Table 2. Asymmetric reduction of ketones using CBS catalyst
a
8
O
3
Ph
Ph
O
N
CBS catalyst
4
B
6
rotatable
O
OH
CH3 O BH2
C
H
NH
Yield/%b
ee/%c
Configd
Entry
1
2
3
4
5
6
Ketone
Cat
9
RL: Large group
Rs: Small group
RL
RS
3
3
3
6
6
6
8a
8b
8c
8a
8b
8c
87
92
92
84
89
90
88.4
>99
89.6
83.2
88.4
61.6
R
R
R
R
R
R
C6H5CH=CH2
DVB
e
12
Ph
Ph
CH3B(OH)2 (1.2 equiv)
toluene, reflux
Ph
aUnless otherwise noted, all reactions were carried out with
.1 equiv of catalyst and 0.8 equiv of BH3¢THF at room
temperature; 100% conversion in all reactions. Isolated
yields. Enantiomeric excess was determined by HPLC using
a chiral stationary phase column. Determined by specific
rotation signs and mechanism. 0.05 equiv of catalyst.
Ph
O
OH
NH
O
O
0
N
B
b
CH3
c
10
11
d
e
Scheme 3. Preparation of macroporous-resin-supported CBS
catalysts.
and BH3¢THF, the acetyl group of 3 was also reduced.
Therefore, we tried removing the acetyl group, and converted
Table 3. Reduction of ketone 3 with polymeric catalyst 11 and
the effect of the degree of crosslinking along with the mole ratio
of ligand 9
3
into 6, which was then processed through the same procedure
to obtain 4. However, ketone 6 neither improved enantiomeric
Degree of
crosslinking/%
Ligand 9 Yield
ee
/%
6
Configc
excess (Table 2) nor contributed to synthesis of (R)-phenyl-
Entry
a
b
c
c
/%
/%
ephrine. As a result, considering that 8b is commercially
available, a more stable and enantioselective catalyst, we
decided to employ ketone 3 and catalyst 8b to achieve the
asymmetric hydrogenation process. The chiral alcohol 4 as an
electrophilic reagent was reacted with MeNH2, followed by
subsequent treatment with methanolic HCl to afford target
product (R)-phenylephrine hydrochloride (5).
1
2
3
4
5
6
8
8
8
8
14
20
2
6
10
20
10
10
85
83
94
88
91
93
77.2
85.6
88.5
90.4
80.7
84.4
R
R
R
R
R
R
A readily available method for the synthesis of (R)-phenyl-
ephrine, via CBS reduction, has been presented. However, it is
not cost-effective unless the chiral CBS catalyst can be used
repeatedly, especially when the required quantity and the price
of the catalyst are not negligible. Although CBS catalyst can
aCalculated by the mass percentage of divinylbenzene (DVB)
contained in the comonomers (ligand 9, DVB, styrene).
b
Calculated by the mole ratio of ligand 9 contained in the
c
comonomers. Determined as in Table 2.
4
b
be recycled in the form of its precursor hydrochloride, the
recovery from homogeneous reaction mixtures is still a lengthy
process. Therefore, several polymer-bound catalysts have been
allows the endocyclic boron atom, as a strong Lewis acidic,
8
to bind ketone in an unconstrained stereoselective mode. It is
7
prepared. Considering the convenience of operating the reaction
expected to retain excellent enantioselectivity and be favorable
for copolymerization between ligand 9 and styrene. The B-
in a continuous mode, we decided to immobilize CBS catalyst by
attaching the catalytically active center to macroporous resin.
When immobilized catalyst is recycled in situ, the catalyst and
product purification costs are reduced considerably, which will
be a significant merit for the synthesis of (R)-phenylephrine in
a cost-effective way.
Macroporous-resin-supported catalysts are promising green
catalysts for heterogeneous catalytic transformations due to their
high surface-to-volume ratio, high reusability, and the porous
structure that are favorable for highly effective catalysis.
Macroporous polystyrenedivinylbenzene resin-supported CBS
catalyst 11 was prepared by suspension copolymerization of
ligand 9 together with styrene and divinylbenzene (Scheme 3).
Ligand 9 was prepared according to the literature,7a which is a
superior monomer due to provision of an ether bond as a spacer
group between the polymer backbone and catalyst active site.
The general model 12 shows the functional group is located
away from the polymer backbone, and the rotatable ether bond
8
a
methylated version of catalyst 11 is more stable and it is able to
produce higher enantioselective, which is beneficial for improv-
ing lifetime and obtaining higher enantiomeric excess when the
catalyst is used repeatedly.
The enantioselectivity of the reduction with polymeric CBS
reagents may be affected by the degree of crosslinking and the
mole ratio of ligand 9 contained in the comonomers. Table 3
shows the results of the asymmetric reduction of ketone 3 with
polymeric catalyst 11. The most remarkable finding is that the
enantiomeric excess is significantly influenced by the degree of
crosslinking. With 8% crosslinking, the selectivity was superior
to those in high degree of crosslinking (14%, 20%). It is
presumed that since high crosslinked resins show poor swelling
properties, the swellable 8% crosslinked polystyrene beads can
be made to behave closely to homogeneous catalysts, and benefit
the catalytically active center binding ketone more facile. In
addition, the selectivity of the polymeric catalyst is influenced
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