A chiral bifunctional sulfonamide as an organocatalyst: Alcoholysis of σ-symmetric cyclic dicarboxylic anhydrides

Article abstract of DOI:10.1055/s-0029-1218374

Enantioselective alcoholysis of σ-symmetric cyclic dicarboxylic anhydrides with benzyl alcohol catalyzed by a chiral bifunctional sulfonamide was achieved in up to 98% ee at 5 mol% loading. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218374

LETTER
3279
A Chiral Bifunctional Sulfonamide as an Organocatalyst: Alcoholysis of
s-Symmetric Cyclic Dicarboxylic Anhydrides
A
a
lcoholysis of
s
a
-Symmetr
k
ic Cyclic
D
ic
a
arboxylic
A
s
nhydride
h
s
i Honjo,a Takeshi Tsumura,a Shigeki Sano,*a Yoshimitsu Nagao,a Kentaro Yamaguchi,b Yoshihisa Seib
Graduate School of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505, Japan
Fax +81(88)6339503; E-mail: ssano@ph.tokushima-u.ac.jp
b
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
Received 8 September 2009
Our investigation started with the reaction of 3-phenyl-
glutaric anhydride (2a) with benzyl alcohol in the pres-
ence of a catalytic amount of sulfonamide 1, which was
readily synthesized from (1R,2R)-N,N-dimethyl-1,2-
diphenyl-1,2-ethanediamine.7 The ee (%) of the resultant
benzyl ester monocarboxylic acid 3a was determined by
HPLC analysis with chiral stationary phase (CSP) after
Abstract: Enantioselective alcoholysis of s-symmetric cyclic di-
carboxylic anhydrides with benzyl alcohol catalyzed by a chiral bi-
functional sulfonamide was achieved in up to 98% ee at 5 mol%
loading.
Key words: anhydrides, asymmetric synthesis, homogeneous ca-
talysis, sulfonamides, alcoholysis
methylation
with
(trimethylsilyl)diazomethane
(TMSCHN2), as shown in Table 1. Methyl ester 4a was
obtained in 92% yield and 87% ee when diethyl ether was
employed as a solvent in this reaction (Table 1, entry 1).9
Both the yields and the enantioselectivities were not as
high as those obtained when using diethyl ether (Table 1,
entries 2–5).
Enzymes efficiently catalyze various organic reactions
under mild conditions in nature.1 Thus the development of
artificial organocatalysts that mimic enzyme activity is of
interest from the perspective of asymmetric synthesis.2 On
the other hand, desymmetrization of s-symmetric dicar-
boxylic anhydrides is one of the most important strategies
in organic synthesis.3 Based on the structure of cinchona
alkaloid, Song4 and Connon5 developed a bifunctional or-
ganocatalyst, which efficiently catalyzed enantioselective
methanolysis of s-symmetric dicarboxylic anhydrides. A
cost-effective thiourea bifunctional organocatalyst for
methanolysis of similar cyclic anhydrides has also been
reported by Chen and co-workers.6 We recently described
enantioselective thiolysis of s-symmetric dicarboxylic
anhydrides with benzyl mercaptan utilizing a catalytic
amount of chiral bifunctional sulfonamide 1 as an organo-
catalyst mimicking the organization of functional groups
at the active site of the cysteine protease.7 Here, we ex-
plore the enantioselective alcoholysis of s-symmetric di-
carboxylic anhydrides with benzyl alcohol, utilizing
chiral sulfonamide 1 as an organocatalyst. The reaction is
based on the hydrolysis of amide bonds catalyzed by
serine proteases such as a-chymotrypsin (Figure 1).8
Table 1 Enantioselective Alcoholysis of Cyclic Dicarboxylic An-
hydride 2a Catalyzed by Chiral Sulfonamide 1
O
BnOH (1.2 equiv)
H
CO2Bn
CO2H
1 (5 mol%)
Ph
O
solvent
r.t., 20 h
Ph
O
2a
(S)-3a
H
CO2Bn
TMSCHN2 (2 equiv)
benzene–MeOH
r.t., 15 min
Ph
CO2Me
(S)-4a
F3C
SO2
HN
Ph
Ph
F3C
Me2N
1
N
Gly
193
R2
HN
H
Entry
Solvent
Et2O
Yield (%)a
ee (%)b
O
C
O
O
H
1
2
3
4
5
92
50
53
8
87
77
83
89
81
R1
O
Asp
102
H
N
N
N
H
CH2Cl2
MeCN
THF
Ser
195
His
57
Figure 1 Hydrolysis of amide bonds catalyzed by a-chymotrypsin
PhMe
87
a Isolated yield of 4a.
b Determined by HPLC analysis (Chiralpak AD-H, n-hexane–2-
PrOH).
SYNLETT 2009, No. 20, pp 3279–3282
Advanced online publication: 18.11.2009
x
x
.x
x
.2
0
0
9
DOI: 10.1055/s-0029-1218374; Art ID: U09109ST
© Georg Thieme Verlag Stuttgart · New York

3280
T. Honjo et al.
LETTER
Once the optimized conditions for the alcoholysis of an- selectivities (97–98% ee). Thus far, tricyclic anhydrides
hydride 2a were established, we evaluated a wide range of 2g,h are not accessible through enzymatic hydrolysis be-
cyclic anhydrides to determine the scope of the reaction. cause of their steric bulkiness.10 In particular, it is notable
The results are summarized in Table 2. Monocyclic dicar- that the enantioselectivity in alcoholysis (98% ee) is supe-
boxylic anhydrides 2a–c enantioselectively provided the rior to that in thiolysis (83% ee) of 2e employing catalyst
corresponding methyl esters 4a–c in acceptable yields 1. The absolute configuration of methyl esters 4a–h was
(86–92%). In addition, the alcoholysis of bicyclic and tri- determined by their chemical conversion into the known
cyclic dicarboxylic anhydrides 2d–h afforded methyl chiral compounds.11
esters 4d–h in satisfactory yields (89–99%) and enantio-
Table 2 Enantioselective Alcoholysis of Cyclic Dicarboxylic Anhydrides 2a–h Catalyzed by Chiral Sulfonamide 1
O
BnOH (1.2–5 equiv)
TMSCHN2
(2 equiv)
CO2Bn
CO2Bn
CO2H
1 (5 mol%)
O
R*
R
R*
Et2O
r.t., 20 h
benzene–MeOH
r.t., 15 min
CO2Me
O
2a–h
4a–h
Entry
Anhydride
BnOH (equiv)
Product
Yield (%)a
ee (%)b
87
O
CO2Bn
CO2Me
H
Ph
O
1
1.2
92
Ph
O
(S)-4a
2a
O
O
CO2Bn
CO2Me
H
2
5
86
80
90
95
99
91
83
O
(S)-4b
2b
O
O
CO2Bn
CO2Me
H
91c
98c
98
TBDMSO
2c
3
5
TBDMSO
O
(S)-4c
O
O
CO2Bn
4
3
CO2Me
O
(1S,3R)-4d
2d
2e
2f
O
CO2Me
O
5
5
CO2Bn
O
O
(1S,2R)-4e
CO2Me
CO2Bn
O
6
5
5
97
O
O
(1S,2R)-4f
CO2Bn
7d
98c
O
CO2Me
O
(1R,2S,3R,4S)-4g
2g
Synlett 2009, No. 20, 3279–3282 © Thieme Stuttgart · New York

LETTER
Alcoholysis of s-Symmetric Cyclic Dicarboxylic Anhydrides
3281
Table 2 Enantioselective Alcoholysis of Cyclic Dicarboxylic Anhydrides 2a–h Catalyzed by Chiral Sulfonamide 1 (continued)
O
BnOH (1.2–5 equiv)
TMSCHN2
(2 equiv)
CO2Bn
CO2Bn
CO2H
1 (5 mol%)
O
R*
R
R*
Et2O
r.t., 20 h
benzene–MeOH
r.t., 15 min
CO2Me
O
2a–h
4a–h
Entry
Anhydride
BnOH (equiv)
Product
Yield (%)a
89
ee (%)b
97
O
CO2Me
CO2Bn
O
O
O
8
5
O
(1S,2R,3S,4R)-4h
2h
a Isolated yields of 4a–h.
b Determined by HPLC analysis.
c Determined by HPLC analysis after conversion to a known compound.
d 10 mol% of 1 was used.
Finally, we used cold-spray ionization mass spectrometry References and Notes
(CSI-MS)12 to analyze a 1:1 mixture of organocatalyst 1
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281. (d) Sureshkumar, M.; Lee, C.-K. J. Mol. Catal. B:
Enzym. 2009, 60, 1.
(2) For recent reviews on organocatalysts, see: (a) Ooi, T.;
Maruoka, K. Acc. Chem. Res. 2004, 37, 526. (b) Tian,
S.-K.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L.
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(0.1 mM) and anhydride 2a (0.1 mM) in THF at a spray
temperature of –20 °C. The resulting CSI-MS spectrum
showed a prominent ion peak corresponding to a 1:1 com-
plex of organocatalyst 1 and anhydride 2a at m/z =
706.4.11 Thus, the dual activation of anhydride 2a and
benzyl alcohol by organocatalyst 1 may have been a cause
of the enantioselective alcoholysis, similar to the hydro-
lysis of serine protease (Figure 2).13
O
Ph
O
2a
O
O
CF3
H
H
(j) McGarrigle, E. M.; Myers, E. L.; Illa, O.; Shaw, M. A.;
Riches, S. L.; Aggarwal, V. K. Chem. Rev. 2007, 107, 5841.
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S.; Nolan, S. P. Angew. Chem. Int. Ed. 2007, 46, 2988.
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Nature (London) 2008, 455, 304. (p) Barbas, C. F. III
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Me2N
N
S
CF3
O2
Ph
Ph
1
Figure 2 Plausible dual activation manner of anhydride 2a and benzyl
alcohol by organocatalyst 1
In summary, chiral bifunctional sulfonamide 1 has been
shown to promote highly efficient desymmetrization of
s-symmetric cyclic dicarboxylic anhydrides 2a–h with
benzyl alcohol. Further studies are under way to investi-
gate the stereodifferentiating mechanism of the reaction.
(3) For reviews on desymmetrization of cyclic anhydrides, see:
(a) Spivey, A. C.; Andrews, B. I. Angew. Chem. Int. Ed.
2001, 40, 3131. (b) Chen, Y.; McDaid, P.; Deng, L. Chem.
Rev. 2003, 103, 2965. (c) Atodiresei, I.; Schiffers, I.; Bolm,
C. Chem. Rev. 2007, 107, 5683.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(4) (a) Rho, H. S.; Oh, S. H.; Lee, J. W.; Lee, J. Y.; Chin, J.;
Song, C. E. Chem. Commun. 2008, 1208. (b) Oh, S. H.;
Rho, H. S.; Lee, J. W.; Lee, J. E.; Youk, S. H.; Chin, J.; Song,
C. E. Angew. Chem. Int. Ed. 2008, 47, 7872.
(5) Peschiulli, A.; Gun’ko, Y.; Connon, S. J. J. Org. Chem.
2008, 73, 2454.
Synlett 2009, No. 20, 3279–3282 © Thieme Stuttgart · New York

3282
T. Honjo et al.
LETTER
(6) Wang, S.-X.; Chen, F.-E. Adv. Synth. Catal. 2009, 351, 547.
(7) Honjo, T.; Sano, S.; Shiro, M.; Nagao, Y. Angew. Chem. Int.
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(8) (a) Henderson, R. J. Mol. Biol. 1970, 54, 341. (b) Perona,
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(e) Malthouse, J. P. G. Biochem. Soc. Trans. 2007, 35, 566.
(9) General Experimental Procedure for Chiral
Sulfonamide 1 Catalyzed Alcoholysis of Cyclic
The ee (%) of (S)-4a was determined on a Chiralpak AD-H
column [Daicel, eluent: n-hexane–2-PrOH (15:1), flow rate:
1 mL/min, detection: 254 nm]. The retention times were 12.5
min [minor isomer, (R)-4a] and 13.8 min [major isomer, (S)-
4a], respectively. The absolute configuration of (S)-4a was
explicitly determined by its chemical conversion to thioester
(S)-5 (Scheme 1).7
10% Pd/C (5 mol%)
H
CO2Bn
H2
Ph
EtOH
CO2Me
r.t., 1.5 h
Dicarboxylic Anhydrides
(S)-4a
87% ee
To a solution of 3-phenylglutaric anhydride (2a, 190 mg, 1.0
mmol) and chiral sulfonamide 1 (25.8 mg, 0.05 mmol) in
Et2O (10 mL) was added BnOH (125 mL, 1.2 mmol) at r.t.
After stirring at r.t. for 20 h, the reaction mixture was treated
with 10% HCl followed by extraction with CHCl3. The
extract was dried over anhyd MgSO4, filtered, and
concentrated in vacuo. To a solution of the residue in
benzene–MeOH (7:2, 9 mL) was added a solution of
TMSCHN2 (2.0 M in Et2O, 1 mL, 2.0 mmol). After being
stirred at r.t. for 15 min, the reaction mixture was evaporated
in vacuo. The oily residue was purified by silica gel column
chromatography [EtOAc–n-hexane (1:4)] to afford methyl
ester (S)-4a (286 mg, 92% yield, 87% ee) as a colorless oil.
EDC⋅HCl (1.5 equiv)
DMAP (0.3 equiv)
BnSH (1.1 equiv)
H
COSBn
CH2Cl2
r.t., 2 h
Ph
(S)-5
CO2Me
82%, 87% ee
Scheme1
(10) Zhu, L.-M.; Tedford, M. C. Tetrahedron 1990, 46, 6587.
(11) For details see Supporting Information.
(12) Yamaguchi, K. J. Mass Spectrom. 2003, 38, 473.
(13) Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516.
Synlett 2009, No. 20, 3279–3282 © Thieme Stuttgart · New York

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