Inversion of enantioselectivity in quinine-mediated desymmetrization of glutaric meso-anhydrides

Article abstract of DOI:10.1016/j.tetasy.2009.02.049

An unexpected inversion of enantioselectivity, dependent on the degree of quinine loading, was observed during the desymmetrization of glutaric meso-anhydrides. Decrease in catalyst loading from 1.6 equiv to 0.1 equiv caused a clear inversion of stereoche

Full text of DOI:10.1016/j.tetasy.2009.02.049

Tetrahedron: Asymmetry 20 (2009) 1095–1098
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Inversion of enantioselectivity in quinine-mediated desymmetrization
of glutaric meso-anhydrides
*
´
Trpimir Ivšic, Zdenko Hameršak
´
Department of Organic Chemistry and Biochemistry, Rudjer Boškovic Institute, PO Box 180, 10002 Zagreb, Croatia
a r t i c l e i n f o
a b s t r a c t
Article history:
An unexpected inversion of enantioselectivity, dependent on the degree of quinine loading, was observed
during the desymmetrization of glutaric meso-anhydrides. Decrease in catalyst loading from 1.6 equiv to
0.1 equiv caused a clear inversion of stereochemistry—from about 40% ee of (R)-configuration to about
40% ee of the opposite enantiomer. The effect of various carboxylic acid additives was also studied.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 13 February 2009
Accepted 26 February 2009
Available online 22 April 2009
1. Introduction
dependent on the catalyst loading. Herein, we elaborate upon
those results.
Desymmetrization of meso compounds has proven to be a valu-
able approach in the synthesis of chiral compounds.1 The first cat-
alytic ring-opening of cyclic anhydrides was reported by Oda2 and
shortly thereafter by Aitken;3 methanol was used as a nucleophile
in the presence of 10 mol % of a cinchona alkaloid. Oda examined
the opening of glutaric and succinic anhydrides and observed that
stereochemistry and enantioselectivity are highly dependent on a
specific substrate/alkaloid combination. Aitken noticed that, in
the case of complex epoxy-anhydride, an increase in the catalyst
loading from 10 to 50 mol % increases the enantioselectivity from
38% to 76%. Finally, Bolm and co-workers developed a highly enan-
tioselective protocol for the desymmetrization of meso-anhydrides
2. Results and discussion
When we initiated the synthesis of pregabalin 3 there were only
a few reported enantioselective catalytic desymmetrizations of 3-
substituted glutaric anhydrides. Seebach9 reported opening of
anhydride 6 catalyzed with Ti-TADDOLate with 50% ee, Oda2 re-
ported the opening of 4 and 5 with natural cinchona alkaloids with
5–33% ee, and Deng6 of 4 and 6 in combination with modified cin-
chona alkaloids with 82–91% ee. Moreover, to achieve 82–83% ee of
products possessing an (R)-configuration, 0.3 equiv of bulky,
expensive (DHQ)2AQN was required. Therefore, although this was
not verified on glutaric anhydrides, we decided to apply Bolm’s
methodology.4 Preliminary experiments revealed that hemi-ester
2 with an (R)-configuration could be obtained using stoichiometric
quantities of quinine, benzyl or cinnamyl alcohols as nucleophiles
at À25 °C with 65–70% ee. (Scheme 1). However, Oda reported the
(S)-configuration in the quinine-mediated opening of 4 and 5 with
low enantioselectivity (7%). We initially assigned the discrepancy
in stereochemistry to high nucleophile loading (MeOH, 10 equiv)
and reaction conditions (room temperature). From Oda’s, Aitken’s
and Bolm’s studies on succinic anhydrides it can be concluded that
a free alkaloid base is responsible for the stereoselection, whilst
protonated base (product–base complex), still catalytically active,
produces mainly racemates. Indeed, when cis-1,2-cyclohexane
dicarboxylic acid anhydride 7 was subjected to a quinine-mediated
desymmetrization with benzyl alcohol, the enantioselectivity
dropped from 75% to 3% ee when the catalyst loading was reduced
from 1.6 equiv to 0.1 equiv (Fig. 1).
promoted by a stoichiometric amount of quinine or quinidine.4
A
variety of succinic anhydrides were tested and it was observed,
without exception, that quinine catalyzes nucleophilic attack of
the pro-(R) carbonyl group while quinidine always exhibited the
opposite selectivity.5 In parallel, Deng developed an excellent
method based on a catalytic amount of commercially available
modified cinchona alkaloid.6 Very recently, a new generation of
cinchona-based thiourea catalysts have been developed.7 However,
while modified cinchona catalysts provide outstanding results
with succinic anhydrides, the same catalyst loading gives inferior
results when applied to glutaric anhydrides,6 which are more
demanding substrates. Thus, in the case of glutaric anhydrides,
especially when larger quantities of products are needed, the use
of a stoichiometric quantity of easily available, inexpensive and
recoverable unmodified alkaloid is still the best choice. During
our recent work on pregabalin synthesis8 where quinine-mediated
ring-opening of 3-isobutylglutaric anhydride was the key step, we
noticed an unexpected inversion of enantioselectivity, which was
In contrast, 3-substituted glutaric anhydrides showed a differ-
ent behaviour (Fig. 2). Decreasing the quinine loading caused a
clear inversion of stereochemistry—from about 40% ee of (R)-con-
figuration to about 40% ee of the opposite one. As we reported ear-
* Corresponding author. Tel.: +385 1 4571 300; fax +385 1 4680108.
E-mail address: hamer@irb.hr (Z. Hameršak).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.049

´
T. Ivšic, Z. Hameršak / Tetrahedron: Asymmetry 20 (2009) 1095–1098
1096
RO
O
O
O
quinine, toluene
ROH
OH
O
OH
O
3
2
(R)-
H2N
1
O
Ph
O
O
O
O
O
O
O
O
O
O
O
O
7
6
4
5
Scheme 1.
Figure 2. Influence of quinine loading on the desymmetrization of 3-substituted
glutaric anhydrides 1 and 5. Conditions: constant anhydride concentration (100 mg
scale, 0.05 M in toluene), 0.1–1.6 equiv of quinine, 1.5 equiv of benzyl alcohol, rt,
20 h.
Figure 1. Influence of quinine loading on the desymmetrization of cis-1,2-cyclo-
hexane dicarboxylic acid anhydride 7. Conditions: constant anhydride concentra-
tion (100 mg scale, 0.05 M in toluene), 0.1–1.6 equiv of quinine, 1.5 equiv of benzyl
alcohol, rt, 20 h.
lier,8 the enantioselectivity of the reaction can significantly be im-
proved upon by lowering the reaction temperature when the alka-
loid is employed in stoichiometric quantities. In the case of low
1,2-dicarboxylic acid monomethyl ester 11, a product of anhydride
7 opening, has the same effect on enantioselectivity as acetic acid
12.
In addition, the influence of aromatic acids as additives was also
studied (Table 2). Although the influence of the pKa is observed
(acids 26 and 27) their structure seems to be of greater importance.
The best enantioselectivities were achieved with acids 24, 25, 33,
34 and 36 possessing a phenylacetic acid substructure and also
with 2-thiophene-acetic acid 35, which can be considered as phen-
catalyst loading, lowering the temperature causes
a minor
improvement in enantioselectivity, but a drastic reduction in the
reaction rate. To verify whether a specific product–base complex
or the geometry of anhydride itself was responsible for the inver-
sion of stereochemistry, various aliphatic acids were tested as
additives in the opening of 1 (Scheme 2). The results, summarized
in Table 1, clearly show that the pKa of the acid has a major influ-
ence on the stereoselectivity of the reaction, while the influence of
the acid structure is almost negligible. For example, cyclohexane-
ylacetic acid congener. Obviously,
p–p interactions between the
aromatic ring of the acid additive and the quinoline moiety can
additionally stabilize the catalyst conformation in a manner
O
BnO
O
quinine (0.5 eq), acid (1 eq)
O
BnOH (1.5 eq), toluene, RT
O
OH
(S)-2
1, 0.1 M sol
O
Scheme 2.

´
1097
T. Ivšic, Z. Hameršak / Tetrahedron: Asymmetry 20 (2009) 1095–1098
Table 1
Influence of aliphatic acid additive on the desymmetrization of 3-isobutylglutaric anhydride 1
10
10
Acid
pKa
eea (%)
Acid
pKa
eea (%)
42
F
3C
8
0.52
Rac
14
15
16
CH3(CH2)6COOH
4.89
COOH
9
2.45
3.75
27
29
CH3(CH2)10COOH
43
43
NC
COOH
10
HCOOH
4.84
4.90
COOH
COOH
COOCH3
COOH
11
12
13
35
36
40
17
18
19
45
45
47
H3C
4.76
COOH
COOH
COOH
COOH
COOCH3
5.03
a
Determined by chiral HPLC on Chiralcel AS (EtOH/hexane/TFA = 2/98/0.1).
Table 2
Influence of aromatic acid additive on the desymmetrization of 3-isobutylglutaric anhydride (1)
eea (%)
Acid
pKa
eea (%)
10
10
Acid
pKa
COOH
COOH
COOH
20
21
22
23
4.19
47
29
30
31
32
4.5
42
H3CO
COOH
CH3
3.70
4.17
37
38
15
3.91
45
45
50
COOH
COOH
H3C
COOH
COOH
COOH
4.38
4.31
COOH
24
25
63
53
33
34
54
O
COOH
COOH
48
(continued on next page)

´
1098
T. Ivšic, Z. Hameršak / Tetrahedron: Asymmetry 20 (2009) 1095–1098
Table 2 (continued)
10
10
Acid
pKa
eea (%)
21
Acid
pKa
eea (%)
55
COOH
NO2
S
COOH
COOH
26
27
28
2.16
35
36
37
COOH
3.41
4.08
17
36
4.07
4.44
50
45
O2N
Cl
COOH
OCH3
COOH
a
Determined by chiral HPLC on Chiralcel AS (EtOH/hexane/TFA = 2/98/0.1).
dependent upon the steric interactions of acid and base in the com-
plex. The inversion of enantioselectivity caused by carboxylic acid
additives was also observed in Pd- or Pt-cinchona-catalyzed hydro-
genations and was explained by a change in the reaction mecha-
nism.11 Hydrogen-bonding interactions and the conformational
behaviour of cinchonidine were studied both theoretically and
experimentally (NMR).12 It was found that the population density
of the Open(3) conformer, which is already the most populated
one at room temperature in apolar solvents, was significantly in-
creased by the addition of 2-methyl-2-hexenoic acid. However,
this observation cannot explain the inversion of enantioselectivity
in the desymmetrization of 3-substituted glutaric anhydrides,
which obviously also involves a switch of reaction mechanism.
On the other hand, neither of the two proposed possible mecha-
nisms of amine-catalyzed alcoholytic opening of meso cyclic anhy-
drides, general base catalysis or nucleophilic catalysis,13 can give a
full explanation; anhydride shape should also be taken into
account.
Acknowledgement
We thank the Ministry of Science, Education and Sports of the
Republic of Croatia for financial support (Grant No. 098-
0982933-2908).
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The observed inversion of enantioselectivity in the quinine-
mediated desymmetrization of 3-substituted glutaric meso-anhy-
drides, in a manner dependent on catalyst loading, seems to be
specific to these anhydrides. The study of carboxylic acid additives
revealed that enantioselectivity can be increased to >60% ee of (S)-
product—a level which might be of synthetic interest. This finding
may also contribute to a better understanding of the mechanism of
the cinchona-catalyzed desymmetrizations of cyclic anhydrides.
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