Simply air: Vanadium-catalyzed oxidative kinetic resolution of methyl o-chloromandelate by ambient air

Article abstract of DOI:10.1016/j.cclet.2010.03.002

Vanadium-catalyzed oxidative kinetic resolution (OKR) of methyl o-chloromandelate 2a, key intermediate of the well-known oral antiplatelet agent (S)-clopidogrel, was achieved by ambient air for the first time. The air oxidation system, which was composed of vanadium and tridentate Schiff base ligands derived from amino alcohols and salicylaldehyde derivatives, afforded an efficient and economic approach to the target intermediate with high enantioselectivities (>99% ee).

Full text of DOI:10.1016/j.cclet.2010.03.002

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 774–777
www.elsevier.com/locate/cclet
Simply air: Vanadium-catalyzed oxidative kinetic resolution
of methyl o-chloromandelate by ambient air
b,
a,b
Lu Yin a, Xian Jia a, , Xing Shu Li , Albert S.C. Chan
*
*
a School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
b School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
Received 15 October 2009
Abstract
Vanadium-catalyzed oxidative kinetic resolution (OKR) of methyl o-chloromandelate 2a, key intermediate of the well-known
oral antiplatelet agent (S)-clopidogrel, was achieved by ambient air for the first time. The air oxidation system, which was composed
of vanadium and tridentate Schiff base ligands derived from amino alcohols and salicylaldehyde derivatives, afforded an efficient
and economic approach to the target intermediate with high enantioselectivities (>99% ee).
# 2010 Xian Jia. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Ambient air; Vanadium-catalyzed; OKR; Methyl o-chloromandelate; Schiff base ligands
Air would be an ideal choice for asymmetric oxidation as it is readily available, totally free of charge and no
potential danger exists even in flammable organic solvents, which is also a very challenging problem in this field. On
the other hand, oxidative kinetic resolution (OKR) is an efficient approach to optically pure enantiomers, especially for
biologically active molecules. During the development of OKR, many metal complexes, such as Pd [1], Ir [2], Cu [3],
Ti [4], Mn [5], Co [6], Rh [2b], Ru [2b,7] and V-complex [8], have been investigated. Among them, vanadium
complex, recently applied to aerobic oxidation of alcohols [9], has been demonstrated to be the most effective metal
for the aerobic oxidation of propargylic alcohols and for the OKR of a-hydroxy esters [10]. For instance, pioneering
work of vanadium-catalyzed OKR of a-hydroxy esters using molecular oxygen as the oxidant was disclosed by Toste
and co-workers [11]. More recently, Weng et al. have described an efficient OKR system for aryl a-hydroxy esters and
amides, where a series of chiral vanadyl carboxylates were introduced [12]. However, the only example of using
ambient air as oxidant in oxidative kinetic resolution was reported by Bagdanoff and Stoltz in their palladium-
catalyzed OKR system for secondary alcohols, which has proved that air was enough to mediate the enantioselective
oxidation of secondary alcohols at room temperature [13]. Sparked by the above studies, we began to explore the
possibility of employing vanadium for OKR of methyl o-chloromandelate, key intermediate for enantioselective
synthesis of the well-known (S)-clopidogrel [14], by simply using ambient air as the oxidant.
* Corresponding authors.
E-mail addresses: jiaxian206@163.com (X. Jia), lixsh@mail.sysu.edu.cn (X.S. Li).
1001-8417/$ – see front matter # 2010 Xian Jia. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.03.002

L. Yin et al. / Chinese Chemical Letters 21 (2010) 774–777
775
1. Results and discussion
As Schiff base ligands bearing 3,5-di-tert-butylsalicylaldehyde fraction seemed to have more enantiocontrol due to
steric hindrance [11,12], webeganourstudyfrom the synthesisofaseriesofSchiff baseligands[15](Fig. 1) derivedfrom
different amino alcohols [16] and 3,5-di-tert-butylsalicylaldehyde. With these chiral ligands in hand, we chosevanadium
complex for the screening study of OKR of methyl o-chloromandelate [17] and the results were listed in Table 1. The
analytical data indicated that the enantioselectivity was substantially influenced by the structural change of ligands. With
theincreasingsterichindrance inaminoalcohol part, enantioselectivitiesraiseddramatically(upto99.7%eewithhighest
svalue,Table1, entries1–3). Thistrendwasalsoreflectedbyligandswitharomaticsubstitutions,bicyclicazotictryptosol
derived ligand 1f gave much higher ee than the phenyl one 1d (Table 1, entries 4–6).
Much to our surprise, the ligand derived from salicylaldehyde which structurally has the only tert-butyl group in R3
position (Fig. 1, ligand 1g) also afforded high enantiocontrol (99.6% ee with 65.8% conversion, Table 1, entry 7).
These results suggested that steric hindrance truly have great influence on enantiocontrol for OKR of methyl o-
chloromandelate, no matter the bulkness originated from salicylaldehyde fraction or amino alcohol part.
In addition, ligand derived from iodine substituted salicylaldehyde (Fig. 1, ligand 1h) suffered a sharp slip in both
enantioselectivity and reactivity (48.6% ee with 52.5% conversion in 12 h, Table 1, entry 8), which probably due to its
electron withdrawing property.
Moreover, the existing oxidative system in our study showed no potency to ethyl 2-hydroxy-4-phenylbutanoate 2e
even after 12 h (Table 2, entries 7 and 8), however, other aromatic a-hydroxy esters (Fig. 2, 2b–2d) were resolved
Fig. 1. Schiff base ligands prepared from different amino alcohols and salicylaldehyde derivates.
Table 1
Kinetic resolution of racemic methyl o-chloromandelate ester 2aa
.
Entry
Ligand
T (h)
Conv.b (%)
E.e.c (%)
sd
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
3
77.0
62.1
60.0
60.3
62.8
88.6
65.8
52.5
49.6
99.7
95.4
17.0
67.3
89.2
99.6
48.6
2
12
12
3
24
16
1
12
12
3
4
3
1g
1h
17
4
12
a
Reactions were carried out at 1 mmol scale under stirring with constant and gentle ambient air flow;
The conversions of racemic methyl o-chloromandelate ester were determined by 1H NMR analysis;
Determined by HPLC on chiral OJ-H column (Hex: IPA = 92: 8, 1.0 mL/min, 220 nm);
s = krel(fast/slow) = ln[(1 À C)(1 À ee)]/ln[(1 À C)(1 + ee)].
b
c
d

776
L. Yin et al. / Chinese Chemical Letters 21 (2010) 774–777
Table 2
Kinetic resolution of other a-hydroxy esters 2b–2ea.
Entry
Substrate
Ligand
T (h)
Conv. (%)
Yieldb (%)
E.e. (%)
s
1
2
2b
1b
1c
3
3
56.4
53.2
99.0
94.7
98.8
99.5
37
88
c
3
4
2c
2d
2e
1b
1c
3
3
83.6
89.7
70.3
75.9
98.0
3
3
c
94.7
5
6
1b
1c
8
8
42.5
49.9
92.1
90.0
93.3
90.9
-31
69
7
8
1b
1c
12
12
N.D.d
N.D.a
–
–
–
–
–
–
a
Reaction conditions and analytical methods were the same as those described in Table 1 (for details please see supporting information.)
Isolated yield of both 2(R) and 3 after silica gel chromatography.
Conversions were determined after 12 h.
b
c
d
N.D. = Not detected (monitored by TLC).
Fig. 2. Other a-hydroxy esters investigated in this test.
Fig. 3. Efficient and economic approach to the target intermediate.
smoothly by the same OKR system in short time (up to 99.5% ee, Table 2, entries 1–6), which demonstrated the
flexibility of the ambient air OKR method.
In conclusion, we have developed an effective OKR system for methyl o-chloromandelate 2a, key intermediate of
clopidogrel, by ambient air at room temperature for the first time. Besides, the conventionally undesired product,
methyl o-chlorobenzoylformate 3a, could be directly transformed into the desired (R)-methyl o-chloromandelate by
asymmetric biological [18] or chemical [19] reduction, which along with OKR rendered an efficient and economic
approach to the target intermediate (Fig. 3).
Acknowledgments
This study was supported by National Natural Science Foundation of China (No. 20472116) and 2009 intranational
visiting doctoral student project of Ministry of Education.

L. Yin et al. / Chinese Chemical Letters 21 (2010) 774–777
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