Synthesis of optically active 2-hydroxy monoesters via-kinetic resolution and asymmetric cyclization catalyzed by heterometallic chiral (salen) Co complex

Article abstract of DOI:10.1016/j.tetlet.2006.03.042

The binuclear chiral (salen) Co complexes bearing Lewis acids of Al and Ga catalyze regio- and enantioselective ring opening of terminal epoxides with carboxylic acids. The ring opened product of epichlorohydrin with carboxylic acids followed by cyclization step in the presence of catalyst and base represent straightforward, efficient methods for the synthesis of enatiomerically enriched (>99% ee) valuable terminal epoxides. Strong synergistic effects of different Lewis acid of Co-Al and Co-Ga were exhibited in the catalytic process.

Full text of DOI:10.1016/j.tetlet.2006.03.042

Tetrahedron Letters 47 (2006) 3453–3457
Synthesis of optically active 2-hydroxy monoesters
via-kinetic resolution and asymmetric cyclization catalyzed by
heterometallic chiral (salen) Co complex
a
a
a
a
Wenji Li, Santosh Singh Thakur, Shu-Wei Chen, Chang-Kyo Shin,
a
a,b,
*
Rahul B. Kawthekar and Geon-Joong Kim
a
Department of Chemical Engineering, Inha University, Incheon 402751, South Korea
RStech Corp. #305 Venture Town, 1688-5, Sinil-dong, Daedeok-gu, Daejeon 306-230, South Korea
b
Received 12 September 2005; revised 6 March 2006; accepted 8 March 2006
Available online 3 April 2006
Abstract—The binuclear chiral (salen) Co complexes bearing Lewis acids of Al and Ga catalyze regio- and enantioselective ring
opening of terminal epoxides with carboxylic acids. The ring opened product of epichlorohydrin with carboxylic acids followed
by cyclization step in the presence of catalyst and base represent straightforward, efficient methods for the synthesis of enatiomeri-
cally enriched (>99% ee) valuable terminal epoxides. Strong synergistic effects of different Lewis acid of Co–Al and Co–Ga were
exhibited in the catalytic process.
Ó 2006 Elsevier Ltd. All rights reserved.
Among the myriad of nucleophiles that have been
employed in epoxides ring openings catalyzed by chiral
N
O
N
O
N
O
N
O
1
II
III
(
salen) metal complexes, carboxylic acids (which afford
But
Co
tBu
But
Co
tBu
the corresponding 2-hydroxy monoesters) have been
paid very less attention. In contrast to chemo- and regio-
selective ring openings of terminal epoxides with carb-
tBu
tBu
OAc
tBu
tBu
Chiral (salen)CoII (A)
Jacobsen's Catalyst (B)
2
oxylic acids, only one literature is available for the
enantioselective ring openings of meso epoxides using
carboxylic acid as nucleophile.
tBu
3
tBu
N
O
N
O
II
To broaden the application range of dinuclear chiral
(
N
O
Co
O
But
Co
tBu
salen) Co catalysts1f,4 herein we report the catalytic
MX3
tBu
MX3
tBu
N
tBu
enantioselective ring opening of terminal epoxides with
carboxylic acids. Indeed, the Jacobsen’s chiral (salen)
M; 1 = Al
= Ga
2
1
a
Co complex and HKR catalyst showed low activity
<10% ee) in the present study. The coupled route of
tBu
2
X; a = Cl
(
I
b = Br
c = I
d = NO3
II
ARO/cyclization for epichlorohydrin (ECH) experi-
enced to synthesize highly optically pure valuable termi-
nal epoxides, for example, glycidyl butyrate.
Mononuclear complex
Dinuclear complex
Scheme 1.
We recently reported that dinuclear complexes bearing
Lewis acids of B, Al, and Ga elements (Scheme 1) are
highly efficient catalysts for the enantioselective ring
opening of terminal epoxides with H O and HCl.
1
f,4
2
Keywords: Asymmetric catalysis; Dinuclear chiral catalyst; Asymmet-
ric ring opening reactions; Cyclization.
Encouraged with these results we have extended the
applicability of these catalysts for enantioselective ring
opening of terminal epoxides with carboxylic acids.
*
Corresponding author. Tel.: +82 32 860 7472; fax: +82 32 872
959; e-mail: kimgj@inha.ac.kr
0
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.042

3454
W. Li et al. / Tetrahedron Letters 47 (2006) 3453–3457
Carboxylic acids are interesting candidates because of
their low cost, ease of handling, and reaction with epox-
ides provide a direct route to 2-hydroxy monoesters.
the following order II-1-d > II-2-d ꢀ II-1-c ꢀ II-2-
c ꢀ II-1-b ꢀ II-2-b ꢀ II-1-a > II-2-a > I-1-d > I-2-d ꢀ I-
1-c ꢀ I-2-c ꢀ I-1-b ꢀ I-2-b ꢀ I-2-a > I-1-a. Furthermore,
complex II-1-d was identified as the most effective of
those evaluated, and it was selected for further study
(Table 1).
3
In a representative example of ARO of epichlorohydrin
(
ECH) with propionic acid, a series of chiral (salen) Co
complexes (Scheme 1) were screened in order to identify
the most enantioselective and reactive catalyst (Fig. 1).
Complex II-1-d was proved to be most active and enan-
tioselective (86% ee, 4 h). For a solvent choice in the
present study, non-polar solvent tert-butyl methyl ether
Table 1 shows the optimized reaction conditions for var-
ious terminal epoxides with acetic, propionic, butyric,
and propiolic acids. It is quite obvious from Table 1 that
catalyst II-1-d showed mild (entry 1, 60% ee) to good
(entry 14, 86% ee) enantioselectivity. In all the cases
studied, the conversion of entries 1–25 to the corre-
sponding 2-hydroxy monoesters underwent in one-pot
within 4 h.
(
TBME) dramatically increased the reactivity (Fig. 2)
amongst CH Cl , CH CN, THF, and 1,4-dioxane. The
2
2
3
catalyst loading amount depends on individual reaction
Table 1) and 2–4 mol % was optimum for the reaction
(
to proceed (Fig. 3). Taking in to consideration all these
parameters, the reactivity and enantioselectivity of
the mono and dinuclear complexes were observed in
Complex II-1-d has also shown mild (45% ee) to good
(66% ee) enantioselective ring opening for various termi-
nal epoxides with aromatic carboxylic acid like benzoic
acid and provides corresponding 2-hydroxy monoesters
in a good yield (Table 2). The high selectivity factor
(krel = 60–70) of ring opened product in the present
study allowed to access optically active products in good
II-1-d
8
6
4
2
0
0
0
0
0
II-2-d
II-1-a
I-1-d
I-2-d
I-1-a
5
ee % and useful yields.
Unlikely asymmetric ring opening of terminal epoxides
with H O (HKR), the mononuclear catalyst also showed
2
good reactivity. It seems that Al and Ga Lewis acids
coordinated to oxygen of chiral (salen) Co also play a
crucial role to activate the reacting partners. In our
present finding Co–Al/Co–Ga act as heterometallic
complexes exhibiting two different Lewis acid centers
and show strong synergistic effect. The proposed intra-
molecular pathway for the catalyst monomeric complex
depicted in Scheme 2, which may be similar to enantio-
selective ring opening of epoxides with 4-methoxyphenol
catalyzed by Ga heterobimetallic multifunctional cata-
0
1
2
3
4
5
Time (h)
Figure 1. Comparison of the catalytic activity of the heterometallic
mononuclear and dinuclear complexes for the ECH and propionic acid
taking conditions according to Table 1 (ee % of recovered ECH).
6
lysts was reported by Shibasaki et al.
It appears that central metal atom Co activates, control
the orientation of epoxide, and stereoselectively activate
only one enantiomer and the Al. Ga seems to bind and
control the orientation of nucleophlie carboxylic acid by
enabling an enantioselective ring opening of epoxides
with nucleophiles. However binuclear complexes show
higher reactivity and enantioselectivity than their mono-
meric analogues. The intermolecular mechanism for
mono- and dimeric complexes may follow the earlier
1
00
9
8
0
0
7
6
5
4
3
2
1
0
0
0
0
0
7
report. Although the ARO reaction with carboxylic
II
0
0
0
acids is easily carried out with Co complexes, it
III
appears that the actual reactive species is in fact Co .
GB ee (%)
A ee (%)
conversion (%)
In an important and interesting reaction the optically
active epichlorohydrin and glycidol were obtained in
good ee with over 70% ee and 43% yield, respectively,
catalyzed by the catalyst dimeric complex in the pres-
ence of equivalent amount base with respect to the sub-
strate (Scheme 3). The asymmetric cyclization of 1,3-
dichloro-2-propanol involves asymmetric elimination
of hydrogen chloride with base potassium phosphate.
The asymmetric cyclization of 1, 3-dichloro-2-propanol
could proceed significantly only in the presence of
the catalyst. In the absence of a catalyst the reaction
OH
A= n-Pr
O
Cl
O
Figure 2. Conversions and enantioselectivities for the asymmetric ring
opening of ECH with butyric acid in different solvents using catalyst
II-1-d keeping other reaction conditions identical with that of Scheme
4.

W. Li et al. / Tetrahedron Letters 47 (2006) 3453–3457
3455
Table 1. Asymmetric ring opening of terminal epoxides with carboxylic acids catalyzed by heterometallic chiral (salen) Co complex
OH
O
(
R,R)-Cat. 2-4 mol%
-4 ºC, TBME
R'
O
+
R'COOH
R
0
(
2
±)
.22
equiv.
R
O
1.00
5
3-86 ee%, 35-43 yield %
equiv.
a
b
c
Entry
1
Terminal epoxide (R)
Carboxylic acid
Catalyst type
II-1-d
Catalyst amount
Time (h)
1.0
Product ee % (yield)
O
CH
CH
CH
CH
3
3
3
3
2.0
60.2 (41)
OH
O
2
3
4
5
6
7
8
9
II-1-a
A
2.0
2.0
2.0
2.0
2.0
2.0
4.0
2.0
2.0
2.0
3.0
2.0
2.0
4.0
2.0
2.0
2.0
2.0
4.0
3.0
1.0
1.0
1.0
1.5
3.0
3.0
6.0
2.0
2.0
2.0
2.0
4.0
4.0
5.0
3.0
3.5
4.0
4.0
5.0
3.0
53.7 (37)
23.8 (15)
27.3 (17)
65.7 (40)
67.1 (43)
61.5 (42)
55.8 (39)
66.9 (40)
43.8 (41)
21.6 (14)
67.5 (40)
71.8 (43)
86.3 (41)
53.5 (36)
68.2 (40)
67.5 (41)
69.3 (40)
76.7 (43)
53.2 (39)
65.6 (42)
OH
O
OH
O
B
OH
O
C
2
H
5
II-1-d
II-1-d
II-1-d
II-1-d
II-1-d
II-1-a
A
OH
O
CH
2
2
Br
OH
O
CH
Cl
OH
O
C
6
H
5
OCH
2
OH
O
CH
CH
CH
3
3
3
OH
O
1
1
1
1
1
1
1
1
1
1
2
2
0
1
2
3
4
5
6
7
8
9
0
1
OH
O
OH
O
C
2
H
5
II-1-d
II-1-d
II-1-d
II-1-d
II-1-d
II-1-d
II-1-d
II-1-d
II-1-d
II-1-d
OH
O
CH
2
2
Br
OH
O
CH
Cl
OH
O
C
6
H
5
OCH
2
OH
O
CH
3
OH
O
C
2
H
5
OH
O
CH
2
2
Br
OH
O
CH
Cl
OH
O
6 5 2
C H OCH
OH
O
CH
3
OH
O
22
C
2
H
5
II-1-d
3.0
3.0
67.2 (43)
OH
(
continued on next page)

3456
W. Li et al. / Tetrahedron Letters 47 (2006) 3453–3457
Table 1 (continued)
Entry Terminal epoxide (R)
a
b
c
Carboxylic acid
Catalyst type
II-1-d
Catalyst amount
Time (h)
4.0
Product ee % (yield)
O
2
3
4
CH
2
2
Br
Cl
4.0
73.3 (40)
75.1 (41)
OH
O
2
CH
II-1-d
II-1-d
4.0
4.0
4.0
4.5
OH
O
25
C
6
H
5
OCH
2
52.8 (35)
OH
a
b
c
In mol % loading on a per [Co] basis w.r.t. racemic epoxides.
The products obtained were characterized by H, C, and elemental analyses.
Isolated yield is based on racemic epoxides (theoretical maximum = 45%). Ee % was determined by chiral GC or chiral HPLC.
1
13
8
6
4
2
0
0
0
0
0
OH
4
3
h
h
N
N
O
O
Co
R'
R
O
X
O
( +_ )
R
X
X
O
M
2
h
N
O
N
Co
N
N
O
1 h
Co
X
O
0
.5 h
X
O
X
R'COOH
OH
M
M
N
N
X
X
O
X
O
Co
R
O
R
O
O
R'
X
M
X
X O
O
H
R
0
.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
Catalyst amount in mol %
R'
O
M = Al, Ga
X = Cl, Br, NO3
Figure 3. Effect of catalyst (II-1-d) loading amount on enantioselec-
tivity of the asymmetric ring opening of ECH with butyric acid,
keeping other reaction conditions identical with Table 1 (entry 19) (ee
Scheme 2.
%
of recovered ECH).
(
R,R)-Cat. II-1-d
mol%
OH
O
(R)-
5
Cl
OH
HO
K PO , THF, rt, 7 h
Table 2. Asymmetric ring opening of terminal epoxides with carb-
oxylic acids catalyzed by heterometallic chiral (salen) Co complex
3
4
(
±)
OH
7
0.8% ee, 43 % Yield
O
O
(R,R)-Cat. II-1-d
5 mol%
O
R
Cl
Cl
O
(R,R)-Cat., 2-4 mol%
O
Cl
OH
+
o
K PO , THF, rt, 3 h
0-4 C, TBME
OH
5-66 ee%, 40-43 yield
3
4
(S)-
R
Prochiral
OH
(
2
+)
-
75.6% ee, 70 % Yield
O
4
.22
1.00
equiv.
equiv.
(
R,R)-Cat. II-1-d
Entry
R
Catalyst
Catalyst
loading
Time
(h)
Yield
(%)
ee
(%)
2 mol%
a
b
c
Cl
KOH, 1-4 dioxane, 4 h
7
(
R)-
(
±)
1
2
3
4
5
6
7
CH
CH
CH
CH
3
3
3
3
II-1-d
II-1-a
A
4.0
4.0
4.0
4.0
2.0
4.0
3.0
2.0
2.0
2.0
2.0
2.5
3.0
4.0
41
33
14
18
40
42
43
56.2
45.3
23.2
25.5
65.5
59.3
66.7
8.5% ee, 41 % Yield
Scheme 3.
B
C
2
H
5
II-1-d
II-1-d
II-1-d
CH
CH
2
Br
Cl
resolution. The result shows that (S)-3-chloro-propane-
,2-diol is preferentially cyclized to give (S)-glycidol.
Similarly these asymmetric cyclization may also follow
2
1
a
In mol % loading on a per [Co] basis w.r.t. racemic epoxides.
Isolated yield is based on racemic epoxides (theoretical
maximum = 45%).
b
8
the mechanism reported by Takeichi et al.
c
Ee % was determined by chiral HPLC and the products obtained
The practical utility of the present study is synthesis of
optically pure (R)-glycidyl butyrate (Scheme 4). Butyric
acid and (± ) epichlorohydrin were catalyzed by II-1-d
with complete regioselectivity along with 76% ee and
in a 46% yield (50% theoretical yield). The resolved ring
opened product followed by ring closing in the presence
1
13
were characterized by H, C, and elemental analyses.
proceeded slowly and formed racemic mixture. Similarly
optically active glycidol was synthesized from asymmet-
ric cyclization of 3-chloro-propane-1,2-diol via kinetic

W. Li et al. / Tetrahedron Letters 47 (2006) 3453–3457
3457
O
TMSN : (b) Martinez, L. E.; Leighton, J. L.; Carsten, D.
3
O
OH
H.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5897;
Schaus, S. E.; Larrow, J. F.; Jacobsen, E. N. J. Org. Chem.
1997, 62, 4197; Thiols: (c) Wu, M.; Jacobsen, E. N. J. Org.
Chem. 1998, 63, 5252; Phenols: (d) Ready, J. M.; Jacobsen,
E. N. J. Am. Chem. Soc. 1999, 121, 6086; ArSeH: (e) Yang,
M.; Zhu, C.; Yuan, F.; Huang, Y.; Pan, Y. Org. Lett. 2005,
7, 1927; HCl: (f) Thakur, S. S.; Li, W.; Kim, S. J.; Kim,
O
(
Cl
n-Pr
Cl
(
±)
n-Pr
OH
S)- 76.7 % ee
(A)
(
S,S) Cat. II-1-d, TBME, 0-4 ºC, 4h
O
O
(S,S) Cat. II-1-d
mol %
K PO , rt
2
n-Pr
O
3
4
overnight, TBME
2
G.-J. Tetrahedron Lett. 2005, 46, 2263; NH Boc: (g)
(
R) - 98.9% ee
O
Glycidyl butyrate (GB)
Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Melch-
iorre, P.; Sambri, L. Org. Lett. 2004, 6, 3973; Bartoli, G.;
Bosco, M.; Carlone, A.; Locatelli, M.; Melchiorre, P.;
Sambri, L. Org. Lett. 2004, 6, 2173.
Scheme 4.
2
. Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.; Shai-
bani, R. Tetrahedron 2004, 60, 6105, and references cited
therein; Bukowska, A.; Bukowski, W.; Leszczak, B. M. J.
Chem. Technol. Biotechnol. 1999, 74, 1145; Baum, K.;
Berkowitz, P. T.; Grakauskas, V.; Archibald, T. G. J. Org.
Chem. 1983, 48, 2953; Mirkhani, V.; Tangestaninejada, S.;
Yadollahib, B.; Alipanaha, L. Tetrahedron 2003, 59, 8213;
Junzo, O.; Shinjiro, M. Synthesis 1986, 12, 1019; Khalafi-
Nezhad, A.; Soltani Rad, M. N.; Khoshnood, A. Synthesis
of base and catalyst afforded glycidyl butyrate in high
9
1
8.9% ee and 40% yield. In the absence of catalyst II-
-d, the reaction proceeded slowly and formed racemic
mixture. The role of the catalyst II-1-d for asymmetric
cyclization may be understood by a similar report of
8
Takeichi et al.
(
R)-Glycidyl butyrate is a very important compound
2
003, 16, 2552.
and has been used to introduce a stereogenic center in
9
3. Jacobsen, E. N.; Kakiuchi, F.; Konsler, R. G.; Larrow, J.
F.; Tokunaga, M. Tetrahedron Lett. 1997, 38, 773, and
references cited therein.
the synthesis of Linezolid, which is currently marketed
for the treatment of multidrug resistant Gram-positive
infections such as nosocomial, community-acquired
pneumonia, and skin infections.
4
. (a) Shin, C. K.; Kim, S. J.; Kim, G.-J. Tetrahedron Lett.
004, 45, 7429; (b) Thakur, S. S.; Li, W.; Shin, C. K.; Kim,
G.-J. Catal. Lett. 2005, 104, 151.
2
In summary, the chiral (salen) Co bearing Lewis acids of
Al and Ga were not only able to activate the enantio-
selective ring opening of terminal epoxide with carb-
oxylic acids, it also catalyze asymmetric cyclization
reaction too. Currently we are looking at the synergistic
effect of Co–Al and Co–Ga on other asymmetric
catalytic reaction for a multifunctional characteristic
of the catalyst.
5. The selectivity factor (k ) was calculated using the equa-
rel
tion = ln[1 À c(1 + ee)]/ln[1 À c(1 À ee)] where ee is the
enantiomeric excess of the ring opened product and c is the
conversion (set to equal the isolated yield).
6
7
8
9
. Iida, T.; Yamamoto, N.; Matsunaga, S.; Woo, H.-G.;
Shibasaki, M. Angew. Chem., Int. Ed. 1998, 37, 2223.
. Nielson, L. P. C.; Stevenson, C. P.; Backmond, D. G.;
Jacobson, E. N. J. Am. Chem. Soc. 2004, 126, 1360.
. Takeichi, T.; Arihara, M.; Ishimori, M.; Tsuruta, T.
Tetrahedron 1980, 36, 3391.
. (a) Brickner, S.; Hutchinson, D.; Barbachyn, M.; Manni-
nen, P.; Ulanowicz, D.; Garmon, S.; Grega, K.; Hendges,
S.; Toops, D.; Ford, C.; Zurenko, G. J. Med. Chem. 1996,
39, 673; (b) Weidner-Wells, M. A.; Boggs, C. M.; Foleno,
B. D.; Melton, J.; Bush, K.; Goldschmidt, R. M.; Hlasta,
D. J. Bioorg. Med. Chem. 2002, 10, 2345.
References and notes
1
2
. H O: (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.;
Jacobsen, E. N. Science 1997, 277, 936; Furrow, M. E.;
Schaus, S. E.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 6776;