A family of novel bifunctional organocatalysts: Highly enantioselective alcoholysis of meso cyclic anhydrides and its application for synthesis of the key intermediate of P2X7 receptor antagonists

Article abstract of DOI:10.1016/j.cclet.2013.04.009

A family of novel squaramides/sulfamides based on 1,2-alkamine was developed as chiral bifunctional catalysts to promote the asymmetric alcoholysis of meso cyclic anhydrides. The hemiesters were obtained in high yield with up to 93% ee. The usefulness of this methodology was demonstrated in the asymmetric synthesis of the key intermediate of P2X₇ receptor antagonists.

Full text of DOI:10.1016/j.cclet.2013.04.009

Chinese Chemical Letters 24 (2013) 553–558
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Chinese Chemical Letters
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Original article
A family of novel bifunctional organocatalysts: Highly enantioselective
alcoholysis of meso cyclic anhydrides and its application for synthesis
of the key intermediate of P2X7 receptor antagonists
Hong-Jun Yang a, Fang-Jun Xiong a, Jie Li a, Fen-Er Chen a,b,
*
a Department of Chemistry, Fudan University, Shanghai 200433, China
b Institute of Biomedical Science, Fudan University, Shanghai 200433, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A family of novel squaramides/sulfamides based on 1,2-alkamine was developed as chiral bifunctional
catalysts to promote the asymmetric alcoholysis of meso cyclic anhydrides. The hemiesters were
obtained in high yield with up to 93% ee. The usefulness of this methodology was demonstrated in the
asymmetric synthesis of the key intermediate of P2X7 receptor antagonists.
Received 21 February 2013
Received in revised form 24 March 2013
Accepted 2 April 2013
Available online 14 May 2013
ß 2013 Fen-Er Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords:
Asymmetric alcoholysis
Bifunctional organocatalyst
Cyclic anhydrides
P2X7 receptor antagonists
Sulfamides
1. Introduction
efficient, and excellent enantioselectivity in the methanolysis of
meso cyclic anhydrides. In addition, 1,2-diamines/alkamines 4–7
Over the past decade, organocatalyst promoted asymmetric
catalysis has attractive intense research efforts. Among the different
catalysts reported to date, those based on cinchona alkaloids [1] or
havebeenemployedasorganocatalysts forthereaction bySanoet al.
[5m], Bolm et al. [5n], and Irie et al. [5p]. Therefore, the search of
novel organocatalysts and protocols for this alcoholysis still remains
a challenging topic in asymmetric synthesis.
L-prolines [2] dominate the field. In contrast, other chiral scaffolds
have been much less explored. The identification of novel efficient
catalysts with other chiral fragments, which can be easily synthe-
sized from commercially inexpensive chiral sources and be recycled,
is urgently needed in the field of asymmetric organocatalysis.
The asymmetric alcoholysis of meso cyclic anhydrides is an
attractive method which provides access to multiple stereogenic
centers in one operation [3]. Since the first non-enzymatic and
metal-free catalytic process reported by Oda et al. [4], impressive
progress have been made in the alcoholysis of cyclic anhydrides by
various organocatalysts [4,5]. Among them, non-cinchona alkaloid
derivatives are rarely used (Fig. 1). Uozumi et al. [5j] and Pedrosa
The derivatives of (1S,2S)-2-amino-1-(p-nitrophenyl)propane-
1,3-diol (8a, Fig. 1), a by-product in the industrial production of
chloramphenicol as a chiral source, were employed as ligands or
catalysts in various asymmetric transformations in the past ten
years [6]. Excitingly, high yield and enantioselectivity were
observed for the desymmetrization of meso cyclic anhydrides
using alkamine 8b or thioureas 9, derived from 8a as a catalyst in
our laboratory [5o,7]. As part of our continuous effort to discover
excellent alkamine-derived organocatalysts for asymmetric catal-
ysis and inspired by squaramide and sulfamide catalysts recently
introduced by Rawal [8] and Song et al. [5q,9], we herein report a
family of novel bifunctional sulfamide catalysts 10/squaramides
11 (Scheme 1) that were designed and synthesized for the
enantioselective alcoholysis of cyclic anhydrides as well as the
synthesis of the key intermediate of P2X7 receptor antagonists.
et al. [5k] introduced a-amino acid-derived catalysts 1 and 2, which
promoted enantioselective desymmetrization of meso cyclic anhy-
drides, respectively. Recently, Wakchaure and List [5l] have also
developed BINOL-phosphamide 3, which shows highly catalytic,
2. Experimental
* Corresponding author at: Department of Chemistry, Fudan University, Shanghai
200433, China.
All the solvents were purified according to standard methods.
Unless otherwise specified, all reagents were purchased from
E-mail address: rfchen@fudan.edu.cn (F.-E. Chen).
1001-8417/$ – see front matter ß 2013 Fen-Er Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.04.009

[
H.-J. Yang et al. / Chinese Chemical Letters 24 (2013) 553–558
OH
OH
NH2
R2
R2
OH
a
R1
R1
NH2
O2N
O2N
O2N
8
13a: R1= -NMe2, R2= OTr
12a: R1= -NMe2, R2=OTr
R2= OTr
R2= OTr
R2= OTr
13b: R1=
13c: R1=
12b: R1=
N
N
N
R2= OTr
12c: R1=
N
c
F3C
b
CF3
O
S
O
HN
H
N
CF3
O
O
R2
CF3
R2
R1
NH
R1
O2N
10a: R1= -NMe2, R2= OTr
10b: R1=
10c: R1=
10d: R1=
R2= OTr
N
N
N
O2N
11a: R1=
R2= OTr
R2= OTr
N
N
d
R2= OTr
R2= OH
11b: R1=
Scheme 1. Synthesis of novel bifunctional organocatalysts. (a) Ph3P, diisopropyl azodicarboxylate, diphenyl phosphoryl azide, H2O, THF; (b) 3-(3,5-bis-alkyl-phenylamino)-
4-methoxycyclobut-3-ene-1,2-dione, MeOH; (c) 3,5-bis(trifluoro-methyl)benzene-sulfonyl chloride, Et3N, CH2Cl2; (d) HCl (6 mol/L), EtOH, reflux.
commercial suppliers and used without further purification. 12a
[5o], 13a [5o], and 26 [10] were prepared according to the
literature methods. All other chemicals used in this study were
obtained from commercial sources and used without further
purification. IR spectra were recorded on a Jasco FT/IR-4200
spectrometer. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra
were recorded on a Bruker Avance 400 spectrometer in CDCl3 using
tetramethylsilane (TMS). Mass spectra were recorded on a Bruker
micrOTOF instrument using electrospray ionization (ESI) techni-
ques. Optical rotations were obtained on a Jasco P1020 digital
polarimeter. HPLC analysis was performed using a Shimadzu LC-
10A with Daicel Chiralcel OJ-H (0.46 cm ꢀ 25 cm) column, AD-H
column (0.46 cm ꢀ 25 cm) or Chiralcel OD-H column
(0.46 cm ꢀ 25 cm).
2.1. General procedure for the asymmetric alcoholysis of meso cyclic
anhydride
To a solution of catalyst in methyl tertiary butyl ether (MTBE)
was added cyclic anhydride at room temperature under nitrogen.
After being stirred for 10 min, alcohol was added dropwise and
then the resulting mixture was stirred at the same temperature.
Subsequently, the resulting solution was concentrated under
reduced pressure to dryness. The residue was dissolved in
[(ig._1)TD$FIG]
Ar
CF3
O
NMe2
S
H
S
O
O
P
ArN
OH
HN
N
1
N
H
N
H
N
CF3
2
Ar
3
F3C
F3C
OH
OH
R '
OH
N
SO2
HN
R
Ph
R ''
N
R
N
6
4
5
Me2N
Ph
CF3
H
S
OH
S
N
Ar
N
H
CF3
OR
HN
NH
NH2
OR
O2N
R
N
8a: R=H
8b: R=Tr
N
9
O2N
R
7
Fig. 1. Structures of various organocatalysts.

H.-J. Yang et al. / Chinese Chemical Letters 24 (2013) 553–558
555
Table 1
Table 3
Asymmetric alcoholysis of meso cyclic anhydrides with different catalysts.
[
Asymmetric alcoholysis of cyclic anhydrides with different amounts of catalyst.[TD$LINE]
O
O
CO2Me
CO2H
CO2Me
10b; MeOH (10 equiv.)
Catalyst (5 mol%); MeOH (10 equiv.)
MTBE (0.1 mol/L), r.t.
O
O
MTBE (0.0125 mol/L), r.t.
CO2H
O
O
14
15
15
14
Yielda (%)
eeb (%)
Entry
Catalyst loading (mol%)
Time (h)
Yielda (%)
eeb(%)
Entry
Catalyst
Time (h)
1
2
3
4
5
20
10
5
20
24
94
95
94
85
81
91
92
93
92
90
1
2
3
4
5
6
10a
10b
10c
10d
11a
11b
72
72
72
72
48
48
87
94
90
89
84
87
85
88
81
82
66
34
72
2
96
1
120
a
Yield of isolated product.
b
a
Determined by chiral HPLC analysis.
Yield of isolated product.
b
Determined by chiral HPLC analysis.
dichloromethane, and washed with saturated Na2CO3 (10 mL ꢀ 2).
The combined aqueous layers were acidified with excess 2 mol/L
HCl, followed by extraction with EtOAc (20 mL ꢀ 3). The combined
organic layers were dried over anhydrous Na2SO4 and concentrat-
ed to afford the corresponding hemiester.
(1.2 mmol). After being stirred at room temperature for 3 h, the
reaction was quenched with H2O (10 mL). The organic phase was
separated, washed with saturated aqueous sodium bicarbonate,
dried over anhydrous Na2SO4 and concentrated in vacuo. The residue
was purified by column chromatography (petroleum ether/AcOEt).
N-((1R,2R)-2-(Dimethylamino)-1-(4-nitrophenyl)-3-(trityloxy)
propyl)-3,5-bis(trifluoromethyl)benzene-sulfonamide (10a): Yellow
(1S,2R)-2-(Methoxycarbonyl)cyclohexanecarboxylic acid (15):
Colorless oil; 93% ee, ½a D25
ꢁ
+3.6 (c 1.0, CHCl3); 1H NMR (400 MHz,
1.37–1.53 (m, 4 H), 1.73–1.75 (m, 2 H), 1.96–2.03 (m, 2H),
CDCl3):
d
solid; 0.68 g (90%); ½a D25
ꢁ
+18.7 (c 0.4, MeOH); IR (KBr, cmꢂ1):
n
2.78–2.85 (m, 2 H), 3.64 (s, 3H); 13C NMR (100 MHz, CDCl3):
24.02, 26.23, 26.52, 42.61, 42.82, 51.98, 174.40, 180.40.
d
23.90,
3431, 3210, 2951, 2358, 1797, 1654, 1558, 1519, 1455, 1381, 1349,
1279, 1139, 1129, 837; 1H NMR (400 MHz, CDCl3):
d 2.40 (s, 6 H),
2.73–2.78 (m, 1 H), 2.95–2.98 (m, 1 H), 3.16–3.20 (m, 1 H), 4.21 (d,
2.2. General procedure for the synthesis of sulfonamide catalysts (10)
1H, J = 10.8 Hz), 7.04 (d, 2 H, J = 8.0 Hz), 7.13–7.16 (m, 15 H), 7.80–
7.85 (m, 5 H); 13C NMR (100 MHz, CDCl3):
d 56.68, 58.00, 67.48,
To a solution of (1R, 2R)-3-triphenylmethoxyl-N2,N2-dialkyl-1-(4-
nitrophenyl)propane-1,2-diamine (13, 1 mmol, 1.0 equiv.) in CH2Cl2
(10 mL) was added triethylamine (2 mmol) at room temperature
under nitrogen. The resulting mixture was cooled to 0 8C, followed
by addition of 3,5-bis(trifluoromethyl)benzene-1-sulfonyl chloride
87.69, 123.33, 125.77, 127.24, 127.35, 127.38, 127.77, 128.39,
129.18, 132.15, 132.50, 142.95, 143.21, 144.96, 147.38; ESI (MS):
m/z 758 [M+H]+.
2.3. General procedure for the synthesis of squaramide catalysts (11)
To a solution of 13 (1 mmol) in CH2Cl2 (10 mL) was added 3-
(3,5-Bis(trifluoromethyl)phenylamino)-4-methoxy-cyclobut-3-
ene-1,2-dione (2 mmol). After stirring at room temperature for 3 h,
the solvent was removed under reduced pressure. The residue was
purified by column chromatography (CH2Cl2/MeOH).
Table 2
Asymmetric alcoholysis of meso cyclic anhydrides in various solvent and with
different concentration of the substrate.a
[TD$LINE]
O
CO2Me
CO2H
10b (5 mol%); MeOH (10 equiv.)
3-(3,5-Bis(trifluoromethyl)phenylamino)-4-((1R,2R)-1-(4-nitro-
phenyl)-2-(pyrrolidin-1-yl)-3-(trityloxy)propylamino)cyclobut-3-
O
Solvent, r.t.
ene-1,2-dione (11a): Yellow solid; 0.65 g (80%); ½a D25
ꢂ17.6 (c 0.4,
ꢁ
O
MeOH); IR (KBr, cmꢂ1):
n 3431, 3182, 3073, 2916, 2362, 1530,
14
15
1364, 1348, 1280, 1185, 1159, 1136, 698; 1H NMR (400 MHz,
CDCl3): 1.23 (d, 2 H, J = 6.4 Hz), 1.49 (s, 3 H), 2.64 (s, 3 H), 3.17–
3.42 (m, 3 H), 5.52–5.53 (m, 1H), 7.18–7.32 (m, 16 H), 7.55–7.57
(m, 2 H), 7.84–8.03 (m, 4 H); 13C NMR (100 MHz, CDCl3):
23.76,
d
Entry
Solvent
Concentration (mol/L)
Yieldb (%)
eec (%)
1
2
MeOH
DCM
0.1
100
89
88
92
93
78
95
95
90
97
94
96
92
87
88
93
17
40
50
63
80
35
88
79
88
68
88
76
85
90
92
93
d
0.1
25.43, 48.90, 64.63, 87.64, 118.53, 121.64, 123.91, 124.36, 127.32,
127.86, 128.05, 128.66, 132.44, 132.77, 139.99, 143.11, 147.46,
181.89, 183.12; ESI (MS): m/z 815 [M+H]+.
3
DCE
0.1
4
MeCN
PhMe
DMF
0.1
5
0.1
6
0.1
7
Et2O
0.1
3. Results and discussion
8
THF
0.1
9
Dioxane
Anisole
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
0.1
A family of squaramide/sulfamide catalysts based on 1,2-
alkamine were prepared and applied to enantioselective alcoholysis
of cyclic anhydrides. The synthesis of these catalysts as illustrated in
Scheme 1 began with 8a. Protection of the primary amine and
primary hydroxyl groupprovided compound 12a–c. After treatment
with diphenyl phosphoryl azide in the presence of triphenylpho-
sphine, 12 afforded compound 13. Next, condensation of 13 with 3-
methoxy-4-(arylamino)cyclobut-3-ene-1,2-dion was carried out in
MeOH to give a family of catalyst 11. In addition, 10a–c could be
10
11
12
13
14
15
16
0.1
0.1
0.5
0.2
0.05
0.025
0.0125
a
All reaction were carried out at r.t. for 72 h.
Yield of isolated product.
b
c
Determined by chiral HPLC analysis.

556
H.-J. Yang et al. / Chinese Chemical Letters 24 (2013) 553–558
Table 4
Asymmetric methanolysis of various cyclic anhydrides by catalyst 10b.T[D$LINE]
O
O
O
R''
R''
CO2Me
CO2H
10b (5 mol%), MeOH (10 equiv.)
R'
R'
n
n
MTBE, r.t.
R''
R''
Substrate
Product
Time (h)
72
Yield (%)a
93
ee (%)b,c
93
O
CO2Me
CO2H
[DT$LINE]
[TD$LINE]
O
15
17
14
16
O
72
94
91
O
CO2Me
CO2H
[DT$LINE]
[TD$LINE]
O
O
120
120
96
84
88
90
64d
85d
76
O
O
O
CO2Me
[DT$LINE]
]
O
CO2H
O
19
18
20
O
O
O
CO2Me
CO2H
[DT$LINE]
O
[TD$LINE]
O
21
[DT$LINE]
CO2H
CO2Me
23
O
[TD$LINE]
O
O
22
72
72
97
95
79
91
CO2Me
CO2H
O
O
O
[DT$LINE]
[TD$LINE]
25
24
CO2Me
CO2H
O
Ph
[DT$LINE]
Ph
[TD$LINE]
O
27
O
26
48
92
78d
O
O
BnN
H
NBn
H
BnN
H
NBn
H
[DT$LINE]
[TD$LINE]
MeO2C
COOH
O
O
O
29
28
a
b
c
Yield of isolated product.
Determined by chiral HPLC analysis [5h,5o].
Absolute configuration were determined by comparing the sign of optical rotation of the major enantiomer with known data [5h,5o].
d
All reactions were performed with 10b (20 mol%) in MTBE.
achievedbya treatmentof13with3,5-bis(trifluoromethyl)benzene-
1-sulfonyl chloride in the presence of triethylamine in CH2Cl2. Then,
deprotection of trityl group of 10b produced catalyst 10d.
To optimize the catalysts, a brief study of the relationship
between catalyst structure and reaction enantioselectivity was
performed (Table 1). Sulfamide catalyst 10a was initially tested in
the reaction of methanol and (3aR,7aS)-hexahydroisobenzofuran-
1,3-dione (14). When the reaction was carried out at room
temperature using 5 mol% of the catalyst, the desired product
was formed in 87% yield with 85% enantioselectivity (entry 1). The

H.-J. Yang et al. / Chinese Chemical Letters 24 (2013) 553–558
557
Table 5
With optimal catalyst and reaction conditions established,
varieties of cyclic anhydrides as substrates were then evaluated
and the results were summarized in Table 4. Longer reaction
periods were required for the methanolysis of tricyclic anhydrides.
In contrast, monocyclic glutaric anhydrides and bi-succinic
anhydrides were readily desymmetrized to afford the correspond-
ing hemisters in good yield and enantioselectivity. When cyclic
anhydride 28 containing multiple polar functionalities was
employed, moderate yields were obtained.
Asymmetric alcoholysis of meso cyclic anhydride with various alcohols.T[D$LINE]
O
CO2R
CO2H
10b (5 mol%); ROH (10 equiv.)
O
MTBE (0.0125 mol/L), r.t.
O
15, 30-35
14
Subsequently, the scope of our methodology was further
demonstrated in the alcoholysis of anhydride 14 with different
alcohols (Table 5). As the data in Table 5 reveals, the reaction
showed a very strong steric effect. For model substrate 14, it was
observed that the enantiomer excess of the hemisters was
decreased gradually when employing alcohols more sterically
bulky than methanol as nucleophiles, such as ethanol, 1-propanol,
2-propanol, and allyl alcohol. With respect to aromatic alcohols,
phemethylol only gave 52% ee, however better ee value was
obtained with cinnamyl alcohol.
Entry
ROH
Hemiester
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
Methanol
15
30
31
32
33
34
35
93
93
89
87
83
88
89
93
80
65
17
61
52
80
Ethanol
1-Propanol
2-Propanol
Allyl alcohol
Benzyl alcohol
Cinnamyl alcohol
a
Yield of isolated product.
b
Determined by chiral HPLC analysis.
To illustrate the catalytic usefulness of our methodology,
efficient asymmetric synthesis of piperidone 43, a key intermedi-
ate of P2X7 receptor antagonists [11], could be achieved (Scheme
2). Our synthetic strategy started from the 4-fluorobenzaldehyde
(36). Condensation of 36 with ethyl 2-cyanoacetate in the presence
effect of the substituents on the nitrogen atom of the catalyst was
examined (entries 2 and 3). Catalyst 10b, a pyrrolidine derivative,
improved the enantioselectivity slightly. For the piperidine-
substituted catalyst 10c, similar enantioselectivity was obtained.
When catalyst 10d, bearing a hydroxyl group, was employed, 82% ee
was obtained in the same conditions (entry 4). Encouraged by these
results obtained with bifunctional sulfamides 10a–d, we had also
evaluated catalysts 11a and b derived from squaramides, and
obtained modest enantioselectivity (entries 5 and 6).
A brief survey of solvent was carried out for the methanolysis of
(3aR, 7aS)-hexahydroisobenzofuran 1,3-dione (14) with 5 mol% of
10b and 10 equivalents of methanol at room temperature (Table 2).
As expected, a polar protic solvent (MeOH) resulted in poor
enantioselectivity with quantitative yield (entry 1). When haloge-
nated alkanes were used instead of MeOH, the enantioselectivities
were dramatically improved (entries 2 and 3). In the case of a polar
aprotic solvent, moderate enantioselectivities were obtained
(entries 4–6). Ether solvents, especially MTBE, were found to be
more effective than the others in terms of the enantioselectivity
(entries 7–11). Furthermore, it was observed that the enantiomeric
excess of 15 generally decreased on raising the concentration of the
substrate from 0.0125 mol/L to 0.5 mol/L (entries 11–16).
of ammonium acetate afforded a,b-unsaturated ester 37, and the
conjugate addition of the diethylmalonate carbanion onto 37,
followed by acid-catalyzed hydrolysis that generated the diacid 39.
The diacid 39 was dehydrated with acetyl chloride to furnish cyclic
anhydride 40. We next employed the sulfamide bifunctional
catalyst 10b to synthesize (R)-hemiester 41 from 40 in 96% yield
with 84% ee. After treatment with toluene/petroleum ether, the
ester was formylated by 4 MPa CO with t-BuOK at 50 8C, then
acidified with 3 mol/L HCl to give corresponding
a-formylation
product 42. The -formylation product was cyclized in the
a
presence of ammonium acetate in acetic acid at 80 8C to provide
the chiral piperidone 43. The absolute configuration of chiral
piperidone 43 was determined by comparison of its optical
rotation with the literature value [11].
4. Conclusion
In conclusion, we have designed and synthesized a family of
novel bifunctional squaramide/sulfamide catalysts from a low-cost
chiral source. The catalyst 10b exhibited the best performance in
the desymmetrization of a variety of cyclic anhydrides. The
corresponding hemiesters can be obtained in good yields and
enantioselectivities under mild conditions. Using alcohols other
thanmethanolasnucleophiles led tothecorrespondingring-opened
Next, we examined the effect of catalyst loading in the presence
of 10b using MTBE as solvent (Table 3). The amount of the catalyst
could be reduced to 1 mol%, similar enantioselectivity was
obtained through extending reaction time. On the other hand,
changing the catalyst loading from 5 mol% to 2 mol% or 1 mol%
[(chme_2)TD$FIG]
rS esulted in a lower yield (entries 3–5).
F
F
F
F
ethyl 2-cyanoacetate;
AcONH4, r.t.
diethyl malonate;
AcCl, reflux
t-BuOK; THF; 0 oC
6 mol/L HCl; reflux
90%
75% from 37
94%
CN
EtO2C
NC
CO2Et
CO2Et
HO2C
CO2H
CHO
36
CO2Et
39
37
38
F
F
F
F
MeOH (10 equiv.);
CO; t-BuOK; THF;
AcONH4; AcOH;
80 oC
Catalyst 10b (5 mol%);
4 MPa; 50 oC
MTBE
COOMe
96% yield, 84% ee
53% from 41
HO2C
COOMe
HO2C
CO2Me
CHO
After treatment with PhMe/PE;
O
N
H
O
O
40
O
79% yield, 98% ee
41
42
43
26% overall yield, 99% ee
Scheme 2. Synthesis of (S)-piperidone.

558
H.-J. Yang et al. / Chinese Chemical Letters 24 (2013) 553–558
(f) Y. Chen, S.K. Tian, L. Deng, A highly enantioselective catalytic desymmetriza-
tion of cyclic anhydrides with modified cinchona alkaloids, J. Am. Chem. Soc. 122
(2000) 9542–9543;
(g) S.H. Oh, H.S. Rho, J.W. Lee, et al., A highly reactive and enantioselective
bifunctional organocatalyst for the methanolytic desymmetrization of cyclic
anhydrides: prevention of catalyst aggregation, Angew. Chem. 120 (2008)
7990–7993;
(h) A. Peschiulli, Y. Gun’ko, S.J. Connon, Highly enantioselective desymmetriza-
tion of meso anhydrides by a bifunctional thiourea-based organocatalyst at low
catalyst loadings and room temperature, J. Org. Chem. 73 (2008) 2454–2457;
(i) H.S. Rho, S.H. Oh, J.W. Lee, et al., Bifunctional organocatalyst for methanolytic
desymmetrization of cyclic anhydrides: increasing enantioselectivity by catalyst
dilution, Chem. Commun. (2008) 1208–1210;
products in high yield with modest enantioselectivity. This
methodology was also applied successfully in synthesis of chiral
piperidone 43, which is a key intermediate of P2X7 receptor
antagonists, in which 26% overall yield with 99% ee were obtained.
Further investigations on improving the catalyst and studies on
highlighting the applicability of the methodology to other pharma-
ceutically active substances are in progress in our laboratory.
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