Silica gel-supported bis-cinchona alkaloid: A chiral catalyst for the heterogeneous asymmetric desymmetrization of meso-cyclic anhydrides

Article abstract of DOI:10.1016/j.tetlet.2004.02.079

A one-pot conversion of meso-cyclic anhydrides with alcoholysis in diethyl ether using SGS-(DHQ)₂AQN 4, a silica gel-supported chiral catalyst, into the corresponding desymmetrized mono ester acids was achieved with enantiomeric excesses of up

Full text of DOI:10.1016/j.tetlet.2004.02.079

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3301–3304
Silica gel-supported bis-cinchona alkaloid: a chiral catalyst
for the heterogeneous asymmetric desymmetrization
of meso-cyclic anhydrides
Yu-Mi Song, Jin Seok Choi, Jung Woon Yang and Hogyu Han*
Department of Chemistry, Korea University, 1 Anam-dong, Seoul 136-701, South Korea
Received 12 January 2004; revised 12 February 2004; accepted 16 February 2004
Abstract—A one-pot conversion of meso-cyclic anhydrides with alcoholysis in diethyl ether using SGS-(DHQ)2AQN 4, a silica gel-
supported chiral catalyst, into the corresponding desymmetrized mono ester acids was achieved with enantiomeric excesses of up
to 84% under mild and efficient conditions.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Enantioselective desymmetrization of meso compounds
is a powerful synthetic means of preparing enantio-
N
N
merically enriched products where multiple stereocen-
ters can be introduced in one step, enabling the
conversion of cheap starting materials into more
expensive ones. Examples of substrates for desymmet-
rization reactions include epoxides, aziridines, cyclic
anhydrides, and a variety of diols.1 The transformations
utilized to desymmetrize meso compounds fall roughly
into three major categories: transition metal-mediated,
Lewis acid-mediated, and enzyme-catalyzed processes.1
As one would expect, most of these processes use a
chiral catalyst or reagent that binds to the meso sub-
strate and tranforms the enantiotopic faces and groups
into chemically distinct diastereotopic ones.
MeO
H
N
H
N
OMe
O
O
O
O
1
O
H
H
H
CO2H
catalyst 1
O
MeOH/Et2O
CO2Me
H
O
Scheme 1. Structure of (DHQD)2AQN 1 and its use for the asym-
metric desymmetrization reaction of meso-cyclic anhydrides with
methanol.
Recently, Deng and co-workers2 discovered a general
and highly enantioselective catalytic desymmetrization
of prochiral meso-cyclic anhydrides using commercially
available mono and bis-cinchona alkaloid derivatives as
a catalyst or equivalent. Among them, 1,4-bis(dihydro-
quinidinyl)anthraquinone (DHQD)2AQN 1, in general
afforded high enantioselectivities (up to 98% ee) with
only modest catalyst loading of 8 mol % (Scheme 1).2
For the first time, this method overcomes the frequently
encountered problems of high catalyst loading when
expensive cinchona alkaloid derivatives were employed.
For the reutilization of catalytic ligands in consecutive
asymmetric desymmetrization reactions, several at-
tempts to recover cinchona alkaloids such as quinidine
(QD) and quinine (QN) for the ring-opening of meso-
cyclic anhydrides have been made.3–5 However, in spite
of the utility of (DHQD)2AQN 1 as an excellent catalyst
for the asymmetric desymmetrization of meso-cyclic
anhydrides, there has been only one report so far about
anchoring a homogeneous analogue of 1 onto the
polymer-support.6
Keywords: Catalyst immobilization; Desymmetrization; (DHQ)2AQN;
SGS-(DHQ)2AQN; meso-Cyclic anhydride.
* Corresponding author. Tel.: +82-2-3290-3134; fax: +82-2-3290-3121;
e-mail: hogyuhan@korea.ac.kr
These authors contributed equally to this work.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.079

3302
Y.-M. Song et al. / Tetrahedron Letters 45 (2004) 3301–3304
O
O
O
O
O
H
H
O
O
N
N
MeO
H
N
OMe
H
N
O
O
O
O
O
O
O
O
H
H
O
O
O
O
5a
5b
5c
5d
5e
Figure 1. Various meso-cyclic anhydride substrates 5a–e.
2
OMe
O
O
HS
Si
AIBN, CHCl3
3
OMe
OMe
Si
O
O
O
S
S
Si
O
N
N
MeO
H
N
OMe
H
O
O
O
O
N
Scheme 2. Synthesis of SGS-(DHQ)2AQN 4.
Scheme 3. Desymmetrization of meso-cyclic anhydrides 5a–e with
alcoholysis in diethyl ether using 4 or anti-1 as a catalyst followed by
conversion of the resulting hemiesters 6a–f to the corresponding
amide–esters 7a–f.
Therefore, we became interested in the immobilization
of 1,4-bis(dihydroquininyl)anthraquinone (DHQ)2AQN
anti-1, a homogeneous analogue of 1 onto inorganic
supports to explore the possibility of its efficient reuse.
Generally, inorganic materials often show higher
chemical and thermal stability under catalytic condi-
tions than cross-linked polymers. Thus, we chose com-
mercially available silica gel (70–230 mesh) as a catalyst
support.
mercaptopropylsilanized silica gel 3 in the presence of
a,a0-azoisobutyronitrile (AIBN) as a radical initiator in
CHCl3 (Scheme 2).9 The nitrogen analysis of 4 con-
firmed 10.7 wt % incorporation of monomeric alkaloid 2
onto silica gel (0.126 mmol/g).10
To synthesize a suitable silica gel-supported catalyst, we
started with 1,4-bis(quininyl)anthraquinone (QN)2AQN
2, a homogeneous analogue of anti-1. Alkaloid 2
was prepared by nucleophilic substitution of 1,4-dif-
In a first series of experiments, we examined the
desymmetrization of anhydride 5a in diethyl ether using
SGS-(DHQ)2AQN 4 as a catalyst and methanol as a
nucleophile under heterogeneous conditions (Fig. 1 and
Scheme 3). Our results are summarized in Table 1. To
optimize the experimental conditions, the influence
of catalyst amount, the nucleophile to solvent ratio
luoroanthraquinone with the lithium salt of quinine in
7;8
THFat room temperature. SGS-(DHQ)2AQN 4, a
silica gel-supported bis-cinchona alkaloid (DHQ)2AQN
anti-1, was prepared by reacting chiral monomer 2 with
Table 1. Effects of catalyst amount, the nucleophile to solvent ratio, and temperature on conversion yields and ee values in the desymmetrization
reaction of cis-1,2-cyclohexanedicarboxylic anhydride 5a with methanola
Entry
Productb
Catalystc (mol %)
Ratiod
Temperature (ꢁC)
Conversione (%)
Eef (%)
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6a
6a
6a
6a
2
0.01:1
0.01:1
0.33:1
0.33:1
0.01:1
0.01:1
0.33:1
0.33:1
0
)30
0
63
49
94
99
25
17
95
65
56
66
27
39
48
84
3
2
2
2
)30
0
0.2
0.2
0.2
0.2
)30
0
)30
14
a Reaction time (48 h).
b Absolute configuration (1S,2R).3;4
c SGS-(DHQ)2AQN 4.
d MeOH (nucleophile)/Et2O (solvent).
e Determined by GC analysis of an enantiomeric mixture of 6a using a HP-1 column (30 m · 0.32 mm · 0.25 lm).11
f Determined by HPLC analysis of a diastereomeric mixture of 7a using a Nova-Pakꢂ silica column (15 cm · 3.9 mm · 4 lm).2;12

Y.-M. Song et al. / Tetrahedron Letters 45 (2004) 3301–3304
3303
Table 2. Desymmetrization of meso-cyclic anhydrides 5a–e with alcoholysis in diethyl ether using heterogeneous catalyst 4 or homogeneous catalyst
anti-1
Entry
Anhydride Product Catalysta
(mol %)
Ratio
Temperature
Time (h)
Conversionc (%) Eed (%) Configuratione
(MeOH/Et2O) (ꢁC)
1
5a
5a
5a
5a
5b
5b
5b
5c
5d
5e
5a
6a
6a
6a
6a
6b
6b
6b
6c
6d
6e
6f
4 (5)
4 (5)
0.01:1
0.05:1
0.01:1
0.05:1
0.01:1
0.05:1
0.05:1
0.33:1
0.1:1
)20
)30
)20
)30
)20
)10
)10
)30
)30
25
48
48
48
48
60
72
72
19
48
7
73
85
84
99
56
77
96
78
18
46
76
56
67
93
76
65
62
76
41
83
26
51
1S,2R
1S,2R
1S,2R
1S,2R
1S,2R
1S,2R
1S,2R
2S,3R
2S,3R
3R
2
32
42
5
anti-1 (5)
anti-1 (5)
4 (5)
6
72
4 (2)
anti-1 (2)
4 (2)
4 (2)
8
9
10
11
4 (5)
4 (5)
0.01:1
0.05b:1
0
72
1S,2R
a SGS-(DHQ)2AQN 4 or (DHQ)2AQN anti-1.
b 2-Methyl-1-propanol instead of MeOH as a nucleophile.
c Determined by GC analyses of an enantiomeric mixture of 6a–f using a HP-1 column (30 m · 0.32 mm · 0.25 lm).11
d Determined by HPLC analyses of a diastereomeric mixture of 7a–f using a Nova-Pakꢂ silica column (15 cm · 3.9 mm · 4 lm).2;12
e The absolute configuration of the products 6a–f was determined as described.3;4
(MeOH/ether), and temperature on the efficiency of the
process was investigated, with particular regard to
enantioselectivity. Interestingly, the results from Table 1
show that the conversion yields and ee values increased
accordingly as the catalyst amount increased (entries 1–
4 vs 5–8). In particular, as can be seen from Table 1, the
conversion yields and ee values depend on the methanol
to ether ratio. The more quantity of methanol as a
nucleophile was used, the more the conversion yield
increased, but the ee value decreased (entries 1, 2, 5, 6 vs
3, 4, 7, 8, respectively). This result was independent of
reaction temperature. We observed that the higher
temperature resulted in a decrease in the ee value and
the lower temperature slowed down the reaction rate. As
shown in entry 6 of Table 1, the catalytic amount of 4
(0.2 mol %) with respect to the reacting anhydride 5a
under heterogeneous conditions was utilized to achieve
the good ee value (84% ee by carrying out the reaction
in the mixture of methanol and diethyl ether at a ratio
of 0.01:1 at )30 ꢁC).
compounds 6a and 6b in lower yields but with the ee
values comparable to those obtained using homoge-
neous chiral catalyst anti-1 (Table 2, entries 2, 6 vs 4, 7,
respectively). Due to the negative effect of the support
on the chiral microenvironment around the active cen-
ters, this immobilized chiral catalyst also suffered from
moderate catalytic activity and/or enantioselectivity.
Finally, the recyclability of the catalyst was also exam-
ined by carrying out the reaction with 5 mol % silica gel-
supported chiral catalyst 4 in the mixture of methanol
and diethyl ether at a ratio of 0.05:1 at )30 ꢁC for 48 h.
Enantiomeric excesses ranging from 62% to 67% were
observed in several recycles of the catalytic system
(Table 3). Catalyst 4 could be separated from the reac-
tion mixture by solvent precipitation and was reused for
five consecutive reactions without any significant de-
crease in catalytic activity and enantioselectivity. How-
ever, the catalyst was somewhat leaching from the
reaction mixture. The moderate catalytic activity and
enantioselectivity of silica gel-supported chiral catalyst 4
was likely attributed to its slight solubility in methanol.
Although the selectivity of the reaction was moderate,
this process was quite simple and efficient for catalyst
immobilization.
We examined the desymmetrization of meso-cyclic
anhydrides 5a–e with alcoholysis in diethyl ether using
heterogeneous catalyst 4 or homogeneous catalyst
anti-1. Our results are summarized in Table 2. Hetero-
geneous catalyst 4 gave similar or lower stereoselectivi-
ties compared to the corresponding homogeneous
catalyst anti-1 (Table 2, entries 1, 2 vs 3, 4, respectively).
Interestingly, the use of a catalytic amount of silica gel-
supported chiral catalyst 4 (5 or 2 mol %) produced
In summary, we succeeded in a catalytic heterogeneous
asymmetric methanolysis of various meso-cyclic anhy-
drides in diethyl ether using silica gel-supported chiral
catalyst 4 to afford the corresponding chiral hemiesters
in moderate yields and enantioselectivities. Further-
more, the process retains the ease of catalyst removal/
recycling by simple filtration. The immobilized chiral
catalyst could be reused several times without any sig-
nificant decrease in catalytic activity and enantioselec-
tivity. Further optimization of the reactions is currently
in progress.
Table 3. The recyclability of heterogeneous bis-cinchona alkaloid-
based catalyst 4 in the asymmetric desymmetrization reaction of 5a
with methanola
Ee (%) with consecutive use of recycled catalyst 4
Recycle
Ee (%)
1st
67
2nd
67
3rd
65
4th
62
5th
65
Conversion (%) 85
82
73
72
68
General procedure for the asymmetric methanolysis of
meso-cyclic anhydrides 5a–e (described for the reaction
of cis-1,2-cyclohexanedicarboxylic anhydride 5a in the
mixture of methanol (10 equiv) and ether (5 mL per
a Asymmetric desymmetrization reaction using 5 mol % silica gel-sup-
ported chiral catalyst 4 was carried out in the mixture of methanol
and diethyl ether at a ratio of 0.05:1 at )30 ꢁC for 48 h.

3304
Y.-M. Song et al. / Tetrahedron Letters 45 (2004) 3301–3304
(c) Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2002, 124,
174–175; (d) Uozumi, Y.; Yasoshima, K.; Miyachi, T.;
Nagai, S.-i. Tetrahedron Lett. 2001, 42, 411–414; (e)
Kashima, Y.; Liu, J.; Takenami, S.; Niwayama, S.
Tetrahedron: Asymmetry 2002, 13, 953–956; (f) Patti, A.;
Sanfilippo, C.; Piattelli, M.; Nicolosi, G. J. Org. Chem.
1996, 61, 6458–6461; (g) Harada, T.; Sekiguchi, K.;
Nakamura, T.; Suzuki, J.; Oku, A. Org. Lett. 2001, 3,
3309–3312.
0.1 mmol anhydride) at an approximate ratio of 0.01:1
(v/v)). After a suspension containing cis-1,2-cyclohex-
anedicarboxylic anhydride 5a (25 mg, 0.162 mmol) and
SGS-(DHQ)2AQN 4 (64.3 mg, 5 mol %) in dry diethyl
ether (8.1 mL) at )20 ꢁC was stirred for 10 min, dry
methanol (65.7 lL, 1.62 mmol) was added under argon
atmosphere. After stirring at )20 ꢁC for 48 h, the mix-
ture was filtered, and then filtrate was concentrated in
vacuo. The crude residue was purified by flash chro-
matography on silica gel (EtOAc/n-hexane ¼ 1 : 2) to
afford 6a as a colorless oil. GC analysis of an enantio-
meric mixture of 6a for determining conversion effi-
ciency was performed prior to work-up.11
2. Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000,
122, 9542–9543.
3. Bolm, C.; Schiffers, I.; Atodiresei, I.; Hackenberger, C. P.
R. Tetrahedron: Asymmetry 2003, 14, 3455–3467.
4. Bolm, C.; Schiffers, I.; Dinter, C. L.; Gerlach, A. J. Org.
Chem. 2000, 65, 6984–6991.
5. Bolm, C.; Gerlach, A.; Dinter, C. L. Synlett 1999, 195–
196.
General procedure for the ee determination of hemiesters
6a–f (described for cis-1,2-cyclohexanedicarboxylic acid
monomethyl ester 6a). The enantiomeric excess of the
product was determined by HPLC analysis of a diaste-
reomeric mixture of the corresponding amide–ester 7a
prepared from an enantiomeric mixture of hemiester 6a
according to the literature procedure.2;12
€
6. Woltinger, J.; Krimmer, H.-P.; Drauz, K. Tetrahedron
Lett. 2002, 43, 8531–8533.
7. Becker, H.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl.
1996, 35, 448–451.
8. (QN)2AQN 2. TLC (CHCl3+7% MeOH+0.5% NH4OH)
Rf ¼ 0:23; 1H NMR (500 MHz, CDCl3)
d 8.63 (d,
J ¼ 4:5 Hz, 2H), 8.27 (dd, J ¼ 5:8, 3.3, 2H), 8.03 (d,
J ¼ 9:5, 2H), 7.79 (dd, J ¼ 5:5, 3.5, 2H), 7.41 (d, J ¼ 4:5,
2H), 7.38 (dd, J ¼ 9:0, 2.5, 2H), 7.31 (br s, 2H), 6.60 (br s,
2H), 5.95 (br s, 2H), 5.74 (m, 2H), 4.95 (d, J ¼ 17:0, 2H),
4.90 (d, J ¼ 10:0, 2H), 3.92 (s, 6H), 3.25 (br s, 4H), 3.08
(dd, J ¼ 13:8, 10.3, 2H), 2.68 (d, J ¼ 13:5, 2H), 2.60 (td,
J ¼ 12:0, 3.5, 2H), 2.47 (br s, 2H), 2.27 (br s, 2H), 2.03 (br
To a solution containing cis-1,2-cyclohexanedicarboxy-
lic acid monomethyl ester 6a (39.8 mg, 0.214 mmol)
in CH2Cl2 (10.7 mL) at room temperature was added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-
chloride (EDCI, 49.3 mg, 0.257 mmol). After stirring for
10 min, 4-(dimethylamino)pyridine (4-DMAP, 7.8 mg,
64.2 lmol) and (R)-(+)-1-(1-naphthyl)ethylamine (37.9
lL, 0.235 mmol) were added to the mixture. After stir-
ring at room temperature for 5 h, the mixture was ex-
tracted with dichloromethane, dried over anhydrous
Na2SO4, and then concentrated under reduced pressure.
The crude residue was purified by flash chromatography
on silica gel (EtOAc/n-hexane ¼ 1:2) to afford 7a as a
yellow oil. HPLC analysis of a diastereomeric mixture of
7a for determining the ee value was performed after
column purification.
s, 2H), 1.95 (br s, 2H), 1.67 (br s, 2H), 1.44 (br s, 2H); 13
C
NMR (75 MHz, CDCl3) d 182.74, 158.27, 151.00, 147.60,
144.59, 142.60, 141.97, 134.27, 133.34, 132.06, 126.39,
126.20, 123.39, 122.07, 120.68, 118.75 (br), 114.27, 100.56
(br), 80.08 (br), 60.13, 57.27, 55.84, 43.38, 40.04, 28.03,
27.03, 21.29 (br); HRMS (FAB+) for C54H53N4O6 (MHþ),
25
D
calcd 853.3965; found 853.3990. ½aꢀ ¼ + 583.5 (c ¼ 0:85,
CHCl3).
9. Song, C. E.; Yang, J. W.; Ha, H.-J. Tetrahedron:
Asymmetry 1997, 8, 841–844.
10. Element analysis (wt %) of SGS-(DHQ)2AQN 4. N 0.71, C
13.75, H 2.02, S 3.13.
11. GC analyses of an enantiomeric mixture 6a–f were
performed on a Hewlett Packard 5890A GC System using
a HP-1 column (30 m · 0.32 mm · 0.25 lm) under the
condition: initial temperature, 50 ꢁC; initial time, 3 min;
15.0 ꢁC/min gradient; final temperature, 280 ꢁC, 17 psi.
Retention time (min): 6a, tR ¼ 10:49; 6b, tR ¼ 10:65; 6c,
tR ¼ 11:47; 6d, tR ¼ 12:15; 6e, tR ¼ 8:63; 6f, tR ¼ 12:22.
12. HPLC analyses of a diastereomeric mixture 7a–f were
performed on a Waters 600 HPLC System using a Nova-
Pakꢂ silica column (15 cm · 3.9 mm · 4 lm) under condi-
tions: 7a, n-hexane/2-propanol ¼ 97=3, 1.0 mL/min,
280 nm, tR ¼ 3:58, tR ¼ 4:24 (major); 7b, n-hexane/2-
Acknowledgements
This work was financially supported by the Basic Re-
search (Grant No. R01-2003-000-11623-0) and CRM
programs from KOSEFand Korea University Grant.
Fellowship support from the BK21 program (Y.-M.S.,
J.S.C., J.W.Y.) is gratefully acknowledged.
propanol ¼ 97=3,
1.0 mL/min,
280 nm,
tR ¼ 3:41,
tR ¼ 4:14 (major); 7c, n-hexane/2-propanol ¼ 97=3,
1.0 mL/min, 280 nm, tR ¼ 4:51, tR ¼ 5:60 (major); 7d, n-
References and notes
hexane/2-propanol ¼ 97=3, 1.0 mL/min, 280 nm, tR
¼
5:58, tR ¼ 6:33 (major); 7e, n-hexane/2-propanol ¼ 96=4,
0.9 mL/min, 280 nm, tR ¼ 8:51 (major), tR ¼ 9:11; 7f, n-
€
1. (a) Sodergren, M. J.; Bertilsson, S. K.; Andersson, P. G. J.
Am. Chem. Soc. 2000, 122, 6610–6618; (b) Hodgson, D.
M.; Gras, E. Angew. Chem. Int. Ed. 2002, 41, 2376–2378;
hexane/2-propanol ¼ 97=3, 1.0 mL/min, 280 nm, tR
3:59, tR ¼ 4:22 (major).
¼