Asymmetric synthesis of (S)-metoprolol via sharpless asymmetric dihydroxylation induced by a recoverable polymer ligand QN-AQNOPEG-OMe

Article abstract of DOI:10.2174/157017812802139645

The catalytic asymmetric dihydroxylation (AD) discovered by Sharpless, a Nobel Prize winner in 2001, has rapidly become an invaluable synthetic tool in the possibility of converting prochiral olefins to chiral vicinal diols. After our long-running investi

Full text of DOI:10.2174/157017812802139645

516
Letters in Organic Chemistry, 2012, 9, 516-519
Asymmetric Synthesis of (S)-metoprolol via Sharpless Asymmetric
Dihydroxylation Induced by A Recoverable Polymer Ligand QN-AQN-
OPEG-OMe
Sikun Cheng, Xueying Liu, Pingan Wang, Xiaoye Li, Wei He and Shengyong Zhang*
Department of Medicinal Chemistry, School of Pharmacy, the Fourth Military Medical University, Xi’an, People's
Republic of China
Received November 06, 2011: Revised May 10, 2012: Accepted May 20, 2012
Abstract: The catalytic asymmetric dihydroxylation (AD) discovered by Sharpless, a Nobel Prize winner in 2001, has
rapidly become an invaluable synthetic tool in the possibility of converting prochiral olefins to chiral vicinal diols. After
our long-running investigation of optimized methodology for the production of stereo-defined diols based on the AD reac-
tion, an efficient and environmentally friendly approach for the synthesis of (S)-metoprolol via AD reaction was reported.
The synthetic route proceeded in four-step reactions of nucleophilic substitution, AD reaction, cyclization, and nucleo-
philic ring opening. The key step, AD reaction, proceeded effectively in homogeneous catalysis by using a soluble poly-
mer chiral ligand QN-AQN-OPEG-OMe, which can be easily separated from the reaction system and reused at least four
times while maintaining its high catalytic activity and enantioselectivity. This protocol has been demonstrated to produce
kilogram quantities of (S)-metoprolol on scale.
Keywords: Asymmetric dihydroxylation, asymmetric synthesis, polymer ligand, recoverable, (S)-metoprolol.
INTRODUCTION
O
Stereoselectivity is an important factor in pharmacology
[1]. In the past the pharmacopoeia was dominated by race-
O
NH
mates, but since the 1980s advanced synthesis techniques
have allowed the preparation of pure enantiomers in signifi-
cant quantities. Presently, chiral drugs are currently in high
demand, therefore, advances have been remarkable in chiral
molecule preparation and isolation, including resolution
techniques, biological processes, and biocatalysis, beginning
from a chiral pool and proceeding through catalytic asym-
metric synthesis.
OH
(S )-metoprolol
Scheme 1. Chemical structures of (S)-metoprolol.
techniques for recovering chiral catalysts from the product
mixture are also being rapidly developed [8, 9]. From a
viewpoint of efficiency in organic synthesis, polymer-
supported chiral catalysts are extremely useful to asymmetric
reaction mainly due to they can be easily separated from the
reaction mixture and reused [10-13]. In addition, because
homogeneous catalyst has been found to be more efficient in
asymmetric synthesis than the heterogeneous one, the im-
mobilization of homogeneous reagents and catalysts is of
great interest. The soluble polymer polyethylene glycol
monomethyl ether (HO-PEGOMe) was used for bounding
chiral ligand to promote homogeneous catalysis [14-17].
Therefore, a combination of the two methodologies would
provide a useful tool for efficient asymmetric synthesis of
metoprolol.
Beta-adrenergic blocking agents are administered for the
treatment of cardiovascular diseases (e.g. angina, hyperten-
sion, and heart failure), and are also prescribed to manage
childhood and adolescent disorders including dysrhythmias,
behavioral disorders, migraine headaches, and anxiety [2].
As a selective beta-blocker, metoprolol is an effective one in
clinical treatment. The biological activity of (S)-metoprolol
(Scheme 1) is much higher than that of the corresponding
enantiomer. Enantiomers of metoprolol are usually prepared
from a chiral pool [3-5]. The catalytic asymmetric syntheses
of metoprolol by using a La-Li-BINOL complex or 1,4-
bis(9-O-quinidinyl)phthalazine catalyst have been reported,
but both of the chiral ligands could not be recovered [6, 7].
The development of new ligands for use as chiral cata-
lysts has resulted in products with steadily increasing enanti-
omeric purity in the catalytic asymmetric synthesis. Novel
Our group has carried out in a long-running investigation
of optimized methodology for the production of stereo-
defined diols and ꢀ-amino alcohols based on the AD reaction
[18]. During this study, we observed that up to 99% ee chiral
vicinal diols were obtained by the AD reaction in the pres-
ence of a soluble polymer-anchored cinchona alkaloid ligand
QN-AQN-OPEG-OMe. After the AD reaction, this ligand
was recovered by simple filtration and reused in four succes-
* Address correspondence to this author at the Department of Medicinal
Chemistry, School of Pharmacy, the Fourth Military Medical University,
Xi’an, Shaanxi, People's Republic of China; Tel: 086-029-84776945;
Fax: 086-029-84776945, E-mail: syzhang@fmmu.edu.cn
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

Asymmetric Synthesis of (S)-metoprolol
Letters in Organic Chemistry, 2012, Vol. 9, No. 7
517
O
a
O
+
Br
OH
O
1
2
O
b
d
O
c
O
OH
O
3
O
OH
O
O
NH
OH
62%, 91%ee
4
Reagents and conditions: a. K2CO3, PEG-1000, acetone; b. K2OsO2(OH)4, QN-AQN-OPEG-OMe, K3Fe(CN)6-K2CO3, tBuOH/H2O (1/1, V/V); c. MeC(OMe)3,
PPTS, AcBr, K2CO3; d.ꢀH2O, iPrNH2.
Scheme 2. Synthetic route of (S)-metoprolol.
sive cycles with high enantioselectivity and catalytic activity
[19].
yield and optical purity of 3 remained almost unchanged if
40% of the initial amount of K2OsO2 (OH)4 was added before
every recylcling reaction.
Herein, the full details of preparing of (S)-metoprolol via
the AD reaction catalyzed by using the recoverable polymer
ligand QN-AQN-OPEG-OMe are reported.
With 3 (96% ee) in hand, it is possible to conduct the ep-
oxidation of the vicinal hydroxy groups to the corresponding
1,2-epoxypropanes in the presence of trimethyl orthoacetate,
PPTS, acetyl bromide, and K2CO3. Subsequently, a nucleo-
philic ring- opening reaction involving isopropylamine was
carried out to produce 4 (overall chemical yield 62%, 91%
ee).
RESULTS AND DISCUSSION
Scheme 2 shows the simple four-step synthesis of (S)-
metoprolol (4). In the first step, allyl bromide was nucleo-
philically substituted to 3-[4-(2-methoxyethyl) phenoxy]
propylene (1) in the presence of K2CO3 in dry acetone to
give 2 (87% chemical yield).
The overall route was of low cost and has been utilized to
manufacture (S)-metoprolol on large scales. following the
above mentioned procedures, starting with 1, scale was in-
creased to 10, 100 and 1000 respectively. Yields and ee for
this scale up are reported in Fig. (1). (S)-metoprolol 4 was
produced in high chemical yield and enantioselectivity on
kilogram scale, polymer ligand QN-AQN-OPEG-OMe being
reusued for four cycles.
Ligand QN-AQN-OPEG-OMe was characterized by an
anthraquinone core between anchored PEG-OMe and the 9-
O-position of quinine. It was synthesized in two simple step.
Primarily, 1,4-difluoroanthraquinone was reacted with HO-
OPEG-OMe (FW=5000) by mono-substituted nucleophili-
cally in the presence of KOH and K2CO3 in dry toluene, with
concurrent azeotropic removal of water, to give intermediate
F-AQN-OPEG-OMe in 88% yield. Then, ligand was avail-
able in 96% yield by reaction of F-AQN-OPEG-OMe with
quinine utilizing butyllithium as base [19]. Next, in a
tBuOH/H2O (1/1, V/V) system, by using three equivalents of
K3Fe(CN)6 and three equivalents of K2CO3 as co-oxidants,
0.4 mol% K2OsO2(OH)4, and 10 mol% QN-AQN-OPEG-
OMe at 0°C, 2 was converted to vicinal diol 3 via AD reac-
tion. During the reaction, QN-AQN-OPEG-OMe was ex-
pected to complex with OsO4 in situ to form the chiral cata-
lyst. In addition, as QN-AQN-OPEG-OMe was completely
soluble, it accelerated the homogenous catalysis to achieve a
high chemical yield and optical purity. When the reaction
concluded, QN-AQN-OPEG-OMe can be extracted by using
CH2Cl2 and precipitated by the addition of diethyl ether.
More than 95% of the ligand can be recovered by simple
filtration. The efficiency of ligand recovery was validated by
using the same procedure. After four cycles, the chemical
92
62
60
58
90
88
86
84
82
80
chemical yield
enantiomeric excess
0
200
400
600
800
1000
1
the ratio of charging of
Fig. (1). Overall chemical yield and enantiomeric excess of produc-
ing (S)-metoprolol on large scales.

518 Letters in Organic Chemistry, 2012, Vol. 9, No. 7
Cheng et al.
i
CONCLUSIONS
3 HPLC (Chiralcel OD, Hex/ PrOH =3:1; 0.6 mL/min),
tR(min)= 12.8 (major), 15.9(minor). [ꢁ]D22=+ 8.2°(c 1.0,
MeOH); H NMR(CDCl3): ꢀ 2.69 (br, 2H), 2.81-2.84 (t,2H,
J = 7.6 Hz), 3.34-3.36 (s, 3H), 3.55-3.58 (t,2H, J = 7.6 Hz),
3.75-3.71(m ,1H), 3.83-3.84 (dd, 1H, J1 = 3.6 Hz, J2 = 3.6
Hz), 4.00-4.01 (d,2H, J = 4 Hz), 4.06-4.10 (s,1H), 6.83-6.85
(d, 2H, J= 8.4 Hz), 7.12-7.15 (d,2H, J = 8.4 Hz).13C
NMR(CDCl3, 100 MHz): ꢀ 34.8, 58.2, 68.6, 69.9, 73.3, 76.2,
76.6, 76.8, 113.9, 129.4, 131.2,156.4. MS:[M+H]+ 226.1.
An efficient and environmental friendly route for the
preparation of (S)-metoprolol was developed. The synthetic
route proceeded in four steps: nucleophilic substitution, AD
reaction, cyclization, and nucleophilic ring opening. High
yield and purity were achieved in the homogeneous catalytic
AD reaction by using a soluble polymer chiral ligand QN-
AQN-OPEG-OMe, which can be easily separated from the
reaction system and reused for at least five times while
maintaining its high catalytic activity and enantioselectivity.
This protocol has been demonstrated to produce (S)-
metoprolol on large scale. Further applications of this meth-
odology for the synthesis of (S)- bisoprolol are currently
under the way.
1
Preparation of (S)-Metoprolol 4
For this reaction, 5.65 g (0.025 mol) of 3 was dissolved
in CH2Cl2 (85 mL). Then, 74.6 mg PPTS and 3.65 mL
trimethyl orthoacetate were added and the resulting solution
was stirred at room temperature for 20 min. The solvent was
removed under reduced pressure and the residue was dis-
solved in CH2Cl2 (50.0 mL). Under vigorous stirring, 2.20
mL acetyl bromide was added dropwise (over 6 min) and the
resulting solution was stirred at room temperature for 30
min. After vacuum evaporation of the volatiles, the product
(a yellow oil) was dissolved in MeOH (85 mL). Then, 4.48 g
of anhydrous K2CO3 was added. The resulting solution was
stirred at room temperature for 1.5 h and then was poured
into a saturated NH4Cl solution (25.0 mL). The aqueous
layer was extracted with CH2Cl2 (50.0 mLꢀ3) and the com-
bined organic phases were dried over anhydrous Na2SO4.
The solvent was removed under reduced pressure and the
crude product was obtained by using silica gel flash column
chromatography (EtOAc / haxane, 1:3 to 1:2). Then, 37.3
mL isopropylamine and 2.0 mL H2O were added and the
resulting solution was refluxed for 1.5 h. The solvent was
removed under reduced pressure and the resulting oil was
purified by using silica gel flash column chromatography
(acetone/EtOAc /Et3N, 6:6:1) to give 4 (5.08 g, 76%, 91%
ee).
EXPERIMENTAL
Preparation of Aryl Allyl Ether 2
A flame-dried one-neck round-bottom flask was charged
with 6.08 g (0.04 mol) 3-[4-(2-methoxyethyl) phenoxy] pro-
pylene (1), 27.64 g (0.2 mol) of K2CO3, 0.40 g PEG-1000,
24.20 g (0.2 mol) allyl bromide, and 40 mL anhydrous ace-
tone, The reaction mixture was then refluxed for 5 h. Excess
of allyl bromide and acetone was removed by distillation.
The residue was dissolved in 40 mL of 2 M NaOH (aq.) and
stirred for 20 min. The organic layers were dried over anhy-
drous sodium sulfate. The crude product was purified by
using silica gel column chromatography (Hex/EtOAc),
chemical yielding 2 (6.68g, 87%).
1
2 H NMRꢀCD3COCD3:ꢀ 2.74-2.83(m ,2H), 3.27(s,
3H), 3.48-3.53(t,2H, J = 7 Hz), 4.52-4.55 (m, 2H), 5.21-5.25
(dd,1H, J1 = 1.6 Hz, J2 = 1.6 Hz), 5.37-5.43 (dd,1H, J1 = 1.7
Hz, J2 = 1.7 Hz), 6.02-6.07(m, 1H), 6.84-6.87(dd, 2H, J1 =
2.2 Hz, J2 = 2.1 Hz), 7.13-7.16 (dd, 2H, J1 = 2.1 Hz, J 2 = 2.1
Hz).
4 HPLC (Chiralcel OD-H, Hex / iPrOH / Et3N =6:6:1; 0.5
mL/min), tR(min)= 28.3 (major), 31.5(minor). [ꢁ]D22 =–8.78o
(c 10.0, CHCl3). 1H NMR(CDCl3, 400MHz): ꢀ 1.08 (6H, d,
J=6.2Hz), 2.31(2H, bs), 2.81- 2.91 (2H, m), 2.85 (2H, m),
3.36(3H, s), 3.57 (2H, t, J=7.1 Hz), 3.91 (2H, m), 4.01 (lH,
m), 6.86 (2H, d, J=8.2Hz), 7.14 (2H,d, J=8.2Hz). 13C
NMR(CDCl3, 100MHz): ꢀ 22.7, 35.1, 48.85, 49.4, 58.5,
68.3, 70.6, 73.1, 76.7, 77.0, 77.4, 114.3, 129.7, 131.2, 157.0.
MS(FAB): [M+1]+ 268.1.
Preparation of Diol 3
The following reactants, 16.50 g (3 mmol) QN-AQN-
OPEG-OMe, 29.70 g (0.09 mol) K3Fe(CN)6, 12.6g (0.09
mol) K2CO3, and 42 mg (0.11 mmol) K2OSO2(OH)4 were
t
stirred vigorously in 300 mL BuOH-H2O (1:1, v/v) at 0 °C.
Then, 5.76 g (0.03mol) 2 was added dropwise over 30 min
and the mixture was stirred for 17 h. After TLC analysis
confirmed the absence of the starting material, 24 g Na2SO3
was added and the mixture was stirred at room temperature
for another 2 h. After the addition of 600 mL of CH2Cl2, the
organic phase was separated and the aqueous phase was ex-
tracted by using CH2Cl2 (450 mLꢀ3). The combined organic
phases were dried over anhydrous MgSO4 and concentrated
to about 450 mL. Diethyl ether (3.0 L) was slowly added to
the mixture with vigorously stirring. The obtained precipitate
was collected on a glass filter, and washed with cold abso-
lute EtOH/diethyl ether (1:3) and then dried over P2O5 in
vacuo for recycling. More than 15.96 g of ligand was ob-
tained from this procedure (97% recovery). The filtrate was
evaporated to give the crude product, which was purified by
using flash chromatography (Hex/EtOAc) to furnish diol 3
(6.37g, 94%, 96% ee).
Recycling of AD Reaction by Using Chiral Ligand QN-
AQN-OPEG-OMe
The recycling experiment of the AD reaction was con-
ducted using 2 as the substrate. The recovered ligand was
used in the next run without purification. The first run was
carried out with 29.70 g (0.09 mol) K3Fe(CN)6, 12.60 g
(0.09 mol) K2CO3, 55.27 mg (0.15 mmol) K2OsO2(OH)4, and
5.76 g (0.03mol) of 2 to give 3 in 92% chemical yield, with
95% ee. After the reaction, 15.32 g of the ligand was recov-
ered (96% recovery). The second run was carried out with all
of the recovered ligand, 29.70 g (0.09 mol) of K3Fe(CN)6,
12.6g (0.09 mol) of K2CO3, 70.00 mg (0.19 mmol) of
K2OsO2(OH)4, and 5.76 g (0.03mol) of 2 to give 3 in 95%
chemical yield and 94% ee, after which 14.71 g of the ligand

Asymmetric Synthesis of (S)-metoprolol
Letters in Organic Chemistry, 2012, Vol. 9, No. 7
519
was recovered (96% recovery). The third run was carried out
with all of the recovered ligand, 29.70 g (0.09 mol) of
K3Fe(CN)6, 12.6 g (0.09 mol) of K2CO3, 84.74 mg (0.23
mmol) of K2OsO2(OH)4, and 5.76 g (0.03mol) of 2 to give 3
in 91% chemical yield and 95% ee. Following this step,
14.12 g of the ligand was recovered (96% recovery). The
fourth run was carried out with 14.12 g of the recovered
ligand, 29.70 g (0.09 mol) of K3Fe(CN)6, 12.6 g (0.09 mol)
of K2CO3, 99.48 mg (0.27 mmol) of K2OsO2(OH)4, and 5.76
g (0.03mol) of 2 to deliver 3 in 92% chemical yield and 93%
ee, with 13.41 g of the ligand recovered (95% recovery).
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SUPPLEMENTARY MATERIAL
Supplementary material is available on the publishers
Web site along with the published article.
ACKNOWLEDGEMENTS
The authors are grateful for the financial support of the
National Nature Science Foundation of China (No.
20572131) and the Key Technologies R & D Program in
Shaanxi Province of China (No. 2009K13-01-19).
[14]
[15]
[16]
CONFLICT OF INTEREST
Declared none.
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