Asymmetric cycloaddition routes to both enantiomers of trans-9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboxylic acid

Article abstract of DOI:10.1016/S0957-4166(03)00172-1

Fumarates prepared from a series of optically active alcohols were used as dienophiles in Lewis acid catalyzed asymmetric cycloadditions to anthracene. The reactions gave high yields and d.e.'s of the diester cycloaddition products and acid hydrolysis could be performed under conditions yielding only about 10% racemization. The reactions form a valuable synthetic pathway to both enantiomers of the bicyclic dicarboxylic acid, since di-(-)-menthyl fumarate yielded the (-)-(S,S)-enantiomer and di-(+)-iso-menthyl fumarate the (+)-(R,R)-enantiomer of the acid. The other fumarates, obtained from (-)-borneol, (+)-fenchol and (-)-isopulegol, likewise gave the (-)-(S,S)-enantiomer of the acid. The absolute stereochemistry of the products was confirmed via a single crystal X-ray crystallographic structure determination of the brucine salt of the (-)-(S,S)-enantiomer.

Full text of DOI:10.1016/S0957-4166(03)00172-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1317–1322
Asymmetric cycloaddition routes to both enantiomers of
trans-9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboxylic acid
Linda Thunberg and Stig Allenmark*
Department of Chemistry, Go¨teborg University, SE-412 96 Go¨teborg, Sweden
Received 23 January 2003; accepted 19 February 2003
Abstract—Fumarates prepared from a series of optically active alcohols were used as dienophiles in Lewis acid catalyzed
asymmetric cycloadditions to anthracene. The reactions gave high yields and d.e.’s of the diester cycloaddition products and acid
hydrolysis could be performed under conditions yielding only about 10% racemization. The reactions form a valuable synthetic
pathway to both enantiomers of the bicyclic dicarboxylic acid, since di-(−)-menthyl fumarate yielded the (−)-(S,S)-enantiomer and
di-(+)-iso-menthyl fumarate the (+)-(R,R)-enantiomer of the acid. The other fumarates, obtained from (−)-borneol, (+)-fenchol
and (−)-isopulegol, likewise gave the (−)-(S,S)-enantiomer of the acid. The absolute stereochemistry of the products was confirmed
via a single crystal X-ray crystallographic structure determination of the brucine salt of the (−)-(S,S)-enantiomer. © 2003 Elsevier
Science Ltd. All rights reserved.
1. Introduction
prompted us to investigate the asymmetric cycloaddi-
tion of a series of chiral fumarates to anthracene.
Asymmetric Diels–Alder reactions involving fumaric
acid provide access to optically active C2-symmetric
dicarboxylic acids of interest as chiral building blocks
for the synthesis of enantiopure selectors that might be
useful in asymmetric catalysts or chiral stationary
phases. The exploitation of Lewis acids in asymmetric
cycloadditions has led to increased selectivity owing to
the lower temperature that can be used during the
reaction.1 A further development was made in the late
1970’s when it was found that the chiral auxiliary,
previously being a part of one of the reaction compo-
nents, also could be a part of the catalyst.2
2. Results and discussion
The cycloaddition reactions were run under the condi-
tions outlined in Scheme 1. Due to the low reactivity of
anthracene as compared to the more commonly used
conjugated dienes in Diels–Alder reactions, the temper-
ature had to be significantly higher than what usually
has been the case in catalyzed, asymmetric cycloaddi-
tions.4a Nevertheless, as observed previously for the
reaction with di-(−)-menthyl fumarate,4 high d.e.’s5
were obtained (Table 1).
In connection with our work on new C2-symmetric
chiral selectors for enantioselective liquid chromatogra-
phy, the (−)-(S,S)-enantiomer of trans-9,10-dihydro-
9,10-ethanoanthracene-11,12-dicarboxylic acid was
prepared via the reaction between fumaric acid and
anthracene followed by resolution with brucine.3 This
stereoisomer has been prepared previously via Lewis
acid catalyzed addition of di-(−)-menthyl fumarate to
anthracene.4 The easy access to chiral dienophiles of
this type and the high selectivity (99% d.e.) achieved,
The diesters from the asymmetric Diels–Alder reactions
were hydrolysed to the corresponding dicarboxylic acid
(trans-9,10-dihydro-9,10-ethanoanthracene-11,12-dicar-
boxylic acid, 3), which is resolved by enantioselective
chromatography,6 thus permitting a determination of
the degree of racemization during the hydrolysis. Two
different methods of hydrolysis, as described in the
experimental part, were studied. On alkaline hydrolysis
with the use of dilute sodium hydroxide, the product 3
showed an e.e. about 40% lower than the d.e. of the
diester 2. Acid hydrolysis with a mixture of acetic acid
and hydrochloric acid, though, resulted in a degree of
racemization of only about 10%. Some methods of mild
hydrolysis, such as one involving a transesterification
* Corresponding author. Tel.: +46-31-7723841; fax: +46-31-7723840;
e-mail: allen@organic.gu.se
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00172-1

1318
L. Thunberg, S. Allenmark / Tetrahedron: Asymmetry 14 (2003) 1317–1322
Scheme 1.
with bis(tributyltin) oxide,7 were also tried, but unfortu-
nately gave no reaction.
lyzed CO–ethylene copolymerization8c and Pd-catalyzed
asymmetric allylic alkylations.8d
Despite a certain degree of racemization obtained in the
hydrolysis of 2, the absolute configuration of the
diastereomer obtained in excess was determined by
correlation to the absolute configuration of 3 (Table 1).
The enantiomers of 3 have previously been reported to
be of (−)-(S,S)- or (+)-(R,R)-configuration, as deter-
mined by CD spectroscopy9 and by stereochemical
correlation.9a Due to the complexity involved in these
determinations, however, some degree of uncertainty
still remained. Therefore, in order to confirm conclu-
sively the absolute configuration of the products, an
X-ray crystallographic structural determination of the
brucine salt of (−)-3 was carried out. From the X-ray
structure of the salt given in Figure 2, the (−)-(S,S)-
configuration was definitely verified. Since the absolute
structure parameter was 0.3(8), the absolute configura-
tion was determined by correlation to the known
configuration of brucine. The angles between the aro-
matic rings, C6ꢀC7ꢀC8 and C1ꢀC14ꢀC13, were
107.22(16) and 107.62(15)°, respectively.10 This is less
than in both the unbridged 9,10-dihydroanthracene at
144.7° and in the bridged but unsubstituted 9,10-eth-
ano-9,10-dihydroanthracene at 124.7°.11 From X-ray
crystallographic studies on diethyl 9,10-dihydro-9,10-
ethanoanthracene-11,12-dicarboxylate with an angle of
117.22(4)°, it is found that the O-substituent also
affects the size of the angle.11c Figure 3 shows the
interactions between the brucinium cation and the
monoanion of (−)-3 in the crystal structure.
Lithium aluminium hydride reduction of 2 to the corre-
sponding diol 4 gives no racemization and provides an
independent method to determine the diasteromeric
excesses of all cycloaddition products 2. The enan-
tiomeric excess of 4 was determined by enantioselective
chromatography (Fig. 1). The diol obtained, either in
its (S,S)- or (R,R)-form (Table 1), should be useful in
the synthesis of chiral phosphine ligands8a utilized in
asymmetric catalysis, for example Rh- or Ru-catalyzed
enantioselective hydrogenation reactions,8b Pd-cata-
Table 1. Results obtained from the asymmetric Diels–
Alder reactions
Entry number D.e. (%)
Absolute
configuration
CD, uext (Dmext)
2a
2b
2c
2d
2e
98.9
82.2
95.4
95.2
85.9
(S,S)
(R,R)
(S,S)
(S,S)
(S,S)
206 (+25.39)
206 (−24.04)
207 (+22.26)
207 (+18.23)
206 (+25.99)
From a synthetic point of view, the partial racemization
obtained during the ester hydrolysis presents no prob-
lem, since we found that for e.e. values >75%, the pure
enantiomer of the dicarboxylic acid 3 can be readily
obtained by recrystallization. In previous syntheses,
optically active 3, used as starting material in the
synthesis of several possible chiral selectors,3b has been
obtained by recrystallization of its brucine salts;3a how-
ever, due to the cost and high toxicity of brucine, this is
undesirable in large scale processes.
Figure 1. Chromatographic separation of the enantiomers of
4 on Kromasil CHI-DMB 250×4.6 mm I.D. column; mobile
phase: 5% 2-propanol in hexane; flow rate: 1.5 mL/min;
The stereochemical outcome of the reaction is governed
by the most favourable orientation of the fumarate
dienophile in the transition state, which, in turn, is
dependent on the configuration of the terpenyl moiety.
detection: UV 225 nm; k% =4.11, h=1.29.
1

L. Thunberg, S. Allenmark / Tetrahedron: Asymmetry 14 (2003) 1317–1322
1319
Figure 2. The structure of the brucine salt of (−)-3 with 50%
probability ellipsoids.
Figure 4. CD spectra of the diastereomers of 2a and the
(S,S)-enantiomer of 4.
3. Experimental
3.1. General
Optical rotations were measured at 589 nm in a quartz
microcell of 1 dm pathlength and 0.5 mL volume.
Background-corrected CD spectra were recorded in
acetonitrile with a spectropolarimeter using 1 mm path-
lengths. Routine 1H NMR spectra were recorded at 400
MHz with CDCl3 or acetone-d6 as solvent. Mass spec-
tra were obtained with a high resolution mass spec-
trometer in the EI-MS and the FAB-MS mode. The
mass spectrometer was calibrated with PFK or PEG
600 and 3-nitrobenzyl alcohol or glycerol was used as a
matrix. Analytical liquid chromatography for determi-
nation of enantiomeric and diastereomeric excess was
performed on 250×4.6 mm I.D. columns.13
Figure 3. Interactions between brucine and (−)-3 in the crystal
structure.
3.2. Synthesis of fumarates 1a–e:14 general procedure
Due to the small free energy differences involved, how-
ever, a rationalization of the results given in Table 1 is
hard to make. The effects from small changes are
evident from the reduction of d.e. from 99 to 82% by
changing the configuration at C5 in the menthyl group;
a part of the dienophile quite remote from the reacting
p-bond. The small decrease of d.e. (from 99 to 95%)
seen when changing the dienophile from 1a to 1c might
be due to the slightly reduced steric demand of the
propenyl group as compared to the isopropyl group.
Fumaryl chloride (16 mmol) was added to a solution of
one of the optically active alcohols (32 mmol) in anhy-
drous toluene (30 mL) at 60°C. The solution was
refluxed for 20 h under nitrogen. The cooled solution
was washed with water (3×15 mL) and 10% NaOH
solution (3×15 mL), dried over MgSO4, filtered and the
solvent was evaporated under reduced pressure.
3.2.1. Di-(−)-menthyl fumarate, 1a. Yield 67%. [h]2D0=
−99.9 (c 2.0, CHCl3) (Ref. 15: [h]2D5=−98.5 (c 2.04,
Figure
4
shows the CD spectra of the two
1
CHCl3)). H NMR (400 MHz, CDCl3): l 6.83 (s, 2H),
diastereomers of the dimenthyl ester 2a and the (S,S)-
enantiomer of 4. As expected, the spectra of the two
diastereomers are almost mirror images of each other.
Moreover, the diastereomer obtained from the cycload-
dition reaction and the diol, both of (11S,12S)-configu-
ration, show a positive Cotton effect (CE) at 230 nm
4.80 (m, J=4.39, 10.9 Hz, 2H), 2.03 (d, J=11.9 Hz,
2H), 1.87 (m, J=2.76, 6.91 Hz, 2H), 1.70 (d, J=11.9
Hz, 4H), 1.48, (m, J=3.02, 11.9 Hz, 4H), 1.05 (m, 4H),
0.91 (m, J=6.91 Hz, 14H), 0.76 (d, J=6.90 Hz, 6H)
ppm.16
1
with essentially identical Dm, resulting from a Lb transi-
tion in the aromatic parts. The CE at 206 nm has a
3.2.2. Di-(+)-isomenthyl fumarate, 1b. Yield 68%. [h]2D0=
1
considerably larger Dm for 2a as compared to 4, show-
+21.4 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3): l
1
ing that in 2a this band corresponds not only to the La
6.82 (s, 2H), 5.15 (m, J=3.40, 6.68 Hz, 2H), 1.90 (m,
2H), 1.75 (m, J=6.70 Hz, 2H), 1.62 (m, 4H), 1.50 (m,
6H), 1.38 (m, J=4.07, 6.70 Hz, 2H), 1.24 (m, 2H), 0.95
(m, J=4.05 Hz, 12H), 0.86 (d, J=6.69 Hz, 6H) ppm.
transition in the aromatic parts, but is dominated by
the n“p* transition in the carbonyl group12 of the
ester.

1320
L. Thunberg, S. Allenmark / Tetrahedron: Asymmetry 14 (2003) 1317–1322
EI-MS: m/z calculated for C23H37O4 ((M−15)+)
3.3.2. (11S,12S)-Diisomenthyloxycarbonyl-9,10-dihydro-
9,10-ethanoanthracene, 2b. Yield 96%. d.e.=82.2%. Oil.
[h]2D0=−6.8 (c 2.0, CHCl3). CD (acetonitrile): uext (nm),
Dmext (cm2 mmol−1) 230, −2.864; 206, −24.04; 194,
377.2692, found 377.270.
3.2.3. Di-(−)-isopulegyl fumarate, 1c. Yield 65%. [h]2D0=
1
1
+13.38. H NMR (400 MHz, CDCl3): l 7.36 (m, J=
−25.7 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3): l
1.47, 6.95 Hz, 2H), 7.24 (m, 2H), 7.11 (m, J=1.48, 6.93
Hz, 4H), 4.95 (m, J=3.34, 3.67 Hz, 2H), 4.71 (s, 2H),
3.40 (s, 2H), 1.77 (m, J=6.70 Hz, 2H), 1.65 (m, 2H),
1.54 (m, 2H), 1.38 (m, 2H), 1.30 (m, 2H), 1.19 (m,
J=3.35, 3.65 Hz, 2H), 0.97 (m, 2H), 0.95 (d, J=6.70
Hz, 6H), 0.90 (m, 4H), 0.86 (dd, J=2.26, 6.69 Hz, 12H)
ppm. FAB-MS: m/z calculated for C38H50O4 (MH+)
571.3787, found 571.3837.
6.73 (s, 2H), 4.99 (m, J=4.32, 11.3 Hz, 2H), 4.72 (s,
4H), 2.16 (m, J=3.59, 11.3 Hz, 2H), 2.04 (d, J=11.3
Hz, 2H), 1.70 (m, 4H), 1.66 (s, 8H), 1.40 (m, J=3.60,
12.7 Hz, 2H), 1.07 (m, J=12.6 Hz, 2H), 0.94 (s, 8H)
ppm. EI-MS: m/z calculated for C24H36O4 (M+)
388.2614, found 388.264.
3.2.4. Di-(+)-fenchyl fumarate, 1d. Yield 79%. [h]2D0=
1
+46.6 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3): l
6.88 (s, 2H), 4.49 (m, J=1.88 Hz, 2H), 1.76 (m, J=2.78
Hz, 6H), 1.62 (dd, J=1.55, 10.3 Hz, 2H), 1.49 (m,
J=2.80, 1.53 Hz, 4H), 1.23 (dd, J=1.52, 10.3 Hz, 2H),
1.14 (s, 6H), 1.07 (s, 6H), 0.80 (s, 6H) ppm. EI-MS: m/z
calculated for C24H36O4 (M+) 388.2614, found 388.263.
3.3.3. (11S,12S)-Diisopulegyloxycarbonyl-9,10-dihydro-
9,10-ethanoanthracene, 2c. Yield 34%. d.e.=95.4%. Mp
185.2–186.9°C. [h]2D0=+3.3 (c 2.1, CHCl3). CD (acetoni-
trile): uext (nm), Dmext (cm2 mmol−1) 299, +2.978; 207,
1
+22.26; 194, −25.94. H NMR (400 MHz, CDCl3): l
7.29 (m, 2H), 7.17 (m, 2H), 7.06 (m, 4H), 4.87 (s, 2H),
4.65 (m, J=4.51 Hz, 2H), 4.58 (m, J=8.17 Hz, 4H),
3.28 (s, 2H), 1.86 (dd, J=2.99, 11.7 Hz, 2H), 1.70 (m,
2H), 1.67 (m, 6H), 1.47 (m, 2H), 1.42 (m, 4H), 1.33 (m,
J=2.98 Hz, 2H), 1.04 (m, J=11.7 Hz, 2H), 0.93 (m,
J=6.55 Hz, 4H), 0.87 (m, J=6.55 Hz, 4H) ppm. FAB-
MS: m/z calculated for C38H46O4 (MH+) 567.3474,
found 567.3503. HPLC (Dynamax Si 83-101-C, 35%
3.2.5. Di-(−)-bornyl fumarate, 1e. Yield 75%. [h]2D0=
−58.9 (c 1.0, CHCl3) (Ref. 15: [h]2D5=−60.7 (c 0.93,
1
CHCl3)). H NMR (400 MHz, CDCl3): l 6.87 (s, 2H),
5.00 (m, J=1.82, 2.24, 9.73 Hz, 2H), 2.41 (m, J=1.84,
4.08, 9.70 Hz, 2H), 1.99 (m, J=4.07, 11.1 Hz, 2H), 1.78
(m, 2H), 1.71 (m, J=4.32 Hz, 2H), 1.35 (m, J=4.31
Hz, 2H), 1.26 (m, J=4.33, 11.1 Hz, 2H), 1.03 (dd,
J=3.51, 13.6 Hz, 2H), 0.93 (s, 6H), 0.89 (s, 6H), 0.86 (s,
6H) ppm.17
dichloromethane in hexane, flow=2.0 mL/min) k%=
1
19.5, h=1.43.
3.3. Asymmetric Diels–Alder reactions (2a–e): general
3.3.4. (11S,12S)-Difenchyloxycarbonyl-9,10-dihydro-9,10-
ethanoanthracene, 2d. Yield 69%. d.e.=95.2%. Mp
173.7–173.9°C. [h]2D0=+35.3 (c 2.0, CHCl3). CD (aceto-
nitrile): uext (nm), Dmex1t (cm2 mmol−1) 230, +3.483; 207,
+18.23; 194, −13.13. H NMR (400 MHz, CDCl3): l
7.35 (m, J=1.39, 6.94 Hz, 2H), 7.28 (m, J=1.38 Hz,
2H), 7.10 (m, J=1.37, 6.94 Hz, 4H), 4.72 (s, 2H), 4.24
(s, 2H), 3.43 (s, 2H), 1.67 (m, 2H), 1.53 (m, 8H), 1.44
(m, J=1.27 Hz, 2H), 1.13 (m, J=1.28, 9.78 Hz, 2H),
1.05 (d, J=9.77 Hz, 6H), 0.98 (m, 2H), 0.78 (d, J=6.58
Hz, 6H), 0.76 (m, 4H) ppm. FAB-MS: m/z calculated
for C38H46O4 (MH+) 567.3474, found 567.3424. HPLC
(Dynamax Si 83-101-C, 25% dichloromethane in hex-
procedure
The fumarate (1a–e, 2 mmol) dissolved in anhydrous
toluene (10 mL) was added dropwise to a slurry of
AlCl3 (4 mmol) in the same solvent (20 mL). After 1.5
h of stirring at room temperature, anthracene (6 mmol)
dissolved in toluene (170 mL) was added. The yellow
solution was stirred for 48 h under nitrogen. The
solution was washed with 2 M HCl (4×100 mL) and 2
M NaOH (4×100 mL), dried over MgSO4, filtered and
the solvent was evaporated under reduced pressure. The
product was purified by flash chromatography on silica
with hexane/dichloromethane 50:50 as eluting solvent.
ane, flow=2.0 mL/min) k%=27.7, h=1.10.
1
3.3.1.(11S,12S)-Dimenthyloxycarbonyl-9,10-dihydro-9,10-
ethanoanthracene, 2a. Yield 78%. d.e.=98.8%. Mp
167.8–169.2°C (Ref. 18: mp 168.5–170°C). [h]2D0=−29.3
(c 2.0, CHCl3) (Ref. 18: [h]2D0=−30.0 (c 5.02, CHCl3)).
CD (acetonitrile): uext (nm), Dmext (cm2 mmol−1) 230,
3.3.5. (11S,12S)-Dibornyloxycarbonyl-9,10-dihydro-9,10-
ethanoanthracene, 2e. Yield 78%. d.e.=85.9%. Mp
128.5–129.2°C. [h]2D0=−8.7 (c 2.0, CHCl3). CD (aceto-
nitrile): uext (nm), Dmex1t (cm2 mmol−1) 230, +2.915; 206,
+25.99; 194, −12.70. H NMR (400 MHz, CDCl3): l
7.38 (m, J=1.12, 7.08 Hz, 2H), 7.26 (m, 2H), 7.12 (m,
J=1.15, 7.10 Hz, 4H), 4.75 (m, J=2.66, 9.49 Hz, 2H),
4.71 (s, 2H), 3.44 (s, 2H), 2.24 (m, J=3.90, 9.48 Hz,
2H), 1.88 (m, J=3.92, 10.7 Hz, 2H), 1.72 (m, J=3.90
Hz, 2H), 1.56 (s, 2H), 1.33 (m, 2H), 1.14 (m, J=4.30,
10.7 Hz, 2H), 0.86 (m, 2H), 0.80 (m, J=3.38 Hz,
16H), 0.76 (m, J=3.39 Hz, 2H) ppm. FAB-MS: m/z
calculated for C38H46O4 (MH+) 567.3474, found
567.3411. HPLC (Dynamax Si 83-101-C, 35%
1
+2.939; 206, +25.39; 194, −9.688. H NMR (400 MHz,
CDCl3): l 7.34 (m, J=7.16 Hz, 2H), 7.19 (m, J=7.16
Hz, 2H), 7.08 (m, J=1.31, 7.19 Hz, 4H), 4.66 (s, 2H),
4.54 (m, J=4.28, 10.8 Hz, 2H), 3.35 (s, 2H), 1.96 (m,
J=2.72, 6.74 Hz, 2H), 1.79 (d, J=12.3 Hz, 2H), 1.69,
(m, 4H), 1.38 (m, J=2.56, 10.7 Hz, 4H), 1.01 (m,
J=2.70, 12.3 Hz, 2H), 0.95 (d, J=6.76 Hz, 6H), 0.83
(d, J=6.75 Hz, 6H), 0.80 (m, 4H), 0.72 (d, J=6.78 Hz,
6H) ppm.18 FAB-MS: m/z calculated for C38H50O4
(MH+) 571.3787, found 571.3884. HPLC (Dynamax Si
83-101-C, 30% dichloromethane in hexane, flow=2.0
dichloromethane in hexane, flow=2.0 mL/min) k%=
1
mL/min) k%=16.0, h=1.17.
23.2, h=1.20.
1

L. Thunberg, S. Allenmark / Tetrahedron: Asymmetry 14 (2003) 1317–1322
1321
3.4. Synthesis of racemic 2a–e: general procedure
3.6. Reduction of 2a–e to 11,12-bis-(hydroxymethyl)-
9,10-dihydro-9,10-ethanoanthracene, 4: general
procedure
Dioxane (100 mL) was added to a mixture of fumaric
acid (1.69 g, 14.5 mmol) and anthracene (12.5 g, 67
mmol).19 After refluxing for 70 h the solvent was evap-
orated under reduced pressure. A 5% potassium bicar-
bonate solution (100 mL) was added and the mixture
was stirred for 3 h. The mixture was filtered and conc.
HCl was added to the filtrate until pH 1. The product
was isolated from the remaining fumaric acid by means
of filtration of the hot solution, yielding 82% ( )-3. Mp
253.1–253.7°C (Ref. 3a: mp 252.5°C).
A solution of the diester (2a–e, 0.03 mmol) in anhy-
drous diethyl ether (0.5 mL) was added dropwise to a
slurry of LiAlH4 (0.18 mmol) in the same solvent (0.5
mL). After refluxing for 3 h under nitrogen, diethyl
ether saturated with water (1 mL) was added and the
slurry was refluxed for 10 min. Water (1 mL) and 10%
H2SO4 were added until a clear solution was obtained.
The phases were separated and the organic layer was
washed with water (1 mL), dried over MgSO4, filtered
and the solvent was removed by evaporation under
reduced pressure. Mp (( )-4) 199.4–200.5°C (Ref. 20:
mp (( )-4) 198.5–199.5°C). Mp ((S,S)-4) 132.7–134.2°C
(Ref. 8a: mp ((R,R)-4) 131–132°C). (S,S)-4 [h]2D0=−15.0
(c 1.0, dioxane), [h]2D0=+11.1 (c 0.9, methanol) (Ref. 8a:
[h]52406=−15.2 (c 1, dioxane), [h]2D0=+11.1 (c 1.0,
methanol)). CD (acetonitrile): uext (nm), Dmext (cm2
mmol−1) 270, −0.406; 230, +3.291; 215, −2.015; 207,
Thionyl chloride (12 mmol) was added to a slurry of
( )-3 (3 mmol) in anhydrous toluene (13 mL) and one
drop of DMF. After refluxing for 4 h under a nitrogen
atmosphere, the solvent with the excess of thionyl chlo-
ride was evaporated under reduced pressure. Anhy-
drous toluene (2×10 mL) was added and evaporated
under reduced pressure. The acid chloride was dissolved
in anhydrous toluene (10 mL) and added to a solution
of the respective terpene alcohol (6 mmol) in the same
solvent (8 mL) at 45°C. After refluxing for 15 h under
nitrogen, the solution was washed with water (4×10
mL) and 10% NaOH solution (4×10 mL). The organic
layer was dried over MgSO4, filtered and the solvent
was evaporated under reduced pressure. The product
was purified by flash chromatography on silica with
hexane/dichloromethane 50:50 as eluting solvent.
1
+1.346; 198, −3.641. H NMR (400 MHz, CDCl3): l
7.28 (m, J=2.30 Hz, 2H), 7.24 (m, J=2.32 Hz, 2H),
7.11 (m, J=2.30, 4.85 Hz, 4H), 4.23 (d, J=1.58 Hz,
2H), 3.48 (m, J=6.34 Hz, 2H), 3.09 (m, J=1.60 Hz,
2H), 1.73 (m, J=6.35 Hz, 2H) ppm. HPLC (Kromasil
CHI-DMB, 5% 2-propanol in hexane, flow=1.5 mL/
min): k%=4.11, h=1.29.
1
3.7. X-Ray crystallography
3.5. Hydrolysis of 2a–e to 9,10-dihydro-9,10-ethanoan-
thracene-11,12-dicarboxylic acid, 3: general procedures
Crystal, experimental and refinement data are sum-
marised in Table 2. Diffracted intensities were mea-
sured with a Rigaku R-AXIS IIc image plate system
using graphite-monochromated Mo Ka radiation from
a RU200 rotating anode operated at 50 kV and 90 mA.
Using the CrystalClear software package, 90 oscillation
photos with a rotation angle of 2° were collected and
processed. An empirical absorption correction was
applied using the REQAB program in CrystalClear.
The structure was solved by direct methods (SHELXS)
and refined with full-matrix least-squares calculations
on F2 using SHELXL-97.21 operating in the WinGX
program package.22 Anisotropic thermal displacement
parameters were refined for all non-hydrogen atoms
while hydrogen atoms (except H17 on O1, H18 on N2
and H40) were included in calculated positions and
refined using a riding model. H17, H18 and H40 were
identified from a difference map and the positional
parameters were refined. Figure 2 shows the structure
of the monobrucinium salt of (−)-3 drawn with
ORTEP-3 under WinGX. The illustration of the spatial
organization of brucine and (−)-3 in Figure 3 has been
drawn with PLUTON under WinGX. Crystallographic
data for the structure in this paper has been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC-188176.
Copies of the data can be obtained free of charge at
3.5.1. Method A (alkaline hydrolysis). To a solution of
the diester (2a–e, 0.3 mmol) in toluene (20 mL), a 3 M
NaOH solution (20 mL) was added. After reflux for 2 h
the phases were separated. The aqueous phase was
extracted with diethyl ether (3×10 mL) and conc. HCl
was added until pH 2. The acidic aqueous phase was
extracted with diethyl ether (3×30 mL) and the com-
bined organic layers were dried over MgSO4, filtered
and the solvent was evaporated under reduced pressure.
3.5.2. Method B (acid hydrolysis). The diester (2a–e,
0.03 mmol) was dissolved in acetic acid (1 mL) and
conc. HCl (1 mL). After refluxing for 16 h, a 3 M
NaOH solution was added until pH 14. The solution
was extracted with diethyl ether (3×3 mL) and conc.
HCl was added to the aqueous phase until pH 2,
followed by extraction with diethyl ether (4×5 mL). The
combined organic layers were dried over MgSO4,
filtered and the solvent was evaporated under reduced
pressure. (S,S)-3 (e.e. >99%): Mp 219.8–220.2°C (Ref.
3a: mp 220.5°C). [h]25406=−15.5 (c 2.03, dioxane) (Ref.
3a: [h]25708=−15.3 (c 2, dioxane)). CD (acetonitrile): uext
(nm), Dmext (cm2 mmol−1) 218, −4.740; 206, +3.392; 197,
1
−8.604. H NMR (400 MHz, acetone-d6): l 7.42 (m,
J=1.69, 6.35 Hz, 2H), 7.32 (m, J=1.70, 6.33 Hz, 2H),
7.11 (m, J=1.67, 6.32 Hz, 4H), 4.83 (s, 2H), 3.38 (s,
2H) ppm. HPLC (Kromasil CHI-TBB, 2% 2-propanol
and 0.2% acetic acid in hexane, flow=2.0 mL/min):
http://www.ccdc.cam.ac.uk/conts/retrieving.html
or
from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CD21EZ, UK (fax: +44-1223-
336-033; e-mail: deposit@ccdc.cam.ac.uk).
k%=7.48, h=1.28.
1

1322
L. Thunberg, S. Allenmark / Tetrahedron: Asymmetry 14 (2003) 1317–1322
Table 2. X-Ray crystallographic data for the brucine salt
of (−)-3
E. L.; Mehlmann, J.; Kasparec, J.; Axelsen, P. H. Angew.
Chem., Int. Ed. 2001, 40, 743–745.
5. The diastereomeric excesses were determined by liquid
chromatography on silica using 30% of dichloromethane
in hexane.
6. Resolution is achieved by a Kromasil CHI-TBB 250×4.6
mm I.D. column; mobile phase: 2% 2-propanol and 0.2%
acetic acid in hexane; flow rate: 2 mL/min; detection: UV
Empirical formula
Formula weight (g/mol)
Temperature (K)
C41H40N2O8
688.75
293
0.71073
Orthorhombic
P212121 (c19)
10.3854(14)
13.8236(19)
22.973(3)
90
90
90
3298.1(8)
4
1.387
,
Wavelength (A)
Crystal system
Space group
,
a (A)
225 nm; amount injected: 20 mL of 5 mg/mL; k% =7.28,
1
,
b (A)
h=1.28.
,
c (A)
7. Deb, C.; Basu, B. Indian J. Chem. 1992, 31B, 131–132.
8. (a) Do¨bler, C.; Kreuzfeld, H.-J. J. Prakt. Chem. 1983,
325, 1021–1026; (b) Kreuzfeld, H.-J.; Do¨bler, C. React.
Kinet. Catal. Lett. 1984, 24, 153–156; (c) Doherty, S.;
Robins, E. G.; Knight, J. G.; Newman, C. R.; Rhodes,
B.; Champkin, P. A.; Clegg, W. J. Organomet. Chem.
2001, 640, 182–196; (d) Trost, B. M.; Schroeder, G. M.;
Kristensen, J. Angew. Chem., Int. Ed. 2002, 41, 3492–
3495.
h (°)
i (°)
k (°)
3
,
V (A )
Z
Dcalcd (mg/m3)
Reflections collected
Independent reflections
Absorption coefficient
26980
7466 (Rint=0.0688)
0.096
(mm−1
F(000)
)
9. (a) Brienne, M.-J.; Jacques, J. Bull. Soc. Chim. Fr. 1974,
11, 2647–2652; (b) Hagishita, S.; Kuriyama, K. Tetra-
hedron 1972, 28, 1435–1467.
1456
q Range for data collection 2.61–27.50
(°)
10. (a) These values agree very well with those of the corre-
sponding angles (108.04 and 107.87°, respectively)
obtained from a DFT calculation (NLSDA/BP86 func-
tional with a DN* basis set within the Spartan10b pro-
gram) on the free diacid 3; (b) Spartan Version 5.0,
Wavefunction, Inc., 18401 Von Karman Ave., Suite 370,
Irvine, CA 92612.
11. (a) Herbstein, F. H.; Kapon, M.; Reisner, G. M. Acta
Crystallogr. 1986, B42, 181–187; (b) Burrows, L.; Mas-
novi, J.; Baker, R. J. Acta Crystallogr. 1999, C55, 236–
239; (c) Winicker, D.; Bolte, M. Acta Crystallogr. 2000,
C56, e271–e272.
Completeness to q=27.50° 98.6
(%)
Index ranges
−125h513, −175k517,
−295l529
Crystal size (mm)
0.2×0.2×0.2
Data/restraints/parameters
Goodness-to-fit on F2
Final R indices [I\2|(I)]
7466/0/452
1.004
R1=0.0494, wR2=0.1088
R1=0.0616, wR2=0.1141
0.301, −0.240
R indices (all data)
3
,
Dzmax, Dzmin (e/A )
12. Simonetta, M.; Carra`, S. In The Chemistry of Carboxylic
Acids and Esters; Patai, S., Ed.; John Wiley and Sons:
New York, 1969; pp. 1–52.
Acknowledgements
13. Determination of d.e.’s was performed with the use of a
Dynamax Si 83-101-C column (Rainin Instrument Com-
pany, Inc., Woburn, USA). A Kromasil CHI-DMB
column (EKA Chemicals AB, Bohus, Sweden) was used
to determine e.e. values.
This work was supported by the Swedish Foundation
for Strategic Research. We are grateful to Professor
Mikael Ha˚kansson at our department for his help with
the X-ray crystallographic structure determination.
14. Donnelly, I. H.; Kambouris, P.; Nonhebel, D. C.; Rohr,
T.; Sherrington, D. C. J. Chem. Soc., Perkin Trans. 2
1996, 9, 1821–1829.
References
15. Ferna´ndez, F.; Garc´ıa, G.; Rodr´ıguez, J. E. Synth. Com-
1. (a) Yates, P.; Eaton, P. J. Am. Chem. Soc. 1960, 82,
4436–4437; (b) Poll, T.; Metter, J. O.; Helmchen, G.
Angew. Chem., Int. Ed. Engl. 1985, 24, 112–114; (c)
Reetz, M. T.; Hu¨llman, M.; Massa, W.; Berger, S.;
Rademacher, P.; Heymanns, P. J. Am. Chem. Soc. 1986,
108, 2405–2408.
mun. 1990, 20, 2837–2847.
16. Kiesman, W. F.; Petter, R. C. Tetrahedron: Asymmetry
2002, 13, 957–960.
17. Matsumoto, A.; Sano, Y.; Yoshioka, M.; Otsu, T. Eur.
Polym. J. 1996, 32, 1079–1085.
18. Takacs, J. M.; Quincy, D. A.; Shay, W.; Jones, B. E.;
Ross, C. R. Tetrahedron: Asymmetry 1997, 8, 3079–3087.
19. Bachmann, W. E.; Scott, L. B. J. Am. Chem. Soc. 1948,
70, 1458–1461.
20. Nozaki, H.; Katoˆ, H.; Noyori, R. Tetrahedron 1969, 25,
1661–1665.
21. Sheldrick, G. M. University of Go¨ttingen, Go¨ttingen,
Germany, 1998.
22. Furrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
2. (a) Hashimoto, S.; Komeshima, N.; Koga, K. J. Chem.
Soc. Chem. Commun. 1979, 437–438; (b) For an excellent
review of catalytic asymmetric Diels–Alder reactions, see:
Kagan, H.; Riant, O. Chem. Rev. 1992, 92, 1007–1019.
3. (a) Brienne, M.-J.; Jacques, J. Bull. Soc. Chim. Fr. 1973,
190–197; (b) Allenmark, S.; Skogsberg, U.; Thunberg, L.
Tetrahedron: Asymmetry 2000, 11, 3527–3534.
4. (a) Furuta, K.; Iwanaga, K.; Yamamoto, H. Tetrahedron
Lett. 1986, 27, 4507–4510; (b) Winkler, J. D.; Piatnitski,