Synthesis of a novel ruthenium(I{cyrillic, ukrainian}I{cyrillic, ukrainian}) complex and its unique behaviors in enzymatic dynamic kinetic resolution of secondary alcohols

Article abstract of DOI:10.1016/j.tet.2010.03.069

A cyclopentadienyl benzoyl ruthenium(I{cyrillic, ukrainian}I{cyrillic, ukrainian}) complex 3 was first prepared as an efficient catalyst in Candida Antarctica lipase B (CALB) mediated dynamic kinetic resolution (DKR) of secondary alcohols. With the aid of this ruthenium complex 3, (S)-1-phenylethanol was completely racemized within 25 min, and in combination with CALB, series of secondary alcohols bearing various functional groups were resolved in an efficient DKR manner. A detailed mechanism involving the C-H bond activation was presented for the formation of complex 3 by capturing the crucial intermediate in this pathway. Related mechanistic studies were carried out to illustrate this type of DKR catalyst is based on the racemization of secondary alcohols. The novelty of its structure, its unique catalytic behavior as well as its wide scope of application of various substrates and its higher efficiency make complex 3 as an important alternative to those complexes, which are commonly used in DKR process.

Full text of DOI:10.1016/j.tet.2010.03.069

Tetrahedron 66 (2010) 3707–3716
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Tetrahedron
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Synthesis of a novel ruthenium(__) complex and its unique behaviors in enzymatic
dynamic kinetic resolution of secondary alcohols
,
,
Qihui Chen a b, Chengye Yuan a
*
a State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Feng-lin Rd.,
Shanghai 200032, China
b State Key Laboratory of Structure Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A cyclopentadienyl benzoyl ruthenium(__) complex 3 was first prepared as an efficient catalyst in Candida
Antarctica lipase B (CALB) mediated dynamic kinetic resolution (DKR) of secondary alcohols. With the aid
of this ruthenium complex 3, (S)-1-phenylethanol was completely racemized within 25 min, and in
combination with CALB, series of secondary alcohols bearing various functional groups were resolved in
an efficient DKR manner. A detailed mechanism involving the C–H bond activation was presented for the
formation of complex 3 by capturing the crucial intermediate in this pathway. Related mechanistic
studies were carried out to illustrate this type of DKR catalyst is based on the racemization of secondary
alcohols. The novelty of its structure, its unique catalytic behavior as well as its wide scope of application
of various substrates and its higher efficiency make complex 3 as an important alternative to those
complexes, which are commonly used in DKR process.
Received 12 January 2010
Received in revised form 17 March 2010
Accepted 19 March 2010
Available online 24 March 2010
Keywords:
Dynamic kinetic resolution
Cyclopentadienyl benzoyl ruthenium
Racemization
Candida Antarctica lipase B
Secondary alcohols
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
OAc
R'
OH
Lipase, ROAc
Enzymatic kinetic resolution (KR) as a useful protocol for the
preparation of chiral compounds has been widely used in phar-
maceutical and agrochemical industries.1 However, it has an
intrinsic disadvantage that only 50% of the stereoisomers that
needed could be obtained. In order to overcome this limitation,
dynamic kinetic resolution (DKR), in which an in situ racemization
process is coupled with kinetic resolution (KR) improved by lipase,
has been developed. In recent years, the metal-catalyzed dynamic
kinetic resolution of racemic alcohols has drawn increasing atten-
tions (Scheme 1).2
R
R
R
R
R'
[M]
OH
Fast
OAc
R'
Lipase, ROAc
Slow
R'
Scheme 1. Metal-catalyzed DKR for alcohols.
The first example of dynamic kinetic resolution of alcohols was
reported by Williams, in which a simple transition–metal complex
[Rh2(OAc)4] was used as racemization catalyst for secondary alco-
hols. However, this system seemed less effective.3 In 1997, the
Ba¨ckwall group firstly introduced a practical system for dynamic
kinetic resolution of secondary alcohols by using Shvo’s complex 1
in combination with an immobilized lipase,4 and with the aid of
this system; various types of alcohols have been studied by the
Ba¨ckvall group and later by the Park group.5 However, high reaction
temperature and special additive were usually needed for this
system. Until 2002, the Park group reported another type of race-
mization catalyst 2a, which could racemize chiral alcohols quickly
and make dynamic kinetic resolution of alcohols more effective
than any other catalyst, but strong base t-BuOK and prolonged
reaction time are necessary.6 Later, the Ba¨ckwall group found that
a more active catalyst 2b made DKR of secondary alcohols
completed in 3 h, but also this system requires strong base.7 More
recently, the Kim and Park group found some DKR systems milder
and reusable by using catalyst 2c–e.8 However, for catalysts 2a–e,
a good leaving group is usually needed. Furthermore, for some
substrates, which easily coordinate to ruthenium atom such as
b
-hydroxyl phosphonate, only less efficient DKR systems were
* Corresponding author. Fax: þ86 21 5492 5379; e-mail address: yuancy@
mail.sioc.ac.cn (C. Yuan).
reported.5j Thus, new classes of metal catalysts are needed for the
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.069

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Q. Chen, C. Yuan / Tetrahedron 66 (2010) 3707–3716
racemization of alcohol leading to a DKR process. Very recently, an
unexpected ruthenium complex, namely cyclopentadienyl benzoyl
ruthenium(__) complex 3 (as shown in Fig. 1) was reported in our
laboratory, which makes DKR of secondary alcohols efficient by
combining Candida Antarctica lipase B.9 However, the mechanism
of synthesis of catalyst 3 and the mechanism comprised in race-
mization process haven’t been fully elucidated. Herein, we intend to
give insight into synthesis of complex 3 and its racemization
mechanism. Beside this, the scope of substrates structure was
significantly enlarged including those substrates that easily
coordinate with ruthenium atom.
molecular of H2O is formed. The phenyl anion coordinates to the
ruthenium(__) atom at the same time, resulting in the formation of
complex c. Also due to the strong steric strain of four member
metallic spiro, the unstable complex c easily coordinates to the CO
existed in the reaction system to produce a more stable ruth-
enium(__) complex 3.
Our initial attempts to capture complex a or complex b directly
by slow down the reaction temperature or shortening the reaction
time were unsuccessful. This may be ascribed to that ruthenium
complex a is hard to be formed at low temperature, while at the
higher temperature complex a is very active, complex a is very
Ph
Ph
Ph
OC
R
Ph
Ph
Ph
H
H
Ph
Ph
Ru
Ph
Ph
O
Ph
Ph
O
Cl
Ph
L
Ru
O
Ru
OC CO
Ru
OC
Ph
2a, R=-NH(CH3)2, L= CO
2b, R=Ph, L= CO
Ph
CO
OC
Ph
CO
3
2c
, R=OBn, L=CO
1
2d, R=Ph, L=PPh3
2e, R=OBz, L=CO
Figure 1. Racemization catalysts.
2. Results and discussion
active and easily converted to compound b and then to compound
c. This postulation may be supported by the reported synthesis of
tetraphenylcyclopenta-2, 4-dienonyl tricarbonyl ruthenium(0)
complex (the reaction temperature usually required 150 ꢀC).5l
Gratifyingly, the existence of the key species, complex c, can be
confirmed by adding 4-methoxyphenylisocyanide. The expected
insertion product 4 was isolated when excessive 4-methoxy-
phenylisocyanide was added.
2.1. Insight into the reaction pathway in the synthesis
of catalyst 3
As indicated by Scheme 2, pentaphenylcyclopenta-2, 4-dienol
was reacted with Ru3(CO)12 in toluene in schlenk tube at 150 ꢀC for
72 h to give cyclopentadienyl benzoyl ruthenium(__) complex 3 in
a yield of 41%. Surprisingly, ruthenium(__) complex 3 bears an
unusually metallic spiro structure, which has been confirmed by
single crystal X-ray diffraction analyses.
From the proposed mechanism, it is clear that one molecule of
water should be created during the formation of complex 3. Our
experimental data demonstrated that addition of 4 Å molecular
HO
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ru3(CO)12
Ru
O
Toluene, 150ºC
Ph
CO
OC
Ph
3
Yield: 41%
Scheme 2. Synthesis of cyclopentadienyl benzoyl ruthenium(__) complex 3.
We propose a mechanism for the preparation of complex 3
(Scheme 3) by capturing some crucial intermediates in our exper-
iments. First, Ru3(CO)12 may coordinate to pentaphenylcyclopenta-
2, 4-dienol in toluene at high temperature and release two
molecules of CO to form ruthenium(0) complex a. Complex a is very
active at high temperature, thus an intramolecular oxidation
addition may take place, leading to the ruthenium(__) complex b, in
which ruthenium(__) atom coordinates to the conjugated penta-
phenylcyclodienyl. Due to the strong steric hindrance of phenyl
groups, the ruthenium atom can approach the C–H bond of phenyl
ring and activate it. (The similar phenomenon was also observed in
ruthenium complex 2b in Ba¨ckwall’s work.7b) Then the OHꢁ may
snatch the hydrogen activated by ruthenium(__) atom, and one
sieves will result substantial increase the chemical yield of ruth-
enium(__) complex 3 was increased from 41% to 57% (Scheme 4).
This is an indirect experimental evidence showing the formation of
water. However, the catalytic effect of the molecular sieve could not
be excluded in such case.
So far, we can ensure that both intermediate c and water are
formed during the preparation of complex 3. We deduced that the
OHꢁ snatches the hydrogen, which is activated by ruthenium(__)
atom, and one molecular of H2O and compound c are formed
(as shown as Scheme 3 (3)). A similar reaction system was designed
as shown in the part ((7)–(8)) of Scheme 3. It is known that
pentaphenylcyclopentadienyl chloride can easily react to
Ru3(CO)12, affording pentaphenylcyclopentadienyl ruthenium(__)

Q. Chen, C. Yuan / Tetrahedron 66 (2010) 3707–3716
3709
Ph
Ph
Ph
HO
Ph
Ph
Ph
Ru3(CO)12
Ph
+
Ru
O
Ph
Ph
Ph
Ph
CO
OC
Ru CO
Ph
d
3
Ph
(5)
-2CO
(1)
CO
OC
(4)
Ph
Ru
+ CO
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
Ph
(2)
Ph
Ph
OH
(3)
Ph
OC
OC
Ph
Ph
OC
Ph
CO
Ru
OC CO
Ru
-H2O
Ru
OH
CO
Ph Ph
CO
OH
b
a
b
c
(6)
NC
(8)
MeO
-HCl
Ph
Ph
Cl
Ru3(CO)12
Cs2CO3
Ph
Ph
-2CO
Ph
Ph
OC
Ph
Ph
Ph
Ru
Ph
Ru
Cl
Ph
OC
(7)
H
Ph
Ph
N
OMe
CO
g
OC
4
Scheme 3. Insight into the mechanism of preparation of complex 3.
Scheme 4. Comparisons with different reaction systems.
chloride.7a–b The inorganic base Cs2CO3 was used here to eliminate
the HCl resulted from the reaction. As we expected, a small mount
of complex 3 with 10% chemical yield was isolated. Because the
OHꢁ is a stronger base, more amounts of complex 3 can be obtained
in our reaction system. So far, we can demonstrate that a route that
contains ruthenium(__) mediated C–H bond activation exists in our
synthesis of cyclopentadienyl benzoyl ruthenium(__) complex 3.
Figure 2. Racemization of (S)-1-phenylethanol catalyzed by 5% ruthenium 3 and
K3PO4.
Compare with catalyst 2a–e, our ruthenium complex 3 does
not bear a good leaving group coordinated to ruthenium atom, so
there should be an alternative hydrogen transfer route in ru-
thenium complex 3 catalyzed racemization. The color change
during the racemization indicates that a new complex must be
formed. So NMR experiments were firstly carried out to explain
the racemization. It was pity that there were no resonances that
show the formation of new species such as a ruthenium hydride
in the racemization system. The only clue was that the 1H NMR of
pure phenylethanol was different from it in the racemization
system.10
2.2. A mechanistic study on catalyst 3 mediated racemization
of secondary alcohols
We found that complex 3 catalyzed the racemization of chiral
secondary alcohols quite efficiently even at room temperature.
A more recent study showed that, complex 3 (5 mol %) could
racemize (S)-1-phenylethanol within 25 min (Scheme 5, Fig. 2), 90%
of 3 being recycled without observed loss of activity. We also
observed that this reaction system turned pale red after 15 min.
To further understand the raceimzation process, we wish to
study the racemization kinetics. As 5% ruthenium 3 racemizes (S)-
1-phenylethanol completely within 25 min, it is hard to track it; so
we turn to study the racemization kinetics catalyzed by 0.5%
ruthenium 3. From the Figure 3, we can find that, in the first 9 min,
the chiral alcohol cannot be racemized; which implies that the
ruthenium 3 cannot catalyze the racemization directly. Thus the
real active intermediate must be a new complex formed after 9 min
in the racemization system. Very recently, the Ba¨ckvall group found
that the ligand CO could be exchanged, which also might improve
Scheme 5. Racemization of (S)-1-phenylethanol catalyzed by 5% ruthenium 3 and
K3PO4.

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Q. Chen, C. Yuan / Tetrahedron 66 (2010) 3707–3716
As far as we know, racemization of alcohols catalyzed by
transition-metal is usually a hydrogen transfer process, which in
most cases runs as a first-order reaction. However, in our racemi-
zation system, the concentration of real catalyst is changing during
the whole reaction. So the equation was described as Scheme 8.
Scheme 8. Kinetic equation for the racemization catalyzed by ruthenium 3.
This equation is supporting the fact that the racemization
process was catalyzed kinetically by ruthenium 3 (Fig. 3). In the
first 9 min, the active ruthenium complex has not formed, so the
alcohol could not be racemized. In the second part (for the time
from 9 min to 20 min), the rate of racemization(v) increases
remarkably due to the rate of increase of the active ruthenium
complex is faster than that of the decrease of chiral alcohol. Next,
the rate of racemization(v) was slower down is related to the
diminish amount of chiral alcohol. While the alcohol is completely
racemized, the rate of racemization(v) is zero, although the
hydrogen transfer process still undergoes quite nicely. Compared
to Figure 4, the rate of racemization catalyzed by ruthenium
Figure 3. Racemization of (S)-1-phenylethanol catalyzed by 0.5% ruthenium 3.
the racemization of secondary alcohol.11 So we postulated that the
real active intermediate was composed of ruthenium 3 and alco-
holic minus-ion (Scheme 6).
complex
3 and t-BuOK turns out slower, this experimental
observation could be rationalized by the decrease of chiral alcohol
in the reaction system.
Actually, the value of k of ruthenium 3 can be calculated.
When racemization was carried out as shown in Scheme 7, the
concentration of active ruthenium complex is a constant, so the
value of k can be probably calculated as shown in Figure 5
Scheme 6. A possible active intermediate.
(kA¼0.021 minꢁ1
,
kB¼0.019 minꢁ1). This proves that, for the
substrates, the racemization is a first-order reaction. So the value
of k in this racemization system may be 0.020 minꢁ1, but the rate
of racemization (v) is also affected by the concentration of active
ruthenium complex.
It is difficult to capture or isolate the possible active in-
termediate as shown in Scheme 6. In order to prove this possible
active intermediate, we prepared a similar system in situ by mixing
the ruthenium complex 3 with equal t-BuOK (Scheme 7, Fig. 4).
With aid of this new system, the (S)-1-phenylethanol could be
racemized immediately; the pale red color was also observed in this
case. This phenomenon may demonstrate that the active in-
termediate is indeed composed of ruthenium 3 and alcoholic-
minus.
Based on these experiments, a possible mechanism of racemi-
zation of chiral alcohol catalyzed by ruthenium 3 in the presence of
K3PO4 could be tentatively postulated as shown in Scheme 9. As
proposed by us, in the racemization system, when the ruthenium 3
and the chiral secondary alcohol approach the heterogeneous
K3PO4 in the form of (a) (as supported by lit.10), the alcoholic
hydroxyl is activated by ruthenium 3. So the base K3PO4 can easily
snatch the hydrogen of the chiral alcohol to produce an active
intermediate (b), which was also supported by our investigation on
racemization kinetics as well as the color change during the
experiment. Meanwhile, in the DKR process, the acetone resulted
from KR does not interfere with the racemization process. These
evidences indicated that in our present case, the racemization is an
intramolecular hydrogen transfer process. As shown by Backvall7b
,
Scheme 7. Racemization of (S)-1-phenylethanol catalyzed by 0.5% ruthenium 3 and
t-BuOK.
that racemization of chiral secondary alcohol by catalyst 2b is
a process via an intramolecular hydrogen transfer mechanism.
Similarly, we supposed that a reversible intramolecular hydrogen
transfer process as shown by (b), (c), and (d) may exist in our DKR
system. In the structure of (c), the ketone that coordinates to
ruthenium atom can be rotated freely, so the chiral alcohol could be
racemized by unselective ruthenium hydrogen insertion. In addi-
tion to our above experimental observations, other chiral alcohol,
including some racemized alcohol will replace the racemic alco-
holic minus-ion to proceed the catalytical cycle. Affected by the
increasing racemic alcohol, the racemization process of chiral
alcohol will be slower (as shown in Fig. 2–4); however, the rate of
intramolecular hydrogen transfer process of alcohols keeps
unchanged. In DKR, when the alcohol is transformed to corre-
sponding acetate, the hydrogen transfer process catalyzed by
ruthenium complex 3 will be terminated and the ruthenium
complex 3 could be recycled.
Figure 4. Racemization of (S)-1-phenylethanol catalyzed by 0.5% ruthenium 3 and
t-BuOK.

Q. Chen, C. Yuan / Tetrahedron 66 (2010) 3707–3716
3711
Figure 5. Calculation of the value of k catalyzed by 0.5% ruthenium 3 and t-BuOK.
2.3. Dynamic kinetic resolution of secondary alcohols by
catalyst 3 and CALB
t-BuOK, the base system used in Ba¨ckvall and Park’s work,6,7 also
proved ineffective (Table 1, entry 3). Considering trace water
contaminated in CALB might affect the racemization, we added
some 4 Å MS in our DKR system, and the product was obtained
with 99% yield and 59% ee (Table 1, entry 4). Although it still
seemed not very satisfactory, we ensured that partial racemiza-
tion of chiral phenylethanol was accompanied with the kinetic
resolution catalyzed by CALB. Reduction of CALB (8 mg) to di-
minish the water amount led to the total loss of optical activity
(Table 1, entry 5). The reason may be that subtle water comprised
in lipase was absorbed by 4 Å Molecular Sieves, and then directly
catalyzed by t-BuOK, 1-phenylethanol was rapidly converted to
Although many metals have been used to racemize chiral
alcohols,2a,12 only a few of them accord with the enzymatic
kinetic resolution very well.4,6–9 Our initial attempts to combine
enzymatic kinetic resolution with our racemization system were
not successful until we reduced the amount of lipase and added
some 4 Å Molecular Sieves as shown in Scheme 10. In our first
trial, 50 mg CALB was used with different acyl donors, but only
less satisfactory results were obtained (Table 1, entries 1–2).
Introduction of equivalent Na2CO3 and catalytical amount of
Scheme 9. A possible mechanism for racemization of chiral secondary alcohol.

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Q. Chen, C. Yuan / Tetrahedron 66 (2010) 3707–3716
Table 2
corresponding acetate, so the product without optical activity was
obtained. After many trials, a new system of dynamic kinetic
resolution of 1-phenylethanol was developed using molecular
sieve as an additive and K3PO4 as the base, and an excellent result
with 97% yield and 99% ee was achieved as shown in entry 6,
Table 1.
DKR of various secondary alcohols
Entry Substrates (1a–r) CALB
t
T
Products (2a–r) Yielda [%] eeb [%]
[mg] [h] [ꢀC]
1
10
10 25
94 (97)
99
2
10
10
10
6
10 25
10 25
20 25
20 50
20 50
20 50
20 25
20 25
20 25
20 25
20 25
20 25
20 25
20 25
20 25
20 25
92 (96)
90 (90)
95 (99)
90 (92)
92 (95)
92 (95)
99
98
OAc
OH
3
5%ruthenium , CALB
3
99
acyl donor, toluene,
base, additive
4
99
Scheme 10. Dynamic kinetic resolution of 1-phenylethanol.
5
99
Table 1
Some tries about dynamic kinetic resolution of 1-phenylethanol
6
4
96
Entry CALB(mg) Base
Acyl donor
Additive Time Yield ee
(h)
(%)
(%)
7
6
92
1
2
3
4
5
50
50
K3PO4
d
20
55c
d
OAc
O
O
8
20
50
25
25
25
25
80
30
30
30
97c
94
K3PO4
d
20
20
12
10
50c
50c
99b
d
Cl
100
100
8
Na2CO3/tBuOK
Na2CO3/tBuOK
Na2CO3/tBuOK
d
d
OAc
9
94
MSa
MSa
59b
OAc
OAc
10
11
12
13
14
15
16
17
85f
95
99b,d 0b,d
97b 99b
86f
93
6
10
K3PO4
MSa
10
OAc
a
b
c
170 mg 4 Å Molecular Sieves was added.
Determined by GC with RT BDEXM column.
95f
95
Determined by 1H NMR of the reaction mixture.
d
Directly transesterification catalyzed by t-BuOK was also observed in our
83f
92
laboratory.
80e
92
When the optimization of the DKR reaction of typical secondary
alcohol was established, a series of secondary alcohols bearing
various functional groups was examined under similar conditions.
(Scheme 11). The results as displayed in Table 2, This DKR system
seems not only accord with simple secondary alcohols, such as
aromatic alcohols and aliphatic alcohols; but also with more
complicated secondary alcohols with various functional groups,
such as sulfonyl group, ester, phosphonate. 1-Phenylethanol could
be transformed to its corresponding acetate with 94% yield (iso-
lated yield) and 99% ee within 10 h (Table 1, entry 1). For other
substituted phenylethanols, whether with electron-donating
group, 1-(4-methylphenyl) ethanol or with electron-withdrawing
group, 1-(4-fluorophenyl) ethanol, both gave chiral products with
high chemical yield and excellent enantioselectivity. (Table 2,
entries 2–3). As substituted phenylethanols, a naphthyl derivative
also gave excellent result with longer reaction time up to 20 h
(Table 2, entry 4). Since chiral aliphatic alcohols are usually not easy
to be prepared by asymmetric hydrogenation,13 consequently,
85e,f
90d
>95d
92d
70e,f
75e,f
18
80
20 25
88e
>95d
a
All numbers were isolated yields, Some numbers in parentheses were de-
termined by GC or HPLC.
b
Unless otherwise noted, all the enantiomeric excess values were determined by
GC or HPLC with chiral columns, for more detailed information, you can see ex-
perimental section.
c
The product was firstly deacetylated with the solution (K2CO3 and (H2O/
MeOH¼1:4)), and then the enantiomeric excess value was determined by GC with
RT BDEXM column.
d
These products were firstly hydrolyzed by NH3/MeOH solution, and then those
ee values were determined by 31P NMR of their hydrolyzation mixed with quinine.
e
The amount of K3PO4 was reduced to 10% and the mount of catalyst up to 9%.
These reactions were carried out on 0.5 mmol scale.
OAc
OH
f
ruthenium 3, CALB
R
R
K3PO4, toluene,
dynamic kinetic resolution of aliphatic alcohols turns up more
important. Compared to aromatic alcohol, the acidity of hydroxyl
function of aliphatic alcohol is markedly weaker, so more harsh
reaction conditions (higher reaction temperature, up to 50 ꢀC) was
1a-r
2a-r
MS,
OAc
Scheme 11. 11DKR of various secondary alcohols.

Q. Chen, C. Yuan / Tetrahedron 66 (2010) 3707–3716
3713
needed (Table 2, entries 5–6). For 4-phenylbut-3-en-2-ol, the
expected product could be obtained with 95% chemical yield and
92% ee (Table 1, entry 7). b-Hydroxyl ester is a class of important
react with isopropenyl acetate and be converted to the corre-
sponding acetate. So in our DKR system, only a small amount of
K3PO4 was needed, and the enantioselectivity seemed lower than
synthon, and a typical 3-hydroxybutyric acid tert-butyl ester was
examined in our system, we were pleased to find that a product
with 99% chemical yield and 97% ee was isolated (Table 2, entry 8).
other alcohols. When b-hydroxyalkylphosphonate coordinates to
ruthenium atom in type of iv or v, this coordination will reduce the
efficiency of racemization catalyzed by ruthenium complex 3, so
Chiral
b-hydroxyalkyl sulfones have been widely used as key
the yield is lower. For the a-hydroxylalkylphosphonate, the corre-
synthons in organic synthesis due to their specific characteristics:
the sulfonyl group is not only capable to stabilize an adjacent car-
banionic center, but also can be easily reduced. So far, many
methods have been developed for their preparation, for example,
sponding acetoxyphosphonate was obtained in higher chemical
yield and more excellent enantioselectivity, and this may be due to
the increasing hindrance, which makes it hard to coordinate to
ruthenium atom. Furthermore, the steric hindrance around the
ruthenium atom in ruthenium 3 seems stronger than active
intermediate of ruthenium 1 as shown in Scheme 13, so our DKR
system shows more suitable for substrates, which easily coordinate
to ruthenium atom.5i,p
enantioselective reduction of
kinetic resolution of racemic
lipase, asymmetric hydrogenation of
tion of chiral -hydroxyalkyl sulfones based on DKR was first
reported by the Rutjes group, however, their DKR system was time-
consuming and less effective.5p Therefore, a series of
-hydroxy-
b
b
-ketosulfones catalyzed by yeast,
-hydroxyalkyl sulfones by using
-ketosulfones.5p,14 Prepara-
b
b
b
alkyl sulfones were investigated in our DKR system. As shown in
entries 9–13, of Table 2, all substituted phenylsulfonyl-2-propanols
were successfully converted to corresponding acetates smoothly
with high yield and excellent enantioselectivity. These results
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ru
CO
Ru
O
OC
Ph
clearly indicated that b-hydroxyalkyl sulfones may coordinate to
CO
OC
ruthenium atom. Chiral hydroxyalkylphosphonates have attracted
increasing attentions due to their potential bioactivity and widely
application in organic synthesis. Many protocols including asym-
metric reduction of ketophosphonates, kinetic resolution of race-
mic hydroxyalkylphosphonate, have been developed for their
synthesis in past years.5i,15 To the best of our knowledge, only one
dynamic kinetic resolution system catalyzed by ruthenium 1 has
been used to catalyze DKR of hydroxyalkylphosphonate, however,
to carry on such reaction, harsh conditions are usually required and
the reaction products are contaminated by oxidation side-products.
3
active intermediate of ruthenium 1
Scheme 13. Comparison with ruthenium 3 and ruthenium 1.
3. Conclusions
In summary, the ruthenium catalyst 3 has been conveniently
synthesized from pentaphenylcyclopenta-2, 4-dienol and Ru3(CO)12
.
A plausible pathway involving ruthenium mediated C–H activation
was proposed and a key intermediate c in this pathway was captured
by reacting with 4-methoxyphenylisocyanide. One comparative ex-
periment using pentaphenylcyclopentaienyl ruthenium(II) chloride
and Cs2CO3 also led to the formation of catalyst 3, which strongly
supported our proposed pathway. The above mechanistic study shed
light on the future improvement of catalyst 3, which shows high
efficiency in racemization of chiral secondary alcohols. The kinetic
study of the racemiation, the observation of color change and an 1H
NMR study of the substrate’s change in racemization supported
a reversible intramolecular hydrogen transfer mechanism, as shown
in Scheme 9. In combinationwith CALB, our catalyst system provides
high activity and selectivity in dynamic kinetic resolution of a wide
range of secondary alcohols, rendering it an important alternative to
currently used DKR catalysts.
Furthermore, this system is less effective with
alkylphosphonates, probably due to their easily coordination to
ruthenium atom.5i Some
-hydroxyalkylphosphonates have also
b-hydroxy-
b
been synthesized and examined (Table 2, entries 14–17). More
amount of ruthenium 3 and less amount of K3PO4 will make these
reactions more fluently and satisfactory. Compared to other alco-
hols studied in this paper, the yields and ee values of the products
of this system are a less satisfactory. A possible explanation was
given in Scheme 12,
form of i, in which the phosphorus atom connects with the oxygen
through d–p bond, however due to the oxygen shows stronger
b-hydroxyalkylphosphonates usually exists in
p
electronegativity than the phosphorus atom, its resonance struc-
ture ii is therefore well-known, while the oxygen atom and phos-
phorous atom are bonded ionic in nature (Scheme 12). In our DKR
system, existence of various species (iii–v) is possible. For example,
intramolecular hydrogen bond caused by former iii will increase
4. Experimental section
4.1. General
the acidic activity of hydroxyl of
in presence of the base (K3PO4),
b
-hydroxyalkylphosphonates, and
-hydroxyalkylphosphonate can
b
Toluene was dried over CaH2 overnight, distilled under argon,
and stored over 4-Å molecular sieves. Isopropenyl acetate was
washed with saturated K2CO3, dried over CaCl2, and distilled under
argon. IR spectra were recorded on a Shimadzu IR-440 spectrom-
eter. EI mass spectra (MS) were run on a HP-5989A massspec-
trometer. 1H NMR and 13C NMR spectra were recorded on Bruker
AM 330 (300 MHz) or Bruker AM-400 (400 MHZ) spectrometer in
CDCl3 and chemical shifts were reported in part per million
downfield relative to TMS (internal standard); 31P NMR was
reported on a Bruker AM-400 (400 MHZ) spectrometer with CDCl3
as the solvent and H3PO4 as the external standard. Elemental
analysis values were detected on Heraeus Rapid-CHNO apparatus.
The enantiomeric excess values of products were determined by GC
(HP 6890) with chiral columns (RT BDEXM and J-W CYCLOSIL-B) or
HPLC (Waters) with chiral columns (CHIRALPAK AD-H and
OH
O
P OR
OR
OH
O
P OR
OR
Ru
HO
H
Ru
O
O
P OR
OR
O
O
P OR
OR
O
P OR
OR
Scheme 12. Some possible formers of b-hydroxyalkylphosphonate in DKR.

3714
Q. Chen, C. Yuan / Tetrahedron 66 (2010) 3707–3716
CHIRALPAK OD, and CHIRALPAK AS). The optical rotation values
were determined by polarimeter (J-S P-1030).
mixture by means of a syringe, diluted to 1 mL with CH2Cl2/MeOH
(1:1). After reaction, 27 mg ruthenium 3 was recovered.
II: Racemization of 1 mmol (S)-1-phenylethanol catalyzed by
0.5% ruthenium 3 and K3PO4: (Fig. 3). In a 25 mL absolute dry
schlenk flask, 220 mg dry potassium phosphate and 3 mg ruthe-
nium 3 were placed in, the Schlenk flask was evacuated and filled
with argon another three times, then toluene (3 mL), and (S)-1-
Phenylethanol (120 mL, 1 mmol) were injected; keep the reaction
under argon atmosphere. The ee values were determined by GC
with RT BDEXM column until the reaction ended.
III: Racemization of (S)-1-phenylethanol catalyzed by 0.5% ruthe-
nium 3 and 0.5% t-BuOK (Fig. 4): in a 25 mL absolute dry schlenk flask,
3 mg ruthenium 3 was added, the Schlenk flask was evacuated and
filled withargonanother three times, then toluene(3 mL)and t-BuOK
4.2. Synthesis of cyclopentadienyl benzoyl ruthenium(__)
complex 3
I: Ru3(CO)12 (213 mg, 0.3 mmol) and 1,2,3,4,5-pentaphenyl-
cyclopenta-2,4-dienol (462 mg, 1 mmol) were placed in a schlenk
tube. Toluene (5 mL) was added and the mixture was flushed with
argon 5 min before the system was closed. The reaction was stirred
at 150 ꢀC (bath temperature) for 24 h, then cooled down to remove
the carbon monoxide in solution. The system was closed and stirred
at the same temperature for additional 48 h. The reaction was
cooled down again, and the resulting solution was concentrated
and chromatographed on aluminum oxide column to give a pale
yellow solid 260 mg, yield: 41%. (When molecular sieve was added
to this reaction, 360 mg ruthenium complex 3 was obtained,
chemical yield was increased to 57%).
in THF solution (5
mL,1.0 M) were injected, this solution immediately
turns to pale red, after 5 min, (S)-1-Phenylethanol (120
mL, 1 mmol)
was also injected. Keep the reaction under argon atmosphere. The ee
values were determined by GC with RT BDEXM column.
II: Ru3(CO)12 (71 mg, 0.11 mmol) and 1,2,3,4,5-pentaphenyl-
cyclopenta-2, 4-dienyl chloride (160 mg 0.3 mmol), and 100 mg
Cs2CO3were placed in a schlenk tube, toluene (5 mL) was added and
the mixture was flushed with argon 5 min before the system was
closed. The reaction was stirred at 150 ꢀC (bath temperature) during
24 h, then cooled down to removed the carbon monoxide in solu-
tion. The system was closed and stirred at the same temperature for
additional 48 h. The reaction was cooled down once more, the
resulting solution was concentrated and chromatographed on alu-
minum oxide column to give a pale yellow solid 19 mg, yield: 10%.
Ruthenium complex 3, mp: 285 ꢀC (decomposed); 1H NMR
4.5. Calculation of the value of k catalyzed by 0.5% ruthenium
3 and 0.5% t-BuOK (Fig. 5)
In the racemization system as shown in Scheme 7, the concen-
tration of active ruthenium complex is a constant determined by
the amount of ruthenium 3, so v¼dc/dt¼k [chiral alcohols], when
t¼tA, the concentration of chiral alcohol is determined by the ee%
(tA)ꢂ0.33 mol/L, the value of vA is the slope of point A, which can be
calculated by drawing the tangent through the point of A in the
curve of AB. Finally, we find that kA¼0.021 minꢁ1. In the same way,
we also can find that kB¼0.019 minꢁ1
.
(400 MHz, CDCl3)
(1H, t, J¼7 Hz), 6.99–7.17 (21H, m).
d
: 7.60 (1H, d, J¼7 Hz), 7.43 (1H, d, J¼7 Hz), 7.27
4.6. General procedure for dynamic kinetic resolution of
secondary alcohols
4.3. Synthesis of ruthenium(__) complex 4
Dynamic kinetic resolution of 1-phenylethanol: in a 25 mL dry
schlenk flask, 220 mg potassium phosphate, and 170 mg molecular
sieve 4 Å were placed in. The Schlenk flask was evacuated and filled
with argon, CALB 10 mg and Ru catalyst 3 (32 mg 0.05 mmol) were
quickly added, then toluene (3 mL) was added, and the mixture was
Ru3(CO)12 (213 mg, 0.33 mmol) and 1,2,3,4,5-pentaphenyl-cyclo-
penta-2, 4-dienol (462 mg 1 mmol) were placed in a schlenk tube,
toluene (5 mL) was added and the mixture was flushed with argon
5 min before the systemwas closed. The reactionwasstirred at 150 ꢀC
(bath temperature) during 24 h, then cooled down, and removed the
carbon monoxide in solution, after the 4-methoxyphenylisocyanide
(150 mg) was added, then the system was closed and stirred at the
same temperature for additional 48 h. The reaction was cooled down
once more, the resulting solution was concentrated and chromato-
graphed on aluminum oxide column (PE/CH2Cl2¼2/1–0/1) to give
a brown solid 83 mg, yield: 11%, mp: 237 ꢀC (decomposed). 1H NMR
stirredfor 5 min,1-phenylethanol 1a(120
and after 5 min isopropenyl acetate (200
Argon atmosphere was maintained throughout the reaction. Yield and
ee value were determined by GC: Samples of 20 L were withdrawn
mL,1 mmol)was then added,
mL, 1.8 mmol) was added.
m
from the reaction mixture by means of a syringe, diluted to 1 mL with
CH2Cl2/MeOH (1:1), and filtered through a pad of cotton. The solution
was filtered and washed with EtOAc, and the solvent was evaporated in
vacuo. The residue was purified by column chromatography on silica
gel with petroleum ether/CH2Cl2 (1:1 to 1:10). The product 2a was
obtained as a colorless liquid (151 mg, yield: 94%, ee: 99%).
(300 MHz, CDCl3)
7.12 (16H, m), 6.87–6.92 (6H, m), 6.65 (2H, m), 3.78 (3H, s); 13C NMR
(75 MHz, CDCl3) : 199.92, 184.79, 162.66, 154.89, 150.44, 132.95,
d:7.93(1H, m), 7.34(1H, m), 7.16–7.19(2H, m), 6.99–
d
131.00, 130.94, 129.50, 128.18, 127.44, 127.01, 126.69, 126.66, 126.64,
126.54,123.67,122.76,119.74,113.36,110.85,109.67,106.08, 54.52; IR:
2015,1962,1603,1580,1500,1444,1240,1179,1030,877, 755,734, 696,
587, 572 cmꢁ1; MALDI-MS (m/z): (MþH)þ 735; HRMS-MALDI: calcd
for C45H32NO3Ru96þ (MþH)þ 730.1465; found: 730.1465.
4.6.1. Compound 2a. (R)-acetic acid 1-phenyl-ethyl ester, obtained
as a colorless liquid, 151 mg, yield: 94%, 97% (GC), ee: 99% (using RT
27
25
BDEXM column), [
a
]
D
þ104 (c 0.60, CHCl3); lit.16: [
a]
þ106 (c 1.00,
D
Et2O); 1H NMR (300 MHz, CDCl3)
d: 7.25–7.36 (5H, m), 5.85–5.92
(1H, m), 2.07 (3H, s), 1.53 (3H, d, J¼6 Hz).
4.4. Procedures for racemization of (S)-1-phenylethanol
4.6.2. Compound 2b. (R)-acetic acid 1-p-tolyl-ethyl ester, obtained
I: Racemization of 1 mmol (S)-1-phenylethanol catalyzed by 5%
ruthenium 3 and K3PO4: (Fig. 2). In a 25 mL absolute dry schlenk
flask, 220 mg dry potassium phosphate and 30 mg ruthenium 3
wereplaced in, theSchlenk flaskwasevacuated andfilled with argon
another three times, then toluene (3 mL) and (S)-1-Phenylethanol
as a colorless liquid, 161 mg, yield: 92%, 96% (GC), ee: 98% (using RT
26
25
BDEXM column), [
a
]
D
þ113 (c 0.87, CHCl3); lit.17: [
a
]
þ94.6
D
(c 5.20, CHCl3); 1H NMR (300 MHz, CDCl3)
d
: 7.25 (2H, d, J¼8 Hz),
7.15 (2H, d, J¼8 Hz), 5.82–5.89 (1H, m), 2.33 (3H, s), 2.05 (3H, s), 1.52
(3H, d, J¼6 Hz).
(120 mL, 1 mmol) were injected; keep the reaction under argon
atmosphere. About 15 min later, the racemization system turns to
pale red. The ee values were determined by GC with RT BDEXM
4.6.3. Compound 2c. (R)-Acetic acid 1-(4-fluoro-phenyl)-ethyl es-
ter, obtained as a colorless liquid, 160 mg, yield: 90%, 90% (GC), ee:
26
26
column: Samples of 20
mL were withdrawn from the reaction
99% (using RT BDEXM column), [
a
]
þ89 (c 0.98, CHCl3); [
a]
þ113
D
D

Q. Chen, C. Yuan / Tetrahedron 66 (2010) 3707–3716
3715
32
(c 0.87, CHCl3); lit.18: [
CDCl3)
a]
þ92.8 (c 3.36, CHCl3); 1H NMR (300 MHz,
Retention time: (R)-enantioisomer, 51.38 min; (S)-enantioisomer,
D
26
d
: 7.26–7.35 (2H, m), 6.99–7.05 (2H, m), 5.82–5.89 (1H, m),
2.06 (3H, s), 1.52 (3H, d, J¼6 Hz).
47.88 min), [
a]
þ2.4 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3)
d:
D
7.72–7.79 (4H, m), 5.26–5.30 (1H, m), 3.47–3.53 (1H, m), 3.22–3.27
(1H, m),1.82 (3H, s),1.34 (3H, d, J¼6 Hz); 13C NMR (100 MHz, CDCl3)
4.6.4. Compound 2d. (R)-Acetic acid 1-naphthalen-2-yl-ethyl ester,
d: 169.52, 138.42, 132.53, 129.65, 129.13, 64.90, 60.61, 20.67, 20.14;
obtained as a colorless liquid, 200 mg, yield: 95%, 99% (HPLC), ee:
IR (film): 3090, 2983, 2936, 1741, 1576, 1473, 1390, 1374, 1317, 1238,
1153, 1129, 1086, 1069, 1044, 1011, 782, 570 cmꢁ1; ESIMS (m/z): 338
(MþNH4)þ; Anal. Calcd for C11H13BrO4S: C, 41.54; H, 4.40. Found: C,
41.13; H, 4.08.
29
99% (using OD column, hexane/iPrOH¼95/5, 0.8 mL/min), [
a
]
þ46
D
20
(c 0.88, CHCl3); lit.19: [
a
]
þ33 (c 1.00, CHCl3); 1H NMR (300 MHz,
D
CDCl3)
d
: 8.08 (1H, d, J¼8 Hz), 7.84–7.88 (1H, m), 7.79 (1H, d,
J¼8 Hz), 7.43–7.61 (4H, m), 6.65 (1H, t, J¼6 Hz), 2.11 (3H, s), 1.70
(3H, d, J¼6 Hz).
4.6.13. Compound 2m. (R)-Acetic acid 2-(4-methoxylphenyl)sul-
fonyl-1-methyl-ethyl ester, obtained as a pale yellow liquid, 96 mg,
yield: 83%, ee: 92% (using AD-H column, hexane/iPrOH¼90/10,
4.6.5. Compound 2e. (R)-Acetic acid 1-cyclohexyl-ethyl ester, obt-
ained as a colorless liquid, 150 mg, yield: 90%, 92% (GC) ee: 99%
0.7 mL/min. Retention time: (R)-enantioisomer, 34.19 min; (S)-
27
24
26
(using RT BDEXM column), [
a]
þ7.2 (c 0.77, CHCl3); lit.20: [
a]
enantioisomer, 32.60 min), [
(300 MHz, CDCl3)
a]
D
þ0.33 (c 1.06, CHCl3); 1H NMR
D
D
þ6.6 (c 2.6, CHCl3); 1H NMR (300 MHz, CDCl3)
d
: 4.69–4.74 (1H, m),
d
: 7.83 (2H, d, J¼9 Hz),7.30 (2H, d, J¼9 Hz), 5.25–
2.02 (3H, s), 1.65–1.76 (5H, m), 1.12–1.43 (4H, m), 1.16 (3H, d,
5.28 (1H, m), 3.89 (3H, s), 3.43–3.51 (1H, m), 3.17–3.24 (1H, m), 1.84
J¼6 Hz), 0.93–1.01 (2H, m).
(3H, s), 1.33 (3H, d, J¼6 Hz); 13C NMR (100 MHz, CDCl3)
d: 169.70,
163.89, 131.12, 130.37, 114.50, 65.25, 61.04, 55.72, 20.86, 20.27; IR
(film): 2983, 2937, 2845, 1741, 1596, 1499, 1374, 1318, 1299, 1260,
1237, 1145, 1089, 1043, 838, 815, 804, 772, 573 cmꢁ1; ESIMS (m/z):
290 (MþNHþ4 ), 295 (MþNaþ). Anal. Calcd for C12H16O5S: C, 53.04; H,
6.03. Found: C, 52.93; H, 5.92.
4.6.6. Compound 2f. (R)-Acetic acid 1-methyl-heptyl ester, obta-
ined as a colorless liquid, 155 mg, yield: 92%, 95% (GC), ee: 96%
27
25
(using RT BDEXM column), [
a]
ꢁ2.3 (c 0.73, CHCl3); lit.21: [
a]
D
D
ꢁ1.9 (c 1.50, EtOH); 1H NMR (300 MHz, CDCl3)
d: 4.86–4.92 (1H, m),
2.03 (3H, s), 1.45–1.59 (2H, m), 1.28–1.33 (8H, m), 1.20 (3H, m), 0.88
(3H, t, J¼6 Hz).
4.6.14. Compound 2n. (R)-Acetic acid 2-(diethoxy-phosphoryl)-1-
methyl-ethyl ester, obtained as a pale yellow liquid, 180 mg, yield:
26
4.6.7. Compound 2g. (R)-Acetic acid 1-methyl-3-phenyl-allyl ester,
obtained as a colorless liquid, 174 mg, yield: 92%, 95% (GC) ee: 92%
80%, ee: 92% (using J-W CYCLOSIL-B column), [
a]
þ8.92 (c 1.00,
D
25
CHCl3); lit.23: [
a]
þ9.7 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3)
D
27
20
(using RT BDEXM column), [
a]
þ130 (c 0.73, CHCl3); lit.22: [
a
]
d: 5.17–5.21 (1H, m), 4.08–4.15 (4H, m), 1.99–2.21 (5H, m), 1.32–1.39
D
D
þ80 (c 0.25, CHCl3); 1H NMR (300 MHz, CDCl3)
d
: 7.24–7.39 (5H, m),
(9H, m); 31P NMR (121.5 MHz, CDCl3, H3PO4)
d: 27.07.
6.60 (1H, d, J¼11 Hz), 6.15–6.22 (1H, m), 5.51–5.55 (1H, m), 2.07
(3H, s), 1.41 (3H, d, J¼6 Hz).
4.6.15. Compound 2o. (R)-Acetic acid 2-(dipropoxy-phosphoryl)-1-
methyl-ethyl ester, obtained as a pale yellow liquid, 108 mg, yield:
27
4.6.8. Compound 2h. (R)-3-Acetoxy-butyric acid tert-butyl ester,
obtained as a colorless liquid, 195 mg, yield: 99%, ee: 97% (de-
85%, ee: 90% (determined by 31P NMR), [
a]
þ9.37 (c 1.00, CHCl3);
D
1H NMR (400 MHz, CDCl3)
d: 5.18–5.22 (1H, m), 3.97–4.03 (4H, m),
27
termined by its deacetylation by using RT BDEXM column), [
a
]
1.99–2.21 (5H, m), 1.67–1.72 (4H, m), 1.38 (3H, d, J¼6 Hz), 0.96
D
25
þ5.5 (c 1.06, CHCl3); lit.5m: [
a
]
þ7.59 (c 1.00, CHCl3); 1H NMR
(6H, t, J¼7 Hz); 13C NMR (100 MHz, CDCl3)
d: 170.00, 67.14–67.23
D
(300 MHz, CDCl3)
d
: 5.15–5.32 (1H, m), 2.35–2.55 (2H, m), 1.99
(m), 66.19, 33.26, 31.87, 23.78–23.84 (m), 21.02–21.15 (m), 9.97; 31P
(3H, s), 1.41 (9H, s), 1.24 (3H, d, J¼6 Hz).
NMR (121.5 MHz, CDCl3, H3PO4) d: 27.12; IR (film): 3469,
2969, 2880, 1739, 1373, 1243, 995, 556 cmꢁ1; ESIMS (m/z): 267.0
[MþH]þ; HRMS-ESI: calcd for C11H24O5P(MþH)þ: 267.1357; found:
267.1356.
4.6.9. Compound 2i. (R)-Acetic acid 2-(4-chlorophenyl)sulfonyl-1-
methyl-ethyl ester, obtained as a colorless liquid, 250 mg, yield:
94%, ee: 94% (using AD-H column, hexane/iPrOH¼95/5, 0.7 mL/
26
min), [
a
]
D
þ1.4 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3)
d
: 7.85
4.6.16. Compound 2p. (R)-Acetic acid 2-(diisopropoxy-phospho-
(2H, d, J¼9 Hz),7.56 (2H, d, J¼9 Hz), 5.27–5.30 (1H, m), 3.46–3.54
ryl)-1-methyl-ethyl ester, obtained as a pale yellow liquid, 70 mg,
27
(1H, m), 3.20–3.27 (1H, m), 1.82 (3H, s), 1.34 (3H, d, J¼6 Hz).
yield: 70%, ee: >95% (determined by 31P NMR), [
a
]
D
þ10.39 (c 0.60,
20
CHCl3); lit.24: [
a
]
þ11.1 (c 1.80, acetone); 1H NMR (400 MHz,
D
4.6.10. Compound 2j. (R)-Acetic acid 2-phenylsulfonyl-1-methyl-
CDCl3) d: 5.16–5.20 (1H, m), 4.68–4.73 (2H, m), 1.89–2.21 (5H, m),
ethyl ester, obtained as a white solid, mp: 87–89 ꢀC, 85 mg, yield:
1.26–1.37 (15H, m); 31P NMR (121.5 MHz, CDCl3, H3PO4)
d: 25.34.
85%, ee: 95% (using AS column, hexane/iPrOH¼60/40, 0.7 mL/min),
26
[
a]
þ0.24 (c 1.00, CHCl3); lit.5p: [
a
]
D þ0.6 (c 1.50, CHCl3); 1H NMR
4.6.17. Compound 2q. (R)-Acetic acid 2-(dibutoxy-phosphoryl)-1-
D
(300 MHz, CDCl3)
d
: 7.89 (2H, d, J¼7 Hz), 7.64–7.66 (1H, m), 7.56
methyl-ethyl ester, obtained as a pale yellow liquid, 85 mg, yield:
27
(1H, d, J¼7 Hz), 5.28–5.29 (1H, m), 3.46–3.54 (1H, m), 3.20–3.25
75%, ee: 92% (determined by 31P NMR), [
a]
þ9.34 (c 1.00, CHCl3);
D
(1H, m), 1.75 (3H, s), 1.32 (3H, d, J¼6 Hz).
1H NMR (400 MHz, CDCl3)
d: 5.18 (1H, m), 4.00–4.07 (4H, m), 1.95–
2.24 (5H, m), 1.62–1.69 (4H, m), 1.37–1.46 (7H, m), 0.94 (6H, t,
4.6.11. Compound 2k. (R)-Acetic acid 2-(4-methylphenyl)sulfonyl-
J¼8 Hz); 13C NMR (100 MHz, CDCl3)
d: 169.96, 66.16, 65.37
(q, J¼4 Hz), 33.19, 32.40–32.47 (m), 31.79, 20.99–21.15 (m), 18.64,
1-methyl-ethyl ester, obtained as
a
white solid, mp: 64–
65 ꢀC,102 mg, yield: 86%, ee: 93% (using AD-H column,
13.50; 31P NMR (121.5 MHz, CDCl3, H3PO4)
d: 27.44; IR (film): 3468,
26
hexane/iPrOH¼95/5, 0.7 mL/min), [
a
]
þ0.10 (c 1.32, CHCl3); lit.5p
:
2960, 2935, 2875, 1740, 1459, 1373, 1243, 1031, 979, 956, 902,
556 cmꢁ1; ESIMS (m/z): 295.0 (MþH)þ; HRMS-ESI: calcd for
C13H28O5P(MþH)þ: 295.1670; found: 295.1669.
D
[
a]
D þ0.6 (CHCl3); 1H NMR (300 MHz, CDCl3)
d: 7.77–7.80 (2H, m),
7.36–7.39 (2H, m), 5.26–5.28 (1H, m), 3.44–3.53 (1H, m), 3.18–3.25
(1H,m), 2.46 (3H, s), 1.80 (3H, s), 1.34 (3H, d, J¼6 Hz).
4.6.18. Compound 2r. (R)-Acetic acid 1-(diisopropoxy-phospho-
4.6.12. Compound 2l. (R)-Acetic acid 2-(4-bromophenyl)sulfonyl-
1-methyl-ethyl ester, obtained as a colorless liquid, 115 mg, yield:
95%, ee: 95% (using AD-H column, hexane/iPrOH¼95/5, 0.7 mL/min.
ryl)-ethyl ester, obtained as a pale yellow liquid, 215 mg, yield: 88%,
27
ee: >95% (Determined by 31P NMR), [
a
]
D
þ17.4 (c 0.92, CHCl3);
25
lit.23: [
a
]
D
þ20.1 (c 1.70, CHCl3); 1H NMR (400 MHz, CDCl3)
d:

3716
Q. Chen, C. Yuan / Tetrahedron 66 (2010) 3707–3716
Boga´r, K.; Kaynak, F. B.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 2005, 127, 8817; (c) Tra¨ff,
5.13–5.21 (1H, m), 4.69–4.79 (2H, m), 2.09 (3H, s),1.38–1.45 (3H, m),
´
¨
A.; Bogacr, K.; Warner, M.; Backvall, J.-E. Org. Lett. 2008, 10, 4807.
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Ko, S. B.; Baburaj, B.; Kim, M. J.; Park, J. J. Org. Chem. 2007, 72, 6860; (c) Kim, M.
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1.23–1.33 (12H, m); 31P NMR (121.5 MHz, CDCl3, H3PO4)
d: 20.28.
Acknowledgements
10. The chemical shift of OH of 1-phenylethanol is about 1.61 ppm, however,
its value is only about 1.23 ppm in the racemization system, which may
indicate that when 1-phenylethanol coordinates to the ruthenium catalyst,
the original hydrogen bond between two 1-phenylethanols disappears.
We appreciate kind suggestions from Prof. J.-B. Chen, and Dr.
Y.-H. Zhang. This Project was financially supported by the National
Natural Science Foundation of China (Grant No. 20872125 and
20672132).
Record on 1H NMR of racemization system: in
a
25 mL absolute dry
schlenk flask, 50 mg dry potassium phosphate and 15 mg ruthenium
3
were placed in, the Schlenk flask was evacuated and filled with argon
another three time, then toluene-d8 (0.75 mL) and (S)-1-Phenylethanol
(12 mL, 0.1 mmol) were injected; keep the reaction under argon atmo-
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