Practical and Highly Enantioselective Ring Opening of Cyclic Meso-Anhydrides Mediated by Cinchona Alkaloids

Article abstract of DOI:10.1021/jo000638t

The cinchona alkaloid-mediated opening of prochiral cyclic anhydrides in the presence of methanol leading to optically active hemiesters is described. Very structurally diverse anhydrides are converted into their corresponding methyl monoesters, and either enantiomer can be obtained with up to 99% ee by using quinine or quinidine as directing additive. After the reaction, the alkaloids can be recovered almost quantitatively and reused without loss of enantioselectivity. Additionally, a catalytic protocol which permits the substoichiometric use of quinidine in the presence of easily accessible pentamethylpiperidine (pempidine) is presented.

Full text of DOI:10.1021/jo000638t

6984
J . Org. Chem. 2000, 65, 6984-6991
P r a ctica l a n d High ly En a n tioselective Rin g Op en in g of Cyclic
Meso-An h yd r id es Med ia ted by Cin ch on a Alk a loid s
Carsten Bolm,* Ingo Schiffers, Christian L. Dinter, and Arne Gerlach
Institut fu¨r Organische Chemie der RWTH Aachen, Prof.-Pirlet-Strasse 1, D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received April 25, 2000
The cinchona alkaloid-mediated opening of prochiral cyclic anhydrides in the presence of methanol
leading to optically active hemiesters is described. Very structurally diverse anhydrides are
converted into their corresponding methyl monoesters, and either enantiomer can be obtained with
up to 99% ee by using quinine or quinidine as directing additive. After the reaction, the alkaloids
can be recovered almost quantitatively and reused without loss of enantioselectivity. Additionally,
a catalytic protocol which permits the substoichiometric use of quinidine in the presence of easily
accessible pentamethylpiperidine (pempidine) is presented.
Sch em e 1
In tr od u ction
Desymmetrization of meso-compounds is an efficient
strategy in asymmetric synthesis, because it allows to
control the generation of multiple stereogenic centers in
a single step.1 For example, starting from symmetrically
substituted diesters or anhydrides, desymmetrization
with the help of enzymes2 or chiral reagents provides
dicarboxylic acid monoesters3 which are easily trans-
ferred to other versatile chiral building blocks for numer-
ous synthetic applications (Scheme 1).4
The enantioselectivity in enzyme-catalyzed hydrolyses
is often very high, even on a 100-mol scale in some cases,
and for example with pig liver esterase several hundred
successful transformations have been described in the
literature as yet.2d,e A disadvantage of this enzymatic
approach is that most of the time only one enantiomer
of the product can be obtained directly. In contrast,
anhydride openings with chiral nucleophiles are usually
not limited by this restriction, because often both enan-
tiomers of the chiral reagent are available and thus
several methods for the preparation of diastereomerically
and enantiomerically enriched monoesters or monoam-
ides have been reported.5 Nevertheless, practical proce-
dures are still quite rare and often limited to only a few
examples. Unlike methods which give ring-opened prod-
ucts with covalently linked chiral auxiliaries,1,5 the
Seebach system, using a slight excess of diisopropoxyti-
tanium-TADDOLates, delivers directly enantiomerically
enriched isopropyl monoesters of bi- and tricyclic anhy-
drides with uniformly high ee and yield.6 This concept of
an alkoxide transfer from the chiral ligand sphere to the
Lewis acid-activated substrate7 permitted even the de-
(4) Recent examples: (a) Tamura, N.; Kawano, Y.; Matsushita, Y.;
Yoshioka, K.; Ochiai, M. Tetrahedron Lett. 1986, 27, 3749. (b) Ohtani,
M.; Matsuura, T.; Watanabe, F.; Narisada, M. J . Org. Chem. 1991,
56, 2122. (c) Watanabe, F.; Matsuura, T.; Shirahase, K.; Ohtani, M.
Chem. Pharm. Bull. 1991, 39, 2842. (d) Brion, F.; Marie, C.; Mack-
iewicz, P.; Roul, J . M.; Buendia, J . Tetrahedron Lett. 1992, 33, 4889.
(e) Houpis, I. N.; Molina, A.; Reamer, R. A.; Lynch, J . E.; Volante, R.
P.; Reider, P. J . Tetrahedron Lett. 1993, 34, 2593. (f) Norman, M. H.;
Rigdon, G. C.; Navas, F., III; Cooper, B. R. J . Med. Chem. 1994, 37,
2552. (g) Ghosh, A. K.; Lee, H. Y.; Wayne, J . T.; Culberson, C.;
Holloway, M. K.; McKee, S. P.; Munson, P. M.; Duong, T. T.; Smith,
A. M.; Darke, P. L.; Zugay, J . A.; Emini, E. A.; Schleif, W. A.; Haff, J .
R.; Anderson, P. S. J . Med. Chem. 1994, 37, 1178. (h) Borzilleri, R.
M.; Weinreb, S. M. J . Am. Chem. Soc. 1994, 116, 9789. (i) Konoike, T.;
Araki, Y. J . Org. Chem. 1994, 59, 7849. (j) Harmat, N. J . S.; Di Bugno,
C.; Criscuoli, M.; Giorgi, R.; Lippi, A.; Martinelli, A.; Monti, S.; Subissi,
A. Bioorg. Med. Chem. Lett. 1998, 8, 1249. (k) Dube´, D.; Blonin, M.;
Brideau, C.; Chan, C.-C.; Desmarais, S.; Ethier, D.; Falgueyret, J .-P.;
Friesen, R. W.; Girard, M.; Girard, Y.; Guay, J .; Riendeau, D.; Tagari,
P.; Young, R. N. Bioorg. Med. Chem. Lett. 1998, 8, 1255. (l) Mart´ın-
Vila`, M.; Minguillo´n, C.; Ortun˜o, R. M. Tetrahedron: Asymmetry 1998,
9, 4291. (m) Couche´, E.; Deschatrettes, R.; Poumellec, K.; Bortolussi,
M.; Mandville, G.; Bloch, R. Synlett 1999, 87. (n) J ones, I. G.; J ones,
W.; North, M. Tetrahedron 1999, 55, 279.
(5) (a) Kawakami, Y.; Hiratake, J .; Yamamoto, Y.; Oda, J . J . Chem.
Soc., Chem. Commun. 1984, 779. (b) Rosen, T.; Heathcock, C. H.; J .
Am. Chem. Soc. 1985, 107, 3731. (c) Theisen, P. D.; Heathcock, C. H.
J . Org. Chem. 1993, 58, 142. (d) Ohntani, M.; Matsuura, T.; Watanabe,
F.; Narisada, M. J . Org. Chem. 1991, 56, 4120. (e) Suda, Y.; Yago, S.;
Shiro, M.; Taguchi, T. Chem. Lett. 1992, 389. (f) Imado, H.; Ishizuka,
T.; Kunieda, T. Tetrahedron Lett. 1995, 36, 931. (g) Albers, T.; Biagini,
S. C. G.; Hibbs, D. E.; Hursthouse, M. B.; Malik, K. M. A.; North, M.;
Uriarte, E.; Zagotto, G. Synthesis 1996, 393. (h) J ones, I. G.; J ones,
W.; North, M. Synlett 1997, 63. (i) Hibbs, D. E.; Hursthouse, M.; J ones,
I. G.; J ones, W.; Malik, K. M. A.; North, M. J . Org. Chem. 1998, 63,
1496.
* To whom correspondence should be addressed. Fax: (Int.) +49
241 8888 391. Phone: (Int.) +49 241 80 4675.
(1) Recent review: Willis, M. C. J . Chem. Soc., Perkin Trans. 1 1999,
175.
(2) Reviews: (a) Ohno, M.; Otsuka, M. Org. React. 1989, 37, 1. (b)
Danieli, B.; Lesma, G.; Passarella, D.; Riva, S. In Advances in the Use
of Synthons in Organic Chemistry; Dondoni, A., Ed.; J AI Press:
London, 1993; Vol. 1, pp 143-219. (c) Wong, C.-H.; Whitesides, G. M.
In Enzymes in Synthetic Organic Chemistry; Baldwin, J . E., Magnus,
P. D., Ed.; Elsevier Science Ltd: Oxford; 1994; Vol. 12, pp 41-130. (d)
Gais, H.-J . In Enzyme Catalysis in Organic Synthesis; Drauz, K.,
Waldmann, H., Ed.; VCH: Weinheim; 1995; Vol. 1; pp 165-261. (e)
Procter, G. Asymmetric Synthesis; Oxford University Press: Oxford;
1996; p 215. (f) Gais, H.-J .; Lukas, K. L. In Biocatalysts for Fine
Chemicals Synthesis; Roberts, S. M., Ed.; Wiley: Chichester, 1999;
Chapter 1:1.1. (g) Bornscheuer, U. T.; Kazlauskas, R. J . Hydrolases in
Organic Synthesis - Regio- and Stereoselective Biotransformations;
Wiley-VCH: Weinheim, 1999.
(3) Recent examples: (a) Ward, R. S.; Pelter, A.; Edwards, M. I.;
Gilmore, J . Tetrahedron Asymmetry 1995, 6, 843. (b) Hashimoto, K.;
Kitaguchi, J .; Mizuno, Y.; Kobayashi, T.; Shirahama, H. Tetrahedron
Lett. 1996, 37, 2275. (c) Kraft, P.; Cadalbert, R. Synthesis 1998, 1662.
10.1021/jo000638t CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/27/2000

Ring Opening of Cyclic Meso-Anhydrides
J . Org. Chem., Vol. 65, No. 21, 2000 6985
Sch em e 2
velopment of a catalytic version though on the expense
of longer reaction times.6c
In the late 1980s, Aitken8 and Oda9 independently
reported on a particularly interesting metal-free asym-
metric anhydride opening utilizing readily available
alkaloids as catalysts. Here, we now describe an improve-
ment of the existing procedure and the development of a
simple and highly enantioselective methanolysis of cyclic
meso-anhydrides giving a broad variety of hemiesters
with up to 99% ee. Inexpensive and quantitatively
recoverable cinchona alkaloids serve as directing addi-
tives and methanol as nucleophile.10 In addition, we
found a new catalytic version of this process, using 10
mol % of alkaloid in the presence of stoichiometric
amounts of a sterically hindered achiral base.
Ta ble 1. In flu en ce of th e Solven t on th e
Qu in id in e-Med ia ted Op en in g of An h yd r id e 1a
entry
solvent
acetone
polarity (ꢀr)b ee (%)c yield of 2 (%)
1
2
3
4
5
6
7
8
9
20.56
49
72
75
79
78
72
80
83
86
61
83
73
79
87
83
82
78
85
77
84
76
83
THF
7.58
4.20
diethyl ether
di-n-butyl ether
toluene
mesitylene
p-xylene
benzene
CCl4
n-pentane
toluene/CCl4
3.08 (20 °C)
2.38
2.30
Resu lts a n d Discu ssion
2.27 (20 °C)
2.27
Rin g-Op en in g Rea ction Usin g a Stoich iom etr ic
Am ou n t of Cin ch on a Alk a loid . Beside ephedrine and
other chiral amino alcohols, cinchona alkaloids have
commonly been used for the resolution of racemic dicar-
boxylic acid monoesters through their corresponding
ammonium salts.11 It was as early as 1929 when use of
quinine led to the isolation of the (-)-monomethyl ester
of cis-cyclohexane dicarboxylic acid.12 On the basis of
these observations and given the findings of Aitken8 and
Oda,9 we decided to test a variety of chiral amines on
their ability to catalyze asymmetric anhydride openings
in order to develop a highly practical route to products
with uniformly high enantiomeric excesses.13 First, the
effect of the amine structure and the type of nucleophile
on the enantioselectivity was investigated. Using anhy-
dride 1 as model substrate and performing the reactions
in toluene at ambient temperature, the best results were
obtained with combinations of commercially available
quinidine as chiral additive (1.1 equiv) and methanol as
nucleophile (78% ee). Increasing the alkaloid amount did
not lead to an improvement of enantioselectivity. Use of
derivatives of quinidine with protected hydroxyl or modi-
2.23
10
11
1.84 (20 °C)
-
a
All reactions were performed at ambient temperature for 24
h using 1.1 equiv of quinidine and 3.0 equiv of methanol in a 0.05
M solution relative to anhydride. b Relative permittivity (dielectric
constant)14 for the pure liquid at 25 °C (other temperatures are
given in parentheses). c Determined by HPLC-analysis of the
corresponding p-bromophenyl methyl diester.
fied vinyl groups gave lower asymmetric induction. Both
sterically more hindered alcohols such as ethanol or
2-propanol as well as thiols and primary or secondary
amines resulted in decreased reaction rates and lower
enantioselectivities.
To optimize the reaction outlined in Scheme 2 further,
the influence of the solvent and its polarity on the
enantioselectivity was investigated. The most represen-
tative results are summarized in Table 1.
In solvents of low polarity the highest enantioselec-
tivities were observed (Table 1). As an exception, n-
pentane deviated clearly and led to a decreased selectivity
(entry 10). The best asymmetric inductions were achieved
when the desymmetrizations were performed in benzene
or tetrachloromethane (entries 8 and 9). However, due
to the relatively high melting points of these solvents,
they were unsuitable for reactions at lower temperature.
Therefore, further studies were performed in a solvent
system consisting of toluene and CCl4 in a 1:1-ratio,
which also afforded the product with high enantiomeric
excess (entry 11). In reactions at -55 °C a considerable
increase in enantioselectivity was observed, which un-
fortunately was accompanied by longer reaction times
(from 24 to 60 h). Finally, under optimized conditions use
of 1.1 equiv of quinidine in toluene/CCl4 (0.2 M with
respect to the anhydride) at -55 °C led to the formation
of methyl monoester 2 with 99% ee in excellent yield.
Diastereomeric quinine, which can be considered as
pseudo-enantiomer of quinidine, generated ent-2 with the
same enantiomeric excess. In this case, the reaction
mixture had to be more dilute due to solubility reasons
(0.05 M with respect to the anhydride). Besides the
excellent enantioselectivity in the formation of either
enantiomer of 2, the ease of workup is noteworthy. After
completion of the methanolysis, simple acidic extraction
of the reaction mixture afforded the product in pure form
and no additional purification of the methyl monoester
by chromatography or recrystallization was required. The
cinchona alkaloids were easily recovered almost quanti-
(6) (a) Seebach, D.; J aeschke, G.; Wang, Y. M. Angew. Chem. 1995,
107, 2605; Angew. Chem., Int. Ed. Engl. 1995, 34, 2395. (b) Seebach,
D.; J aeschke, G.; Gottwald, K.; Matsuda, K.; Formisano, R.; Chaplin,
D. A. Tetrahedron 1997, 53, 7539. (c) J aeschke, G.; Seebach, D. J . Org.
Chem. 1998, 63, 1190.
(7) (a) Narasaka, K.; Kanai, F.; Okudo, M.; Miyoshi, N. Chem. Lett.
1989, 1187. (b) For the use of mixtures of amino alcohols, ZnEt2, and
ROH in asymmetric anhydride openings (giving moderate yields and
17-91% ee), see: Shimizu, M.; Matsukawa, K.; Fujisawa, T. Bull.
Chem. Soc. J pn. 1993, 66, 2128.
(8) (a) Aitken, R. A.; Gopal, J . Tetrahedron: Asymmetry 1990, 1,
517. (b) Aitken, R. A.; Gopal, J .; Hirst, J . A. J . Chem Soc., Chem.
Commun. 1988, 632.
(9) (a) Hiratake, J .; Inagaki, M.; Yamamoto, Y.; Oda, J . J . Chem.
Soc., Perkin Trans. 1 1987, 1053. (b) Hiratake, J .; Yamamoto, Y.; Oda,
J . J . Chem. Soc., Chem. Commun. 1985, 1717.
(10) (a) For early results, see: Bolm, C.; Gerlach, A.; Dinter, C. L.
Synlett 1999, 195. (b) For a first application of this improved protocol
in synthesis, see: Bernardi, A.; Arosio, D.; Dellavecchia, D.; Micheli,
F. Tetrahedron: Asymmetry 1999, 10, 3403.
(11) (a) Tamura, N.; Kawano, Y.; Matsushita, Y.; Yoshioka, K.;
Ochiai, M. Tetrahedron Lett. 1986, 27, 3749. (b) Polonski, T.; Milewska,
M. J .; Gdaniec, M.; Gilski, M. J . Org. Chem. 1993, 58, 3134. (c)
Milewska, M. J .; Gdaniec, M.; Polonski, T. Tetrahedron: Asymmetry
1996, 7, 3169.
(12) Vavon, M. M.; Peignier, P. Bull. Soc. Chim. Fr. 1929, 45, 293.
(13) Alkaloid-mediated asymmetric anhydride openings on a larger
scale have been employed for the synthesis of cyclopentane-â-amino
acids. With a protocol involving a precipitation of the acid/alkaloid salt,
excellent enantioselectivies have been achieved. (a) Mittendorf, J .;
Arold, H.; Fey, P.; Matzke, M.; Militzer, H.-C.; Mohrs, K.-H. Patent
DE 44 00 749 A1, 1994. (b) Mittendorf, J . Patent EP 0 805 145 A1,
1997.

6986 J . Org. Chem., Vol. 65, No. 21, 2000
Bolm et al.
Ta ble 2. Qu in id in e- a n d Qu in in e-Med ia ted Meth a n olysis
Ta ble 3. Qu in id in e-Med ia ted Op en in g of
Meso-An h yd r id es in Tolu en e a s Solven ta
of Va r iou s Meso-a n h yd r id esa
quinidine-mediated
quinine-mediated
entry
anhydride
ester
ee (%)b
yield, %
hemi-
ee
yield hemi-
ee
yield
(%)
1
2
3
4
5
6
7
8
1
5
2
6
96c
94d
86
85
97
70
94
96
93
91
96
entry anhydride ester
(%)b
(%)
ester
(%)b
11
17
19
21
25
27
12
18
20
22
26
28
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
3
5
7
9
11
13
15
17
19
21
23
25
27
2
4
6
99
94c
96c
95c
96
93
94
85e
90
94
95
93
95
97
98
84
99
95
96
61
69
96
97
99
97
98
93
96
ent-2
ent-4
ent-6
ent-8
99
92
86
98
96
94
71
79
95
96
93
99
91
99
97
87c
94
94c
98c
92c
95
94
96
8
10
12
14
16
18
20
22
24
26
28
ent-10 93d
ent-12 75
ent-14 93
ent-16 85e
ent-18 84d
ent-20 87
ent-22 93
ent-24 87
ent-26 93
ent-28 94
a
All reactions were performed at -55 °C for 60 h using 1.1 equiv
of alkaloid and 3.0 equiv of methanol in a 0.1 M solution related
b
to anhydride. Determined by GC-analysis of the corresponding
lactones using a chiral stationary phase. c Recrystallization fur-
d
nished an increase on >99% ee. Determined by HPLC-analysis
of the corresponding p-bromophenyl methyl diester.
probably due to, first, the considerable higher water
solubility of the monoesters, which results in loss of
product during the aqueous workup, and second, a
certain instability of the oxygen bridge toward basic
reagents. Recrystallization of the esters obtained from 9
and 17 led to an enantiomer enrichment of >99% ee
(entries 5 and 9). The alkaloid-mediated methanolysis is
also applicable to monocyclic substrates, such as, for
example, meso-dimethylsuccinic anhydride. However, in
this case the appropriate methyl-monoester was obtained
as an unseparable mixture with ca. 14% of the epimer-
ization product.15 Presumably due to steric reasons
anhydrides 29-31 did not react at all (see below).
a
All reactions were performed at -55 °C for 60 h using 1.1 equiv
of alkaloid and 3.0 equiv of methanol in a toluene/CCl4-mixture
(1:1); for quinidine: 0.2 M with respect to the anhydride, for
b
quinine: 0.05 M. Determined by GC-analysis of the correspond-
ing lactones using a chiral stationary phase. c Determined by
HPLC-analysis of the corresponding p-bromophenyl methyl di-
d
ester. Recrystallization furnished an increase on >99% ee.
e Determined by GC-analysis of the corresponding isopropyl methyl
diester.
tatively as their hydrochloride salts and after basic work
up reused without loss of selectivity (tested in three
sequential reactions).
As discussed above, the best solvent system for the low-
temperature reactions consisted of a 1:1 mixture of
toluene and CCl4. Various attempts to replace the toxic
CCl4 by less harmful solvents of comparable polarity and
solution characteristics resulted in a decrease of asym-
metric induction and reaction rate. Finally we found that
by performing the quinidine-mediated methanolysis at
lower concentration in pure toluene (0.1 M with respect
to the anhydride), the use of CCl4 could be avoided
completely. Thus, with the only exception of 11, the
anhydride openings occurred with almost the same
enantioselectivities and yields under these modified
conditions (Table 3).
Det er m in a t ion of t h e Ab solu t e Con figu r a t ion s.
Apart from the products derived from the ring opening
of the anhydrides 5, 7, and 27, the absolute configura-
tions of the monoesters were determined by comparison
of their senses of optical rotation with those reported in
the literature. For esters 10 and 14 the configuration was
verified additionally via the known lactones,16 which were
obtained by selective reduction of the methyl ester group
with LiBEt3H followed by catalyzed lactonization.6c Fi-
Scop e a n d Lim ita tion s. Next, we evaluated the scope
of the reaction and found that under the optimized
conditions, a large variety of bicyclic- and tricyclic an-
hydrides could be opened with very high enantioselec-
tivities and excellent yields (Table 2).
In general, quinidine-mediated ring openings furnished
monoesters with slightly higher or equal enantiomeric
excesses in comparison to the quinine reactions. The
moderate yields in the conversion of the two oxatricyclic
compounds 11 and 13 (Table 2, entries 6 and 7) are
(14) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry,
2nd ed.; VCH: Weinheim; 1990; p 407.
(15) As determined by GC-MS and NMR analysis.
(16) (a) Lok, K. P.; J akovac, I. J .; J ones, J . B. J . Am. Chem. Soc.
1985, 107, 2521. (b) Bloch, R.; Guibe-J ampel, E.; Girad, C. Tetrahedron
Lett. 1985, 26, 4087.

Ring Opening of Cyclic Meso-Anhydrides
J . Org. Chem., Vol. 65, No. 21, 2000 6987
Sch em e 3
With respect to the mechanism we assume that an
acylammonium-type intermediate is formed by nucleo-
philic attack of the alkaloid on the less-hindered front
face of the anhydride. This intermediate is then converted
to the product by a rear side attack of methanol to give
the desired monoester.20 If the carbonyls are sterically
blocked, no reaction can take place. This assumption is
confirmed by the experiments using anhydrides 29-31,
which all did not react even at elevated temperature (up
to 100 °C).21
Sch em e 4
Ca ta lytic Use of th e Alk a loid . Next, we focused on
the development of a process which required less alkaloid
but retained the high enantioselectivity. The following
scenario was assumed: After the anhydride opening, the
resulting acid transfers its proton to the alkaloid8b which
then becomes prone to form aggregates with the carboxy-
late of the former anhydride. Such acid-base complexes
have previously been described by Baiker and co-workers,
who found a stable 2:1 acid-alkaloid complex in a study
of the molecular interactions between cinchonidine and
acetic acid.22 In the context of the mechanistic path of
the asymmetric anhydride opening it is important to note
that this protonated alkaloid also adopted the open(3)-
conformation and that Aiken et al. demonstrated that
species of such type could be catalytically active but that
the enantioselectivities were rather low.8 To render the
asymmetric anhydride opening catalytically more ef-
ficient, we wondered about the possibility to remove the
ammonium proton with the help of a sterically hindered
base in order to liberate the alkaloid. The latter could
then take part in further catalytic cycles which would
allow a more economic alkaloid application for openings
on larger scale.
As reference for the development of the catalytic
version, the methanolysis reaction of anhydride 1 pre-
sented in Scheme 2 was selected, using only 10 mol % of
quinidine. Under the optimized conditions, a conversion
of 50% was observed, and ester 2 was obtained with an
enantiomeric excess of 35% (Table 4, entry 1). Addition
of the nonnucleophilic base DBU (33) or the proton
sponge 1,8-bis(dimethylamino)naphthalene (34) remained
unsuccessful, whereas reactions in the presence of Hu¨nig’s
base (35) indicated the potential of this concept. Use of
the sterically more-hindered triisopropylamine (36) led
to a decrease in enantioselectivity (entries 5 and 6). As a
consequence, amines with one unbranched alkyl group
next to two sterically demanding substituents were tested
(entries 7-11). The highest asymmetric induction was
obtained using pempidine (40) as auxiliary base. Thus,
at full substrate conversion ester 2 was isolated in 98%
yield having an enantiomeric excess of 90% (entry 10).
Unfortunately, this catalytic protocol now required an
nally, the hemiesters from 1 and 11 were hydrogenated,
and the products were compared with their saturated
analogues. The absolute configuration of 28, which was
obtained by quinidine opening of 27, was assigned by
correlation with the known trans-diol 32 (Scheme 3).
In all cases the stereochemical outcome of the reaction
was uniform: the quinidine-mediated ring opening of
anhydrides generated the ester function always at the
carbonyl group indicated in Scheme 4. For the anhydrides
containing unsubstituted all-carbon backbones, this is the
si-carbonyl group; due to the reversal of the CIP-priorities
it is the re-carbonyl group of anhydrides 11, 13, and 17.
In the same consequence quinine always exhibited the
opposite selectivity. In view of the fact that this rule is
strictly kept over a wide range of substrates, we deduce
that the absolute configuration of the products derived
from anhydrides 5 and 7 follows accordingly although
this fact has not been proven rigorously.
The differentiation between the enantiotopic carbonyl
groups by the alkaloids must be based on the recognition
of certain structural components in the anhydride mor-
phology. Due to the high degree of conformational
freedom of the alkaloid it is difficult to develop a simple
hypothesis, which describes the cause of this differentia-
tion. The solvent influence outlined in Table 1 suggests
that a certain alkaloid conformation is mainly responsible
for the asymmetric induction in the opening reaction and
that a less-pronounced stabilization of this particular
conformation by another solvent leads to the observed
reduced selectivity. In this context Bu¨rgi and Baiker
recently described NMR and ab initio studies on the
conformational behavior of cinchonidine17 and found that,
with respect to the dielectric constant of the solvent, the
proportion of the energetically most favorable conforma-
tion of the alkaloid in solution (the so-called open(3)-form)
goes in parallel with the enantiomeric excess achieved
in the asymmetric hydrogenation of ketopantolactone
over cinchonidine-modified Pt.18 According to their in-
vestigation, the open(3)-conformation is stabilized by
nonpolar solvents wherein it is present at room temper-
ature to 60-70%. Polar solvents reduce the energetic
difference to closed structures which causes the drastic
selectivity reduction when using solvents with higher
polarity. Since Wynberg and co-workers have postulated
similar conformations for quinidine or dihydroquini-
dine,19 the trend observable in Table 1 appears consistent
with these results.
(19) (a) Dijkstra, G. D. H.; Kellogg, R. M.; Wynberg, W.; Svendsen,
J . S.; Marko´, I.; Sharpless, K. B. J . Am. Chem. Soc. 1989, 111, 8069.
(b) Dijkstra, G. D. H.; Kellogg, R. M.; Wynberg, W. J . Org. Chem. 1990,
55, 6121. (c) Berg, U.; Aune, M.; Matsson, O. Tetrahedron Lett. 1995,
36, 2137. (d) Aune, M.; Gogoll, A.; Matsson, O. J . Org. Chem. 1995,
60, 1356.
(20) (a) For early mechanistic studies on the reaction of cyclic
anhydrides and tert-amines (in water), see: Kluger, R.; Hunt, J . C. J .
Am. Chem. Soc. 1989, 111, 3325. (b) Review on DMAP as acyl-transfer
catalyst: Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H. Angew. Chem. 1978,
90, 602; Angew. Chem., Int. Ed. Engl. 1978, 17, 569.
(21) In agreement with this is the observation by North et al., who
found that anhydride 29 does also not react with (S)-proline methyl
ester hydrochloride in the presence of Et3N to give the corresponding
opening product (see ref 5g).
(22) Ferri, D.; Bu¨rgi, T.; Baiker, A. J . Chem. Soc., Perkin Trans. 2
1999, 1305.
(17) Bu¨rgi, T.; Baiker, A. J . Am. Chem. Soc. 1998, 120, 12920.
(18) (a) Schu¨rch, M.; Schwalm, O.; Mallat, T.; Weber, J .; Baiker, A.
J . Catal. 1997, 169, 275. (b) Schu¨rch, M.; Ku¨nzle, N.; Mallat, T.; Weber,
J .; Baiker, A. J . Catal. 1998, 176, 569.

6988 J . Org. Chem., Vol. 65, No. 21, 2000
Bolm et al.
Ta ble 4. Su bstoich iom etr ic Use of Qu in id in e for th e
Rin g Op en in g of An h yd r id e 1a
excesses. Presumably, the higher ring strain due to the
smaller carbocyclic backbones in these molecules leads
to an increased reactivity, and with the help of the achiral
auxiliary base an unselective anhydride opening occurs
in parallel which as a consequence leads to a lower
enantiomeric excess of the product.
Finally, we investigated the reuse of the reagents in
the catalytic version. Thus the asymmetric anhydride
opening of 1 with recovered quinidine (washed with
diethyl ether followed by drying in vaccuo) and fresh
pempidine gave identical results as before (comp.: Table
4, entry 10). When both bases, quinidine and pempidine,
were recovered and reused, the conversion of 1 (94%) and
the enantiomeric excess of the resulting 2 (84% ee) were
only slighly lower, demonstrating the potential of the
catalytic process for multiple use of all reagents.
entry
added amine
none
DBU (33)
proton sponge 34
time (d) conversion (%)b ee (%)c
1
2
3
4
5
6
7
8
9
2.5
2.5
2.5
2.5
3
50
93
95
94
76
35
0
23
79
60
67
72
84
73
90
52
Hu¨nig’s base (35)
36
36
37
38
39
40
41
6
84
6
94
6
95
6
6
7
93
10
11
100d
89
a
All reactions were performed in a toluene/CCl4 mixture (1:1)
at -55 °C using 0.1 equiv of quinidine, 1.0 equiv of the tertiary
amine, and 3.0 equiv of methanol (0.2 M solution related to
b
anhydride). Determined by GC-analysis. c Determined by GC-
Con clu sion a n d Ou tlook . The desymmetrization of
easily accessible meso-anhydrides by cinchona alkaloid-
mediated methanolysis is applicable to a variety of
structurally very different substrates and leads to the
corresponding optically active hemiesters with high
enantioselectivities (up to 99% ee). A simple reaction
protocol was developed which allows synthesis of either
enantiomer selectively. Extension of this study led to the
introduction of a new process using stoichiometric quan-
tities of an achiral base which only requires catalytic
alkaloid amounts and gives ester 2 with up to 90% ee.
Currently, we are focusing our efforts on the application
of this transformation toward the synthesis of bioactive
substances and new ligands for asymmetric catalysis.
analysis of the corresponding lactone using a chiral stationary
phase. A yield of 98% was obtained.
d
Ta ble 5. Ca ta lytic Use of Qu in id in e in th e P r esen ce of
P em p id in e (40) in th e Asym m etr ic An h yd r id e Op en in g of
Va r iou s Su bstr a tesa
entry
anhydride
ester
ee (%)b
yield (%)
1
2
3
4
5
6
1
9
17
19
21
27
2
10
18
20
22
28
90
91
74
81
89
92
98
94
98
97
96
96
a
All reactions were performed at -55 °C for 6 d using 0.1 equiv
of quinidine, 1.0 equiv of pempidine (40), and 3.0 equiv of methanol
(0.2 M solution related to anhydride) in a toluene/CCl4 mixture
b
(1:1). Determined by GC-analysis of the corresponding lactones
Exp er im en ta l Section
using a chiral stationary phase.
Gen er a l. Unless otherwise specified, all reagents were
purchased from commercial suppliers and used without further
purification. Toluene and THF were distilled from sodium
benzophenone ketyl radical under argon. All other solvents
were reagent grade and used as received. Unless otherwise
noted, all reactions were carried out under argon using
standard Schlenk and vacuum line techniques. The anhydrides
15, 23, 25, and 31 as well as the amines 33-35 and 37 were
commercially available. Compounds 1, 11, and 27 were
prepared by Diels-Alder reactions of maleic anhydride and
the corresponding dienes. Eschweiler-Clarke methylation of
commercially available isopropyl-tert-butylamine gave amine
38. Substrate 19 was obtained from the corresponding diacid
by refluxing in acetic anhydride. Hydrogenation of the double
bond (H2/Rh-Al2O3, ethyl acetate) of 1 and 11 delivered
anhydrides 3 and 13. The anhydrides 5,23 7,24 9,25 17,11c 21,26
29,27 and 3028 as well as the amines 36,29 39,30 40,31 and 4132
extended reaction time and complete conversion was only
achieved after 6 days.
(23) (a) Kraihanzel, C. S.; Losee, M. L. J . Am. Chem. Soc. 1968, 90,
4701. (b) Ranganathan, D.; Rao, C. B.; Ranganathan, S.; Mehrota, A.
K.; Iyengar, R. J . Org. Chem. 1980, 45, 1185. (c) Magnus, P.; Cairns,
P. M.; Moursounidis, J . J . Am. Chem. Soc. 1987, 109, 2469.
(24) Alder, K.; Chambers, F. W.; Trimborn, W. Liebigs Ann. Chem.
1950, 566, 27.
(25) Cannone, P.; Belanger, D.; Lemay, G. J . Org. Chem. 1982, 47,
3953.
(26) Padwa, A.; Hornbuckle, S. F.; Fryxell, G. E.; Stull, P. D. J . Org.
Chem. 1989, 54, 817.
Changing the concentration as well as the amount of
auxiliary base and methanol did not result in higher
asymmetric induction. Doubling of the catalyst loading
(20 mol %) gave only a slight increase to 93% ee.
To ensure that this new protocol involving catalytic
amounts of the alkaloid was suitable for other substrates
also, we selected a number of respresentative anhydrides
and investigated their asymmetric openings again. The
results of this study are summarized in Table 5.
As in the opening of 1, the enantioselectivities in
reactions with anhydrides 9, 21, and 27 were only slightly
lower compared to the ones achieved in the stoichiometric
version (∆ee ) 5-6%). In contrast, compounds 17 and
19 behaved differently, and the corresponding products
were obtained with significantly lower enantiomeric
(27) Kalindjian, S. B.; Buck, I. M.; Cushnir, J . R.; Dunstone, D. J .;
Hudson, M. L.; Low, C. M. R.; McDonald, I.; Pether, M. J .; Steel, K. I.
M.; Tozer, M. J . J . Med. Chem. 1995, 38, 4294.
(28) Beck, K.; Brand, U.; Huenig, S.; Martin, H.-D.; Mayer, B.;
Peters, K.; von Schnering, H. G. Liebigs Ann. Chem. 1996, 1881.
(29) Wieland, G.; Simchen, G. Liebigs Ann. Chem. 1985, 2178.
(30) (a) Sandris, C.; Ourisson, G. Bull. Soc. Chim. Fr. 1958, 345.
(b) Couet, W. R.; Brasch, R. C.; Sosnovsky, G.; Lukszo, J .; Prakash, I.;
Gnewuch, C. T.; Tozer, T. N. Tetrahedron 1985, 41, 1165. (c) Dupeyre,
R. M.; Rassat, A.; Rey, P. Bull. Soc. Chim. Fr. 1965, 3643. (d) Frachey,
G.; Gionta, G.; Lillocci, C. Gazz. Chim. Ital. 1993, 123, 463.
(31) (a) Leonard, N. J .; Nommensen, E. W. J . Am. Chem. Soc. 1949,
71, 2808. (b) Hall, H. K. J . Am. Chem. Soc. 1958, 80, 6699.

Ring Opening of Cyclic Meso-Anhydrides
J . Org. Chem., Vol. 65, No. 21, 2000 6989
were prepared according to literature procedures. The enan-
tiomeric ratios of the opening products were determined as
follows: (a) the methyl monoesters were transformed with
2-propanol or p-bromophenol to the corresponding diesters by
DCC-coupling, which were then analyzed by GC or HPLC, or
(b) the hemiesters were reduced with LiBEt3H and cyclized
to the lactones,6c which were then analyzed by GC. Capillary
gas chromatograms were obtained using the following columns
and temperature programs: (a) Lipodex A: 2,3,6-O-Tripentyl-
R-CD. Column head pressure: 1.0 bar H2; 80 °C (30 min),
heating rate 0.5 °C/min up to 100 °C (30 min). (b) Lipodex B:
2,6-O-Dipentyl-3-O-actyl-R-CD. Column head pressure: 0.6 bar
N2; Conditioning of the column: 70 °C, heating rate 1.0 °C/
min up to 100 °C (10 min), heating rate 3.0 °C/min up to 160
°C (20 min); Sample: 120 °C (15 min), heating rate 2.0 °C/
min up to 160 °C (10 min). (c) Lipodex E: 2,6-O-Dipentyl-3-
O-butyryl-γ-CD. Column head pressure: 1.0 bar N2; 100 °C
(50 min), heating rate 3.0 °C/min up to 180 °C (60 min).
Injector temperature 200 °C, detector temperature 250 °C.
HPLC-analysis was performed using a Chiracel OD or a
ee ) 99% [GC-analysis of the lactone: Lipodex E, t1 ) 80.7
(major), t2 ) 81.1 or HPLC-analysis of the methyl-4-bromophe-
nyl diester: Chiralcel OD-H at room temperature, n-heptane/
2-propanol ) 98:2, 0.5 mL/min, 254 nm, t1 ) 20.3 (major), t2
) 23.2].
(2R,3S)-3-en do-Meth oxycar bon yl-bicyclo[2.2.1]h eptan e-
2-en d o-ca r boxylic a cid (4) was obtained from the quinidine
opening of anhydride 3 in 84% yield: mp 75-76 °C (rac),
colorless oil (en), lit.34 mp 77-79 °C (rac); [R]rt ) +16.9 (c )
D
1.59, MeOH), lit.5g [R]23D ) +17.1 (c ) 2.06, MeOH); ee ) 94%
[HPLC-analysis of the methyl-4-bromophenyl diester: Chiracel
OD-H at room temperature, n-heptane/2-propanol ) 98:2, 0.5
1
mL/min, 254 nm, t1 ) 15.4, t2 ) 18.8 (major)]; H NMR (300
MHz, CDCl3): δ 1.37-1.58 (m, 4H), 1.74-1.84 (m, 2H), 2.49-
2.62 (m, 2H), 2.92-3.07 (m, 2H), 3.63 (s, 3H), 10.70 (br s, 1H).
13C NMR (75 MHz, CDCl3): δ 24.0, 24.2, 39.9, 40.2, 40.4, 46.7,
47.2, 51.3, 173.2, 178.3. For IR5g and MS35 data see the
literature.
(2S,3R)-3-en do-Meth oxycar bon yl-bicyclo[2.2.1]h eptan e-
2-en d o-ca r boxylic a cid (en t-4) was obtained from the qui-
nine opening of anhydride 3 in 86% yield as a colorless oil:
[R]rtD ) -16.4 (c ) 2.11, MeOH), lit.5g [R]24D ) -17.4 (c ) 2.05,
MeOH); ee ) 94% [HPLC-analysis of the methyl-4-bromophe-
nyl diester: Chiracel OD-H at room temperature, n-heptane/
2-propanol ) 98:2, 0.5 mL/min, 254 nm, t1 ) 15.4 (major), t2
) 18.8].
1
Chiracel OD-H (Daicel), 4.6 × 250 mm, λ ) 254 nm. H NMR
and 13C NMR spectra were recorded relative to TMS as
internal standard. GCMS spectra were measured on a column
HP-5 MS, 30 m × 0.25 mm × 0.25 µm. Melting Points were
determined in open glass capillaries and are uncorrected.
Optical rotations were measured at room temperature (ca. 20
°C) using HPLC-grade solvents. All microanalyses were con-
ducted at the Institut fu¨r Organische Chemie der RWTH
Aachen.
(2S,3R,7S)-7-a n ti-Tr im et h ylsilyl-3-en d o-m et h oxyca r -
bon yl-bicyclo[2.2.1]h ep t-5-en e-2-en d o-ca r boxylic a cid (6)
was obtained from the quinidine opening of anhydride 5 in
99% yield as a white solid: mp 103 °C (rac), 78-79 °C (en);
[R]rt ) +11.0 (c ) 4.21, MeOH), [R]rt ) -5.1 (c ) 4.03, CH2-
Gen er a l P r oced u r e for th e Alk a loid -Med ia ted Rin g
Op en in g of Cyclic Meso-An h yd r id es. (GP -A) Usin g Sto-
ich iom etr ic Alk a loid Am ou n ts. Methanol (0.122 mL, 3.0
mmol) was added dropwise to a stirred suspension of the
anhydride (1.0 mmol) and the alkaloid (0.357 g, 1.1 mmol) in
a 1:1-mixture of toluene and tetrachloromethane (5 mL in the
case of quinidine, 20 mL in the case of quinine) at -55 °C
under argon. The reaction mixture was stirred at this tem-
perature for 60 h. During this period, the material gradually
dissolved. Subsequently, the resulting clear solution was
concentrated in vacuo to dryness, and the resulting residue
was then dissolved in ethyl acetate. The solution was washed
with 2 N HCl, and after phase separation, followed by
extraction of the aqueous phases with ethyl acetate, the
organic layer was dried over MgSO4, filtered, and concentrated
providing the corresponding hemiester.
Analogously, the quinidine-mediated methanolysis was
executed in pure toluene using 10 mL/mmol anhydride. To
recover the alkaloid, the acidic aqueous phase was neutralized
with Na2CO3 and extracted with CH2Cl2. The combined organic
phases were dried over MgSO4 and filtered. Evaporation of
the solvent yielded the alkaloid almost quantitatively.
(2R,3S)-3-en d o-Meth oxyca r bon yl-bicyclo[2.2.1]h ep t-5-
en e-2-en d o-ca r boxylic a cid (2) was obtained from the
quinidine opening of anhydride 1 in 98% yield as a white
solid: mp 74 °C (rac), 75-78 °C (en), lit.33 mp 74-76 °C (rac);
[R]rtD ) +7.8 (c ) 4.23, CCl4), lit.33 [R]20D ) +7.9 (c ) 4.8, CCl4);
ee ) 99% [GC-analysis of the lactone: Lipodex E, t1 ) 80.7, t2
) 81.1 (major) or HPLC-analysis of the methyl-4-bromophenyl
diester: Chiralcel OD-H at room temperature, n-heptane/2-
propanol ) 98:2, 0.5 mL/min, 254 nm, t1 ) 20.3, t2 ) 23.2
(major)]; 1H NMR (300 MHz, CDCl3): δ 1.32-1.36 (m, 1H),
1.50 (dd, J ) 1.8, 8.9 Hz, 1H), 3.17-3.22 (m, 2H), 3.29-3.32
(m, 2H), 3.60 (s, 3H), 6.32 (dd, J ) 3.0, 4.9 Hz, 1H), 11.12 (br
s, 1H). 13C NMR (75 MHz, CDCl3): δ 46.1, 46.6, 47.9, 48.2,
48.8, 51.6, 134.4, 135.6, 173.1, 177.8. For IR and MS data, see
the literature.33
D
D
Cl2); ee ) 96% [HPLC-analysis of the methyl-4-bromophenyl
diester: Chiracel OD at room temperature, n-heptane/2-
propanol ) 99:1, 0.5 mL/min, 254 nm, t1 ) 11.3, t2 ) 12.7
(major)]; 1H NMR (400 MHz, acetone-d6): δ -0.05 (s, 9H), 1.09
(s, 1H), 3.15-3.18 (m, 1H), 3.21-3.24 (m, 1H), 3.30 (dd, J )
3.3, 10.2 Hz, 1H), 3.39 (dd, J ) 3.3, 10.2 Hz, 1H), 3.49 (s, 3H),
6.02 (dd, J ) 3.0, 5.5 Hz, 1H), 6.14 (dd, J ) 3.0, 5.2 Hz, 1H).
13C NMR (100 MHz, acetone-d6): δ -0.1, 49.5, 50.1, 50.8, 50.9,
51.1, 51.5, 134.3, 135.6, 172.9, 173.3. Anal. Calcd for C13H20O4-
Si (268.23): C, 58.18; H, 7.51. Found: C, 58.39; H, 7.56. For
IR and MS data see Supporting Information.
(2R,3S,7R)-7-a n ti-Tr im et h ylsilyl-3-en d o-m et h oxyca r -
bon yl-bicyclo[2.2.1]h ept-5-en e-2-en do-car boxylic acid (en t-
6) was obtained from the quinine opening of anhydride 5 in
98% yield as a white solid: [R]rt ) -5.2 (c ) 4.75, CH2Cl2),
D
ee ) 98% [HPLC-analysis of the methyl-4-bromophenyl di-
ester: Chiracel OD at room temperature, n-heptane/2-propanol
) 99:1, 0.5 mL/min, 254 nm, t1 ) 11.3 (major), t2 ) 12.7].
(2R,3S)-7-Ben zh yd r ylid en e-3-en d o-m eth oxyca r bon yl-
bicyclo[2.2.1]h ep t-5-en e-2-en d o-ca r boxylic a cid (8) was
obtained from the quinidine opening of anhydride 7 in 95%
yield as a white solid: mp 158 °C (rac), 160 °C (en), lit.24 mp
158 °C (rac); [R]rtD ) +4.6 (c ) 3.43, MeOH); ee ) 95% [HPLC-
analysis of the methyl-4-bromophenyl diester: Chiracel OD-H
at room temperature, n-heptane/2-propanol ) 98:2, 0.7 mL/
min, 254 nm, t1 ) 11.0, t2 ) 17.1 (major)]; 1H NMR (300 MHz,
CDCl3): δ 3.46-3.55 (m, 2H), 3.59 (s, 3H), 3.67-3.73 (m, 2H),
6.44 (dd, J ) 3.0, 5.71 Hz, 1H), 6.51 (dd, J ) 3.0, 6.0 Hz, 1H),
7.03-7.09 (m, 4H), 7.20-7.32 (m, 6H), 9.60 (br s, 1H). 13C NMR
(75 MHz, CDCl3): δ 47.7, 47.9, 51.7, 122.6, 127.0, 128.1, 129.5,
134.8, 135.6, 140.4, 149.4, 172.0, 177.5. Anal. Calcd for
C
23H20O4 (360.41): C, 76.65; H, 5.59. Found: C, 76.29; H, 5.97.
For IR and MS data see Supporting Information.
(2S,3R)-7-Ben zh yd r ylid en e-3-en d o-m eth oxyca r bon yl-
b icyclo[2.2.1]h ep t -5-en e-2-en d o-ca r b oxylic a cid (en t-8)
was obtained from the quinine opening of anhydride 7 in 96%
(2S,3R)-3-en d o-Meth oxyca r bon yl-bicyclo[2.2.1]h ep t-5-
en e-2-en d o-ca r boxylic a cid (en t-2) was obtained from the
quinine opening of anhydride 1 in 92% yield as a white solid:
[R]rtD ) -7.8 (c ) 4.76, CCl4), lit.33 [R]20D ) -7.9 (c ) 4.9, CCl4);
yield as a white solid: [R]rt ) -4.3 (c ) 5.49, MeOH), ee )
D
92% [HPLC-analysis of the methyl-4-bromophenyl diester:
(32) Hall, H. K. J . Am. Chem. Soc. 1957, 79, 5444.
(34) Filler, R.; Camara, B. R.; Naqvi, S. M. J . Am. Chem. Soc. 1959,
81, 658.
(35) Casas, R.; Ibarzo, J .; J imenez, J . M.; Ortuno, R. M. Tetrahe-
dron: Asymmetry 1993, 4, 669.
(33) (a) Storme, P.; Quaeghebeur, L.; Vandewalle, M. Bull. Soc.
Chim. Belg. 1984, 93, 999. (b) Tanaka, K.; Asakawa, N.; Nuruzzaman,
M.; Fuji, K. Tetrahedron: Asymmetry 1997, 8, 3637.

6990 J . Org. Chem., Vol. 65, No. 21, 2000
Bolm et al.
Chiracel OD-H at room temperature, n-heptane/2-propanol )
98:2, 0.7 mL/min, 254 nm, t1 ) 11.0 (major), t2 ) 17.1].
(2R,3S)-3-exo-Met h oxyca r b on yl-b icyclo[2.2.1]h ep t -5-
en e-2-exo-ca r boxylic a cid (10) was obtained from the qui-
nidine opening of anhydride 9 in 96% yield as a white solid:
85% [GC-analysis of the methyl-isopropyl diester: Lipodex A,
t1 ) 50.9, t2 ) 51.5 (major)].
(1S,2R)-cis-2-Meth oxyca r bon yl-3,3-d im eth ylcyclop r o-
p a n e-1-ca r boxylic a cid (18) was obtained from the quinidine
opening of anhydride 17 in 97% yield as a white solid: mp
106 °C (rac), 54 °C (en) lit.11c mp 54-55 °C (en); [R]rtD ) +20.6
(c ) 4.20, MeOH); ee ) 90% [GC-analysis of the lactone:
mp 66 °C (rac), 61 °C (en); [R]rt ) +6.0 (c ) 1.11, CHCl3),
D
[R]rt ) -1.7 (c ) 1.31, MeOH); ee ) 96% [GC-analysis of the
D
lactone: Lipodex E, t1 ) 73.8, t2 ) 74.8 (major)]; 1H NMR (400
MHz, CDCl3): δ 1.50 (dp, J ) 1.7, 9.1 Hz, 1H), 2.10 (dtr, J )
1.7, 9.1 Hz, 1H), 2.65 (d, J ) 1.9 Hz, 2H), 3.11-3.14 (m, 2H),
3.66 (s, 3H), 6.22 (br tr, J ) 1.9 Hz, 2H), 11.02 (br s, 1H). 13C
NMR (100 MHz, CDCl3): δ 45.7, 46.1, 47.7, 47.8, 52.1, 138.1,
138.3, 174.0, 180.2. Anal. Calcd for C10H12O4 (196.20): C, 61.22;
H, 6.16. Found: C, 61.40; H, 6.28. For IR and MS data see
Supporting Information.
1
Lipodex B, t1 ) 11.9 (major), t2 ) 12.7]; H NMR (400 MHz,
CDCl3): δ 1.27 (s, 3H), 1.40 (s, 3H), 1.97 (AB-system, J ) 9.0
Hz, 2H), 3.72 (s, 3H), 11.05 (br s, 1H). 13C NMR (100 MHz,
CDCl3): δ 15.5, 27.5, 28.3, 32.9, 33.0, 52.5, 171.2, 174.2. For
IR and MS data see the literature.39
(1R,2S)-cis-2-Meth oxyca r bon yl-3,3-d im eth ylcyclop r o-
p a n e-1-ca r boxylic a cid (en t-18) was obtained from the
quinine opening of anhydride 17 in 96% yield as a white
solid: [R]rt ) -19.0 (c ) 4.08, MeOH), lit.39 [R]22 ) -19.0 (c
(2S,3R)-3-exo-Met h oxyca r b on yl-b icyclo[2.2.1]h ep t -5-
en e-2-exo-ca r boxylic a cid (en t-10) was obtained from the
quinine opening of anhydride 9 in 94% yield as a white solid:
D
D
) 4, MeOH); ee ) 84% (99.4% ee after recrystallization from
hexanes, Et2O) [GC-analysis of the lactone: Lipodex B, t1
11.9, t2 ) 12.7 (major)].
)
[R]rt ) -5.8 (c ) 1.65, CHCl3); ee ) 93% (99.9% after
D
recrystallization from hexanes, ethyl acetate) [GC-analysis of
the lactone: Lipodex E, t1 ) 73.8 (major), t2 ) 74.8].
(1R,2S)-cis-2-Meth oxyca r bon yl-cyclobu ta n e-1-ca r box-
ylic a cid (20) was obtained from the quinidine opening of
(2S,3R)-3-exo-Meth oxycar bon yl-7-oxabicyclo[2.2.1]h ept-
5-en e-2-exo-ca r boxylic a cid (12) was obtained from the
quinidine opening of anhydride 11 in 61% yield as a white
anhydride 19 in 99% yield as a colorless oil: [R]rt ) +3.4 (c
D
) 2.61, CHCl3); ee ) 94% [GC-analysis of the lactone: Lipodex
E, t1 ) 64.4 (major), t2 ) 64.9]; 1H NMR (300 MHz, CDCl3): δ
2.06-2.40 (m, 4H), 3.32-3.41 (m, 2H), 3.65 (s, 3H), 11.48 (br
s, 1H). 13C NMR (75 MHz, CDCl3): δ 21.6, 22.9, 40.8, 42.1,
51.4, 174.8, 177.8. For IR data see the literature.37 For MS
data see Supporting Information.
solid: mp 105 °C (rac), 111 °C (en) lit.16b mp 110 °C (en); [R]rt
D
) -9.7 (c ) 2.37, MeOH), lit.16b [R]20D ) -10.6 (c ) 2, MeOH);
ee ) 93% [GC-analysis of the hydrogenated lactone:6c Lipodex
E, t1 ) 95.9, t2 ) 98.7 (major)]; 1H NMR (400 MHz, CDCl3): δ
2.87 (AB-system, J ) 9.1 Hz, 2H), 3.71 (s, 3H), 5.28 (br s, 1H),
5.31 (br s, 1H), 5.45-5.46 (m, 2H), 10.29 (br s, 1H). 13C NMR
(100 MHz, CDCl3): δ 46.8, 47.2, 52.3, 80.2, 80.5, 136.2, 136.6,
171.6, 177.2. Anal. Calcd for C9H10O5 (198.17): C, 54.55; H,
5.09. Found: C, 54.54; H, 5.15. For IR and MS data see
Supporting Information.
(1S,2R)-cis-2-Met h oxyca r b on yl-cyclop r op a n e-1-ca r -
boxylic a cid (en t-20) was obtained from the quinine opening
of anhydride 19 in 93% yield as a colorless oil: [R]rt ) -3.3
D
(c ) 2.3, CHCl3), lit.40 [R]25 ) -3.6 (c ) 2.36, CHCl3); ee )
D
87% [GC-analysis of the lactone: Lipodex E, t1 ) 64.4, t2
64.9 (major)].
)
(2R,3S)-3-exo-Meth oxycar bon yl-7-oxabicyclo[2.2.1]h ept-
5-en e-2-exo-ca r boxylic a cid (en t-12) was obtained from the
quinine opening of anhydride 11 in 71% yield as a white
(1R,2S)-cis-2-Meth oxycar bon yl-cyclopen tan e-1-car box-
ylic a cid (22) was obtained from the quinidine opening of
anhydride 21 in 97% yield as a colorless oil: [R]rt ) +8.3 (c
solid: [R]rt ) +8.0 (c ) 2.11, MeOH); ee ) 75% [GC-analysis
D
D
) 2.1, MeOH), [R]rt ) +5.68 (c ) 0.95, CHCl3), lit.1g [R]25
)
of the hydrogenated lactone:6c Lipodex E, t1 ) 95.9 (major), t2
D
D
+5.0 (c ) 1.4, MeOH), lit.37 [R]25 ) +1.0 (c ) 1.0, CHCl3); ee
D
) 98.7].
) 95% [GC-analysis of the lactone: Lipodex E, t1 ) 68.6
(2S,3R)-3-exo-Met h oxyca r b on yl-7-oxa b icyclo[2.2.1]-
h ep ta n e-2-exo-ca r boxylic a cid (14) was obtained from the
quinidine opening of anhydride 13 in 69% yield as a white
1
(major), t2 ) 69.6]; H NMR (300 MHz, CDCl3): δ 1.58-1.73
(m, 1H), 1.82-2.13 (m, 5H), 3.03-3.12 (m, 2H), 3.66 (s, 3H),
10.50 (br s, 1H). 13C NMR (75 MHz, CDCl3): δ 23.8, 28.7, 46.8,
46.9, 51.8, 174.4, 180.4. For IR data see the literature.37 For
MS data see Supporting Information.
solid: mp 122 °C (rac), 136 °C (en) lit.16b mp 104 °C (en); [R]rt
D
) -4.7 (c ) 2.08, MeOH), lit.5g [R]20D ) -4.9 (c ) 2.01, MeOH);
ee ) 94% [GC-analysis of the lactone: Lipodex E, t1 ) 95.9, t2
) 98.7 (major)]; 1H NMR (300 MHz, CDCl3): δ 1.52-1.56 (m,
2H), 1.80-1.85 (m, 2H), 3.03 (AB-system, J ) 9.5 Hz, 2H),
3.67 (s, 3H), 4.91-4.97 (m, 2H), 10.20 (br s, 1H). 13C NMR (75
MHz, CDCl3): δ 29.6, 52.7, 58.3, 78.9, 79.2, 171.2, 177.1. For
IR data see the literature.5g,36 For MS data see Supporting
Information.
(1S,2R)-cis-2-Meth oxycar bon yl-cyclopen tan e-1-car box-
ylic a cid (en t-22) was obtained from the quinine opening of
anhydride 21 in 99% yield as a colorless oil: [R]rt ) -8.0 (c
D
) 2.67, MeOH); ee ) 93% [GC-analysis of the lactone: Lipodex
E, t1 ) 68.6, t2 ) 69.6 (major)].
(1R,2S)-cis-2-Meth oxyca r bon yl-cycloh exa n e-1-ca r box-
ylic a cid (24) was obtained from the quinidine opening of
(2R,3S)-3-exo-Met h oxyca r b on yl-7-oxa b icyclo[2.2.1]-
h ep ta n e-2-exo-ca r boxylic a cid (en t-14) was obtained from
the quinine opening of anhydride 13 in 79% yield as a white
solid: [R]rt ) +4.7 (c ) 2.11, MeOH), lit.5g [R]24 ) +4.4 (c )
anhydride 23 in 98% yield as a colorless oil: [R]rt ) +4.5 (c
D
) 0.98, CHCl3), lit.37 [R]25D ) +4.7 (c ) 0.87, CHCl3); ee ) 93%
[GC-analysis of the lactone: Lipodex E, t1 ) 71.7 (major), t2 )
73.1]; 1H NMR (300 MHz, CDCl3): δ 1.37-1.59 (m, 4H), 1.75-
1.81 (m, 2H), 1.99-2.05 (m, 2H), 2.80-2.87 (m, 2H), 3.68 (s,
3H), 10.30 (br s, 1H). 13C NMR (75 MHz, CDCl3): δ 24.2, 24.3,
26.5, 26.8, 42.9, 43.1, 52.3, 174.7, 180.7. For IR and MS data
see the literature.41
D
D
2.01, MeOH); ee ) 93% [GC-analysis of the lactone:6c Lipodex
E, t1 ) 95.9 (major), t2 ) 98.7].
(1R,2S)-cis-2-Met h oxyca r b on yl-cyclop r op a n e-1-ca r -
boxylic a cid (16) was obtained from the quinidine opening
of anhydride 15 in 96% yield as a colorless oil: [R]rt ) +10.3
D
(c ) 1.73, CHCl3); ee ) 85% [GC-analysis of the methyl-
(1S,2R)-cis-2-Meth oxyca r bon yl-cycloh exa n e-1-ca r box-
ylic a cid (en t-24) was obtained from the quinine opening of
1
isopropyl diester: Lipodex A, t1 ) 50.9 (major), t2 ) 51.5]; H
NMR (300 MHz, CDCl3): δ 1.29-1.37 (m, 1H), 1.66-1.72 (m,
1H), 2.05-2.20 (m, 2H), 3.71 (s, 3H), 11.37 (br s, 1H). 13C NMR
(75 MHz, CDCl3): δ 12.4, 21.2, 22.4, 52.4, 170.4, 176.0. For
IR37 and MS38 data see the literature.
anhydride 23 in 91% yield as a colorless oil: [R]rt ) -4.2 (c
D
) 1.03, CHCl3), lit.41b [R]20 ) -1.7 (c ) 1.08, CHCl3); ee )
D
87% [GC-analysis of the lactone: Lipodex E, t1 ) 71.7, t2
73.1 (major)].
)
(1S,2R)-cis-2-Met h oxyca r b on yl-cyclop r op a n e-1-ca r -
boxylic a cid (en t-16) was obtained from the quinine opening
of anhydride 15 in 95% yield as a colorless oil: [R]rt ) -10.2
(39) Walser, P.; Renold, P.; N’Goka, V.; Hosseinzadeh, F.; Tamm,
C. Helv. Chim. Acta 1991, 74, 1941.
(40) Mart´ın-Vila`, M.; Minguillo´n, C.; Ortun˜o, R. M. Tetrahedron:
Asymmetry 1998, 9, 4291.
D
(c ) 1.78, CHCl3), lit.37 [R]25 ) -13.4 (c ) 0.97, CHCl3); ee )
D
(36) Hagishita, S.; Seno, K. Chem. Pharm. Bull. 1989, 37, 327.
(37) Sabbioni, G.; J ones, J . B. J . Org. Chem. 1987, 52, 4565.
(38) Csuk, R.; von Scholz, Y. Tetrahedron 1994, 50, 10431.
(41) (a) Gais, H.-J .; Lukas, K. L.; Ball, W. A.; Braun, S.; Lindner,
H. J . Liebigs Ann. Chem. 1986, 687. (b) Alonso, I.; Carretero, J . C.;
Ruano, J . L. G. J . Org. Chem. 1994, 59, 1499.

Ring Opening of Cyclic Meso-Anhydrides
J . Org. Chem., Vol. 65, No. 21, 2000 6991
(1R,2S)-cis-2-Met h oxyca r b on yl-cycloh ex-4-en e-1-ca r -
boxylic a cid (26) was obtained from the quinidine opening
(2.3 mL, 23 mmol) in THF (80 mL) was treated with ethyl
chloroformate (2.2 mL, 23 mmol) at -20 °C and stirred at this
temperature for 30 min. The ammonium salt which had formed
was removed by filtration and washed with THF (5 mL). At
-20 °C, the combined filtrates were treated with NaBH4 (870
mg, 23 mmol), and then MeOH (5.8 mL) was carefully added
dropwise. The resulting mixture was stirred at this temper-
ature for 2 h, quenched with saturated aqueous NH4Cl, and
extracted with ethyl acetate. The combined extracts were dried
over MgSO4, filtered, and concentrated providing the corre-
sponding hydroxy ester as a viscous oil. The product was
dissolved in THF (20 mL) and added to a solution of LDA (63
mmol) in THF (200 mL) at -78 °C. After 30 min at this
temperature, the reaction was quenched with saturated aque-
ous NH4Cl, the phases were separated, and the aqueous phase
was extracted with ethyl acetate. The combined organic layers
were dried over MgSO4 and filtered, and evaporation of the
solvents delivered an oily residue which was purified by
column chromatography [using silica gel 60 (0.040-0.063 mm),
ethyl acetate:hexanes ) 1:1]. A solution of the resulting
product in THF (50 mL) was treated with LiAlH4 (1.0 g, 26
mmol). The mixture was stirred at room temperature for 12 h
and carefully quenched with saturated aqueous NH4Cl. After
phase separation, the organic layer was dried over MgSO4,
filtered, and concentrated providing 1.5 g (8.8 mmol, 42%) of
trans-diol 32 as a white solid which was recrystallized from
ethyl acetate/hexanes: mp 131-132 °C (en) lit.43 mp 129-131
of anhydride 25 in 93% yield as a colorless oil: [R]rt ) +10.4
D
(c ) 1.23, acetone), [R]rtD ) +13.1 (c ) 1.13, EtOH), lit.41a [R]25
D
) +10.9 (c ) 1.64, acetone), lit.42 [R]rt ) +14.9 (c ) 1.49,
D
EtOH); ee ) 95% [GC-analysis of the lactone: Lipodex E, t1 )
1
75.1 (major), t2 ) 75.7]; H NMR (300 MHz, CDCl3): δ 2.32-
2.42 (m, 2H), 2.55-2.63 (m, 2H), 3.02-3.09 (m, 2H), 3.70 (s,
3H), 5.68 (AB-system, J ) 1.7 Hz, 2H), 10.52 (br s, 1H). 13C
NMR (75 MHz, CDCl3): δ 26.1, 26.3, 40.0, 40.2, 52.5, 125.6,
125.7, 174.3, 180.3. For IR data see the literature.41a For MS
data see Supporting Information.
(1S,2R)-cis-2-Met h oxyca r b on yl-cycloh ex-4-en e-1-ca r -
boxylic a cid (en t-26) was obtained from the quinine opening
of anhydride 25 in 99% yield as a colorless oil: [R]rt ) -10.3
D
(c ) 1.32, acetone); ee ) 93% [GC-analysis of the lactone:
Lipodex E, t1 ) 75.1, t2 ) 75.7 (major)].
(1R,2S)-cis-2-Meth oxyca r bon yl-4,5-d im eth ylcycloh ex-
4-en e-1-ca r boxylic a cid (28) was obtained from the quini-
dine opening of anhydride 27 in 96% yield as a white solid:
mp 94-95 °C (rac), 60-61 °C (en); [R]rt ) +19.0 (c ) 4.3,
D
MeOH), [R]rtD ) +5.3 (c ) 1.05, CHCl3); ee ) 97% [GC-analysis
of the lactone: Lipodex E, t1 ) 76.6 (major), t2 ) 77.4]; 1H NMR
(400 MHz, CDCl3): δ 1.63 (s, 6H), 2.22-2.29 (m, 2H), 2.42-
2.48 (m, 2H), 2.97-3.07 (m, 2H), 3.69 (s, 3H), 11.20 (br s, 1H).
13C NMR (100 MHz, CDCl3): δ 18.9, 31.6, 31.7, 40.1, 40.3, 51.9,
123.9, 124.0, 173.9, 179.9. Anal. Calcd for C11H16O4 (212.25):
C, 62.25; H, 7.60. Found: C, 62.24; H, 7.65. For IR and MS
data see Supporting Information.
°C (en); [R]rt ) -90.2 (c ) 1.31, MeOH), lit.44 [R]D ) -76.9 (c
D
1
) 1.0, MeOH); H NMR (400 MHz, MeOH-d4): δ 1.58 (br s,
6H), 1.63-1.69 (m, 2H), 1.76-1.85 (m, 2H), 1.91-2.00 (m, 2H),
3.46-3.55 (m, 4H), 4.86 (s, 2H). 13C NMR (100 MHz, MeOH-
d4): δ 18.0, 33.7, 38.6, 64.6, 123.9. For IR data, see the
literature.45 For MS data, see Supporting Information.
(1S,2R)-cis-2-Meth oxyca r bon yl-4,5-d im eth ylcycloh ex-
4-en e-1-ca r boxylic a cid (en t-28) was obtained from the
quinine opening of anhydride 27 in 97% yield as a white
solid: [R]rt ) -18.4 (c ) 4.9, MeOH); ee ) 94% [GC-analysis
D
of the lactone: Lipodex E, t1 ) 76.6, t2 ) 77.4 (major)].
(GP -B) Usin g Su bstoich iom etr ic Am ou n ts of Qu in i-
d in e. Methanol (0.122 mL, 3.0 mmol) was added dropwise to
a stirred suspension of anhydride 1 (0.164 g, 1.0 mmol), the
tertiary amine (1.0 mmol), and quinidine (0.032 g, 0.1 mmol)
in a 1:1-mixture of toluene and tetrachloromethane (5 mL) at
-55 °C under argon. The reaction mixture was stirred at that
temperature for 60-168 h. Workup and purification was
carried out in accordance to the general procedure A. (2R,3S)-
3-endo-Methoxycarbonyl-bicyclo[2.2.1]hept-5-ene-2-endo-car-
boxylic acid (2) was obtained as a white solid. The reaction
times and the results are summarized in Table 4. The
transformations of other substrates were performed in an
analogous manner. The results are summarized in Table 5.
Ch em oselective Tr a n sfor m a tion of Ester 28 to Tr a n s-
Diol 32. A solution of ester 28 (4.428 g, 21 mmol) and Et3N
Ack n ow led gm en t. We thank the Fonds der Che-
mischen Industrie and the Deutsche Forschungsge-
meinschaft (DFG) within the Collaborative Research
Center (SFB) 380 ‘Asymmetric Synthesis by Chemical
and Biological Methods’ for financial support of this
work.
Su p p or tin g In for m a tion Ava ila ble: Spectral character-
ization (1H NMR, 13C NMR, IR and MS) of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O000638T
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