Preparation of new PEG-bound bi-cinchona alkaloid
ligand 4
t
(3.3 mmol) and LiOHÆH2O (3.3 mmol) in BuOH–H2O (1:1).
b Determined by chiral HPLC analysis on a chiralcel AD column
(detected at 254 nm; eluent: n-hexane/iso-propyl alcohol ¼ 80:20 (V/
V)).
Under nitrogen, to a solution of poly(ethylene glycol)
(2 mmol, MW ca. 4000, 6000, or 8000) in freshly distilled
THF (50 mL) in a 100 mL flame-dried three necked flask
at 0 °C was added nBuLi (2.4 mL, 2.5 M in hexane).
After the addition, the mixture was allowed to warm to
room temperature and stirred for 1 h. Mono-substituted
chlorophthalazine 3 (2.44 g, 5.0 mmol) was then added
and the reaction mixture heated to reflux for 18 h. After
cooling to room temperature, water (10 mL) was care-
fully added to the reaction. The organic layer was sep-
arated and the water layer extracted with CH2Cl2
(30 mL ꢁ 3). The combined organic layer was washed
with brine, dried over Na2SO4, and concentrated. The
residue was dissolved with the minimum amount of
CH2Cl2 and diethyl ether (200 mL) then added. The
obtained precipitate was collected by filtration and
washed with cold diethyl ether/ethanol (3:1) several
times. These dissolution and precipitation procedures
were repeated two more times to give ligand 4 as a white
To compare the catalyst efficiency with that of the
known MeO-PEG supported mono-DHQ–PHAL4i, we
prepared the MeO-PEG-bound cinchona alkaloid
ligand and investigated its use in the AA reaction of iso-
propyl trans-cinnamate under the same conditions. In
the similar five runs, the corresponding enantiomeric
excesses of 97%, 92%, 92%, 85%, and 70% were ob-
served, respectively. These results suggested better cat-
alyst efficiency of our PEG-bound bi-cinchona alkaloid
ligand in this reaction.
3. Conclusion
In summary, we have developed an efficient and prac-
tical new PEG-bound bi-cinchona alkaloid ligand and
demonstrated its successful application in the homo-
geneous asymmetric aminohydroxylation of trans-cin-
namate derivatives. The immobilized soluble catalyst
can be readily prepared and easily recovered after the
reaction. In addition, the recovered catalyst could be
further reused more than five times without any signif-
icant loss of its activity. This has greatly improved the
possibility of the potential use of this AA reaction in
industry in near future.
1
solid (ca. 68–75% yield). H NMR (CDCl3, 500 MHz) d
0.85 (t, J ¼ 7:3 Hz, 6H), 1.25–1.80 (m, 14H), 2.17 (s,
2H), 2.43 (m, 2H), 2.67 (m, 2H), 2.87 (m, 2H), 3.12 (m,
2H), 3.30–3.90 (PEG peaks), 4.00 (s, 6H), 4.67 (m, 4H,
DHQ–PHAL–OCH2–), 7.18 (s, 2H), 7.34–7.48 (m, 4H),
7.62 (s, 2H), 7.86–7.94 (m, 4H), 7.99 (d, J ¼ 9:2 Hz, 2H),
8.19 (d, J ¼ 7:7 Hz, 2H), 8.33 (d, J ¼ 7:9 Hz, 2H), 8.63
(d, J ¼ 4:3 Hz, 2H). GPC analysis for ligand 4a (PEG
MW ca. 4000): Mn 4575, Mw 4739, Mp 4911, PDI 1.04.
4.3. General procedure of the homogeneous asymmetric
AA reaction using PEG-bound bi-cinchona alkaloid
ligand 4
4. Experimental
4.1. Preparation of mono-substituted chlorophthalazine
34f,j
To a 50 mL flask charged with 5 mL of aqueous solution
of LiOHÆH2O (42.8 mg, 1.0 mmol) was added
K2OsO2(OH)4 (14.7 mg, 0.04 mmol, 4 mol %). The mix-
Under nitrogen, to a 250 mL flame-dried three-necked
round bottom flask was added dihydroquinine (3.26 g,
10 mmol), 1,4-dichlorophthalazine (2.00 g, 15 mmol),
K2CO3 (4.14 g, 30 mmol), and freshly distilled THF
(50 mL). After the reaction was refluxed for 5 h, KOH
(0.58 g, 10 mmol) was added and the mixture refluxed
for another 18 h. The reaction was cooled to room
temperature and diluted with water (50 mL) and CH2Cl2
(100 mL). The organic layer was separated and the water
layer extracted with CH2Cl2 (30 mL ꢁ 3). The combined
organic layer was washed with brine, dried over
Na2SO4, and concentrated. The crude product was
purified by chromatography on silica gel (petroleum/
ethyl acetate/methanol 8:2:1) to give pure 3 as a white
t
ture was stirred for 30 min to dissolve; BuOH (10 mL)
and ligand 4 (20 mol %) were then added. The resulting
mixture was stirred for 30–40 min at room temperature
to give a clear solution. Water (5 mL) was subsequently
added and the reaction cooled to 5 °C; trans-cinnamate
derivatives (1.0 mmol) was added followed by the addi-
tion of fresh AcNHBr (158 mg, 1.0 mmol) in one por-
tion. The reaction was stirred at 5 °C and monitored by
TLC. After completion, the reaction mixture was treated
with Na2SO3 (0.5 g) and stirred for 30 min at room
temperature after which CH2Cl2 was added. The organic
layer was separated and the water layer extracted with
CH2Cl2 for three times. The combined organic extracts
were washed with brine and dried over Na2SO4. After
1
solid (3.58 g, 73%). H NMR (CDCl3, 300 MHz) d 0.87

1918
X.-W. Yang et al. / Tetrahedron: Asymmetry 15 (2004) 1915–1918
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evaporation of the solvent, the residue was dissolved
with the minimum amount of CH2Cl2; diethyl ether
(ꢀ100 mL) was added to precipitate the immobilized
catalyst. The obtained precipitate was collected by fil-
tration and washed with diethyl ether several times.
After drying under vacuum, the obtained solid could be
reused in subsequent reactions (more than 90% of the
ligand can be recovered). The filtrate was concentrated
and purified by chromatography on silica gel (petro-
leum/ethyl acetate 1:1) to give the product.
2. (a) Nilov, D.; Reiser, O. Adv. Synth. Catal. 2002, 344, 1169,
and references cited therein; (b) Bodkin, J. A.; McLeod, M.
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3. For a review on recoverable catalysts for asymmetric
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Chem. Rev. 2002, 102, 3385.
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AA reaction, see: Song, C. E.; Oh, C. R.; Lee, S. W.; Lee,
S.-G.; Canali, L.; Sherrington, D. C. Chem. Commun. 1998,
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4.4. Determination of the enantiomeric excess
The enantiomeric excess was determined by HPLC
analysis using a chiralcel AD column with n-hexane/iso-
propyl alcohol (80:20 or 90:10) as eluent (flow rate
1.0 mL/min, UV detected at 254 nm). Racemic products
were prepared for comparison.
Acknowledgements
Financial support from the National Natural Science
Foundation of China (203900506) and the Major State
Basic Research Development Program (G2000077506)
are greatly acknowledged.
References and notes
6. For a review: Dickerson, T. J.; Reed, N. N.; Janda, K. D.
Chem. Rev. 2002, 102, 3325.
7. PEG4000 and PEG6000 were purchased from Acros Organics,
PEG8000 was purchased from Shanghai Chemical Reagent
Company.
8. Based on the availability of the different molecular weights
of poly(ethylene glycol) in our lab, ligand 4c prepared from
PEG8000 was the most commonly used in this study.
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