A simple and effective soluble polymer-bound ligand for the asymmetric dihydroxylation of olefins: DHQD-PHAL-OPEG-OMe

Article abstract of DOI:10.1016/S0040-4039(01)01105-4

The synthesis of a novel soluble polymer-bound ligand DHQD-PHAL-OPEG-OMe and its application in the catalytic asymmetric dihydroxylation (AD) reaction are described. 1,4-Dichlorophthalazine was used as the coupling reagent to connect dihydroquinidine and polyethylene glycol monomethyl ether (MW = 5000, Fluka) while providing an aromatic group at the 9-O-position of dihydroquinidine. Enantiomeric excesses for trans-disubstituted olefins in the AD reaction, with K₃Fe(CN)₆ as secondary oxidant, are up to 98%.

Full text of DOI:10.1016/S0040-4039(01)01105-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5925–5927
A simple and effective soluble polymer-bound ligand for the
asymmetric dihydroxylation of olefins:
DHQD-PHAL-OPEG-OMe
Yong-Qing Kuang, Sheng-Yong Zhang* and Ling-Ling Wei
Department of Chemistry, Fourth Military Medical University, Xi’an 710032, China
Received 21 December 2000; revised 30 April 2001; accepted 21 June 2001
Abstract—The synthesis of a novel soluble polymer-bound ligand DHQD-PHAL-OPEG-OMe and its application in the catalytic
asymmetric dihydroxylation (AD) reaction are described. 1,4-Dichlorophthalazine was used as the coupling reagent to connect
dihydroquinidine and polyethylene glycol monomethyl ether (MW=5000, Fluka) while providing an aromatic group at the
9
-O-position of dihydroquinidine. Enantiomeric excesses for trans-disubstituted olefins in the AD reaction, with K Fe(CN) as
3 6
secondary oxidant, are up to 98%. © 2001 Elsevier Science Ltd. All rights reserved.
5
,6
The osmium-catalyzed asymmetric dihydroxylation
AD) of olefins provides one of the most efficien1t
complicated synthetic manipulations. According to
structure–enantioselectivity relationship (SER) studies a
bi- or tricyclic planar aromatic group at the 9-O-posi-
tion of the alkaloid is necessary to achieve optimum
(
methods for the preparation of chiral vicinal diols.
However, there are limitations to performing the cata-
lytic AD reaction on a large scale due to the high cost
of osmium and chiral ligands. To explore the possibility
of the repetitive use of both components, insoluble
polymer-supported ligands have been developed by sev-
7
enantioselectivity in the AD process. Here we report
the synthesis of a simple and effective soluble polymer-
bound ligand 1, with 1,4-dichlorophthalazine as the
coupling reagent while providing an aromatic group at
the 9-O-position of dihydroquinidine, and its successful
use in the AD reaction of various olefins. We synthe-
sized ligand 1 through two different approaches, both
of which include only two steps (Scheme 1). In
approach A, the mono-substituted chlorophthalazine 2
was prepared according to the reported method. Then
was heated with HO-PEG-OMe (MW=5000) in
dimethylsulfoxide in the presence of NaH to give ligand
(2/HO-PEG-OMe=3/1, mol/mol). In approach B, a
mixture of HO-PEG-OMe (MW=5000), 1,4-
2
eral groups. Despite the advantage of easy separation,
the use of insoluble polymer-supported ligands suffered
from lowered catalytic activity and enantioselectivity
due to the restriction of the polymer matrix, which
resulted in limited mobility and accessibility of the
active sites and thus obstructed the ligand-accelerated
8
5
3
,4
catalytic (LAC) AD reaction. To combine the advan-
tages of homogeneous catalysis with the easy separation
of a ligand bound to the solid phase, cinchona alkaloid-
type ligands were anchored on a soluble polymer,
polyethylene glycol monomethyl ether (HO-PEG-
OMe), and showed similar activity and selectivity when
compared to the corresponding free ligands in the AD
2
1
dichlorophthalazine, KOH and K CO in dry toluene
2
3
was refluxed (1,4-dichlorophthalazine/HO-PEG-OMe=
/1, mol/mol), with azeotropic removal of water, to
give PEG-bound chlorophthalazine 3. Then 3 was
treated with dihydroquinidine in dry toluene (DHQD/
3
2
reaction of olefins. However, the PEG-bound mono-
cinchona alkaloid ligand without an aromatic group at
its 9-O-position showed low enantioselectivity (even the
3
=3/1, mol/mol), with butyllithium as base, to give
3
AD reaction of stilbene gave only 88% ee ), and the
ligand 1.
PEG-bound bis-cinchona alkaloid ligands required
Ligand 1 is completely soluble in a tert-butanol/water
mixture (v/v=1/1) allowing homogeneous AD reac-
tions. The AD reaction results for the selected olefins
are shown in Table 1. The features can be summarized
as follows: (1) Ligand 1 produces considerably higher
ees than polyethylene glycol dihydroquinidine glutarate
Keywords: polymer-bound ligand; asymmetric dihydroxylation; 1,4-
dichlorophthalazine; dihydroquinidine; polyethylene glycol mono-
methyl ether.
*
Corresponding author. Tel.: +86-29-3374470; fax: +86-29-3246270;
e-mail: syzhang@fmmu.edu.cn
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01105-4

5
926
Y.-Q. Kuang et al. / Tetrahedron Letters 42 (2001) 5925–5927
1
,4-dichlorophthalazine
N
N N
N
K CO , KOH
2
3
OH
O
Cl
H
toluene, reflux, 72%
H
MeO
MeO
DMSO HO-PEG-O-Me
MW=5000)
(
N
N
8
9% NaH
DHQD
2
N
O
N N
O-PEG-OMe
H
MeO
N
1
toluene DHQD
reflux
1
,4-dichlorophthalazine
K CO , KOH
91% n-BuLi
N
N
2
3
MeO-PEG-O
Cl
HO-PEG-OMe
MW=5000)
toluene , reflux, 95%
(
3
Scheme 1.
a
Table 1. Catalytic asymmetric dihydroxylation reactions using ligand 1
o
Entry
1
Olefin
Yield(%)
93c
ee(%)b
T ( C )
t(h)
18
c
d
e
0
98 (99 , 88 )
d
e
2
0
24
87
89
82 (98 , 60 )
79 (94f)
3
4
0
0
24
24
O
90 (91f)
92
81
83
CO Me
2
5
6
r.t.
r.t.
96
30
30
CO Et
2
93 (97f)
a
b
c
The molar ratio of olefin/OsO /ligand=1/0.004/0.1. The ee values were determined by HPLC analysis of the diols (see Ref. 10 for details). The
4
d
e
average value of five runs (see Table 2). Results for a soluble polymer-bound ligand (DHQD) PHAL-PEG-OMe from Ref. 5. Results for a
soluble polymer-bound ligand polyethylene glycol dihydroquinidine glutarate from Ref. 3. Results for a widely used free ligand (DHQD) PHAL
2
f
2
from Ref. 11.
1
1
for the same olefins tested. (2) Ligand 1 delivers much
better enantioselectivity for trans-disubstituted olefins
than for mono- and gem-disubstituted olefins, consis-
tent with that reported for 9-O-aryl cinchona alkaloid
(DHQD) PHAL. (4) When the reaction is finished,
2
the ligand can be extracted with CH Cl and precipi-
2
2
tated by addition of diethyl ether. More than 95% of
the ligand can be recovered by simple filtration. (5) The
repeated use of the ligand showed almost unchanged ee
values and yields (Table 2).
9
ligands without a binding pocket. (3) Interestingly,
naphthyl allyl ether (entry 4 in Table 1) was trans-
formed into the corresponding chiral diol in a very
good yield and high ee, almost comparable to the
results obtained with the widely used free ligand
In conclusion, we have developed a simple and effective
soluble polymer-bound ligand for the AD reaction.

Y.-Q. Kuang et al. / Tetrahedron Letters 42 (2001) 5925–5927
5927
Table 2. Reuse of ligand 1
References
Ph
HO
Ph
Ph
OsO , K Fe(CN) Ligand 1
4
3
6,
1
. For reviews, see: (a) Kolb, H. C.; VanNieuwenhze, M.
S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547; (b)
Williams, J. M. J. Catalysis in Asymmetric Synthesis;
Sheffield Academic Press Ltd: UK, 1999; pp. 69–77.
. Bolm, C.; Gerlach, A. Eur. J. Org. Chem. 1998, 21–27.
. Han, H.; Janda, K. D. J. Am. Chem. Soc. 1996, 118,
t
K CO , BuOH/H O
2
3
2
Ph
OH
(oC )
18 h
0
2
3
Run
Yield (%)
Ee (%)
7
632–7633.
1
2
3
4
5
92
94
90
93
94
99
96
98
97
98
4
5
6
. Fan, Q. H.; Ren, C. Y.; Yeung, C. H.; Hu, W. H.;
Chan, A. S. C. J. Am. Chem. Soc. 1999, 121, 7407–7408.
. Han, H.; Janda, K. D. Tetrahedron Lett. 1997, 38,
1
527–1530.
. Bolm, C.; Gerlach, A. Angew. Chem., Int. Ed. Engl.
997, 36, 741–743.
1
This ether-bound ligand is more stable than ester-
bound examples under the standard aqueous basic (pH
7. Amberg, W.; Bennani, Y. L.; Chadha, R. K.; Crispino,
G. A.; Davis, W. D.; Hartung, J.; Jeong, K. S.; Oigno,
Y.; Shibata, T.; Sharpless, K. B. J. Org. Chem. 1993, 58,
2
1
2.2) AD reaction conditions with K Fe(CN) as sec-
3 6
ondary oxidant. The recovery and repetitive use of the
ligand is possible without significant loss of enantiose-
lectivity and activity. Among the two synthetic
approaches to ligand 1, approach B is preferable for its
high yield and convenience.
844–849.
1
8. 2: H NMR (CDCl , 400 MHz) l 0.91 (t, J=7.2 Hz,
3
3H), 1.45–1.70 (m, 6H), 1.77 (m, 1H), 2.06 (m, 1H),
2.70–3.00 (m, 4H), 3.49–3.62 (m, 1H), 4.00 (s, 3H), 7.28
(d, J=7.3 Hz, 1H), 7.35 (dd, J=9.3 and 2.7 Hz, 1H),
7
.48 (d, J=4.6 Hz, 1H), 7.64 (d, J=2.7 Hz, 1H), 7.95
Typical procedure for asymmetric dihydroxylation reac-
(
d, J=9.2 Hz, 1H), 7.99 (m, 3H), 8.13–8.21 (m, 1H),
tions. K Fe(CN) (0.980 g, 3.0 mmol), K CO (0.410 g,
1
3
6
2
3
8.33–8.41 (m, 1H), 8.67 (d, J=4.6 Hz, 1H); 3: H NMR
(CDCl , 400 MHz) l 3.2–3.9 (PEG peaks), 4.83 (s, 2H,
3
.0 mmol), ligand 1 (0.55 g, 0.1 mmol), K OsO (OH)
2
2
4
3
(
0.0015 g, 0.004 mmol) were dissolved in tert-butyl
alcohol and water (5.5 mL of each) at room tempera-
ture. For trans-disubstituted olefins, CH SO NH (95
-
PHAL-O-CH -), 7.96 (m, 2H), 8.21 (m, 1H), 8.30 (m,
2
1
1
H); 1: H NMR (CDCl , 400 MHz) l 0.94 (t, J=7.0
3
3
2
2
Hz, 3H), 1.25–1.76 (m, 7H), 2.14 (m, 1H), 2.66–3.10 (m,
H), 3.20–3.85 (PEG peaks), 4.00 (s, 3H), 4.82 (s, 2H,
PHAL-O-CH -), 7.28 (d, J=7.3 Hz, 1H), 7.35–7.45 (m,
mg, 1 mmol) was added. The solution was cooled to
°C (with the exception of trans-methyl cinnamate and
4
-
0
2
trans-ethyl cinnamate, see Table 1) and the olefin (1
mmol) was added. The mixture was stirred vigorously
at 0°C for 18–24 h. Na SO (1.0 g) was added and the
2H), 7.63 (d, J=2.8 Hz, 1H), 7.85–8.00 (m, 3H), 8.16–
8.25 (m, 1H), 8.27–8.33 (m, 1H), 8.62 (d, J=4.8 Hz,
1H).
2
3
mixture was stirred at room temperature for 30 min.
CH Cl was added to the reaction mixture, and after
9
. Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.;
Hartung, J.; Kawanami, Y.; Lubben, D.; Manoury, E.;
Ogino, Y.; Shibata, T.; Ukita, T. J. Org. Chem. 1991,
2
2
separation of the layers the aqueous phase was further
extracted with CH Cl (5 mL×3). If CH SO NH was
2
2
3
2
2
5
6, 4585–4588.
added, the combined organic layers were washed with 2
M NaOH. The combined organic layers were dried over
i
1
0. Entry 1: Chiralcel OJ, hexane/ PrOH=4/1, flow rate=
0
2
.6 mL/min, tR (min)=12.2 (major), 13.8 (minor); entry
anhydrous Na SO4 and concentrated to about half
2
i
: Chiralcel OB-H, hexane/ PrOH=9/1, flow rate=0.5
volume. Diethyl ether (90 mL) was slowly added to the
mixture under vigorous stirring conditions. The precipi-
tate obtained was collected on a glass filter, washed
with ethanol/diethyl ether, and dried in vacuo. The
filtrate was evaporated to give the crude product, which
was further purified by chromatography to afford the
diol.
mL/min, tR (min)=13.9 (major), 17.7 (minor); entry 3:
Chiralcel OD, hexane/ PrOH=40/1, flow rate=1.0 mL/
min, tR (min)=29.9 (major), 32.8 (minor); entry 4: Chi-
ralcel OD, hexane/ PrOH=19/1, flow rate=1.0 mL/min,
tR (min)=14.1 (minor), 20.6 (major); entry 5: Chiralcel
OD, hexane/ PrOH=4/1, flow rate=1.0 mL/min, t
i
i
i
R
(
min)=15.8 (major), 19.8 (minor); entry 6: Chiralcel
i
AD, hexane/ PrOH=9/1, flow rate=1.0 mL/min,
tR(min)=27.5 (major), 30.2 (minor).
Acknowledgements
1
1. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino,
G. A.; Harurng, J.; Jeong, K. S.; Kwong, H. L.;
Morikawa, K.; Wang, Z. M.; Xu, D. Q.; Zhang, X. L.
J. Org. Chem. 1992, 57, 2768–2771.
We thank National Natural Science Foundation of
China (NSFC) for financial support.
.