Resolution of C2-symmetric 9,10-dihydro-9,10-ethanoanthracene- 11,12- dicarboxylic acid and 2,3-diphenylsuccinic acid using (S)-proline

Article abstract of DOI:10.1016/S0957-4166(98)00274-2

Racemic 9,10-dihydro-9, 10-ethanoanthracene- 11,12-dicarboxylic acid is resolved to obtain the corresponding (S,S)-isomer in 96±2%, cc and the (R,R)-isomer in 97 ± 2% ee through complexation with (S)-proline in methanol. The racemic 2,3-diphenylsuccinic acid has been resolved to obtain the (S,S)-isomer in 93% ee using (S)-proline in methanol.

Full text of DOI:10.1016/S0957-4166(98)00274-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2651–2656
Resolution of C -symmetric 9,10-dihydro-9,10-
2
ethanoanthracene-11,12-dicarboxylic acid and
2
,3-diphenylsuccinic acid using (S)-proline
∗
C. Ramaraj Ramanathan and Mariappan Periasamy
School of Chemistry, University of Hyderabad, Hyderabad-500 046, India
Received 21 May 1998; accepted 9 July 1998
Abstract
Racemic 9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboxylic acid is resolved to obtain the corresponding
(
S,S)-isomer in 96ꢀ2% ee and the (R,R)-isomer in 97ꢀ2% ee through complexation with (S)-proline in methanol.
The racemic 2,3-diphenylsuccinic acid has been resolved to obtain the (S,S)-isomer in 93% ee using (S)-proline in
methanol. © 1998 Published by Elsevier Science Ltd. All rights reserved.
1. Introduction
Amino acids are an important class of chiral-pool compounds which are useful in asymmetric
1
2a
synthesis. These compounds are obtained from natural sources or by resolution. For example, (ꢀ)-
2
b
proline was resolved using optically active tartaric acid. Amino acids are also resolved using chiral
resolving agents such as chiral sulphonic acids3 and phosphoric acids. Very recently, we and others
have reported the use of (S)-proline for the resolution of certain racemic compounds through the
corresponding diastereomeric complex formation.4 These results prompted us to examine the use of
a
3b
–6
(
S)-proline as a chiral reagent for the resolution of C -symmetric 9,10-dihydro-9,10-ethanoanthracene-
2
11,12-dicarboxylic acid 1 and 2,3-diphenylsuccinic acid 2, which have proven applications as starting
materials for the preparation of certain useful C -symmetric chiral ligands.
2
∗
Corresponding author.
0957-4166/98/$ - see front matter © 1998 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00274-2

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C. R. Ramanathan, M. Periasamy / Tetrahedron: Asymmetry 9 (1998) 2651–2656
2. Results and discussion
The chiral dicarboxylic acid 1 was previously obtained in enantiomerically pure form either by an
7
8
asymmetric Diels–Alder reaction or by resolution. We have observed that it can be resolved using
(
5
S)-proline 3 following a convenient protocol. When racemic 1 and 3 were dissolved in methanol, a
precipitate was formed after 4 h (Scheme 1). After filtration and decomposition of the precipitate with an
ether/water mixture, (11S,12S)-(−)-1 was isolated (25–28% yield, 96ꢀ2% ee).
Scheme 1.
Fortunately, the residue obtained after evaporation of the fraction of the complex containing (+)-
isomer gave crystals upon recrystallisation from fresh methanol (Scheme 1). After decomposition of
this crystalline complex with an ether/water mixture, (11R,12R)-(+)-1 was isolated (19% yield, 97ꢀ2%
ee). The same result was also obtained by concentration of the filtrate followed by crystallisation. Partial

C. R. Ramanathan, M. Periasamy / Tetrahedron: Asymmetry 9 (1998) 2651–2656
2653
resolution was also achieved using ethanol as solvent. For example, (11S,12S)-(−)-1 (23% yield, 72%
ee) was obtained from the precipitate and the filtrate gave (11R,12R)-(+)-1 (56% yield, 44% ee).
Scheme 2.
It was found that stirring (S)-proline 3 and racemic 1 in methanol at room temperature for 4 h
9
gave a precipitate which, on decomposition and work-up, yielded (11S,12S)-1 in 86% ee (25%). The
(11R,12R)-1 isomer was isolated from the filtrate with 38% ee (71%). This experiment indicates that the
crystal growth may be an important factor for obtaining better results. When solutions of (S)-proline 3
and racemic 1 in methanol were mixed at 0°C and stirred for 4 h, a precipitate was obtained. After work-
up, (11S,12S)-1 was isolated only in 71% ee (40%). The filtrate fraction after work-up gave (11R,12R)-1
with 64% ee (54%). These results indicate that both (−)-1:3 and (+)-1:3 complexes precipitated at 0°C,
resulting in a higher chemical yield with a lower enantiomeric excess.9
We have also examined the resolution of the synthetically useful C -symmetric 2,3-diphenylsuccinic
2
acid 2 using 3. Previously, this acid has been obtained in enantiomerically pure form by asymmetric
10
11
homocoupling, resolution using brucine or through synthesis of the diastereomeric monomenthyl
12
ester. We have observed that when (ꢀ)-2 and 3 (1:1) were dissolved in methanol and allowed to stand
for crystallisation at room temperature (12 h), a white precipitate was formed (Scheme 2). The precipitate
was filtered and decomposed with an ether/water mixture to obtain (2S,3S)-(+)-2 (24% yield, 68% ee).
The filtrate fraction gave (2R,3R)-(−)-2 (17% ee, 64% yield). Since only partial resolution was realised,
we have undertaken efforts to enhance the enantiomeric purity further. When (2S,3S)-(+)-2 (68% ee) was
treated with 3 in methanol, (2S,3S)-(+)-2 with 93% ee (66% yield) was obtained. A similar operation
with (2R,3R)-(−)-2 (25% ee) resulted in a precipitate from which the (2R,3R)-(−)-2 (20% yield, 41% ee)
was regenerated.
The elemental analysis of the precipitate formed in the reaction of (S)-proline 3 with chiral acid (+)-
1
indicated that it was a 1:1 complex. This was further confirmed by X-ray crystal structure analysis
of the crystal of the compound obtained from (11R,12R)-(+)-1 and 3 (Fig. 1). The bond lengths 1.205
Å and 1.199 Å respectively of C(23)–O(6) and C(23)–O(5), show that (S)-proline is in zwitterionic
form. The bond lengths 1.202 Å and 1.315 Å of C(17)–O(1) and C(17)–O(2), respectively, indicate that
the dicarboxylic acid 1 is in the carboxylic acid form. The hydrogen bonding between the ammonium
hydrogens of the zwitterionic form of (S)-proline and the carbonyl oxygen of two different carboxylic
acids is illustrated in the interatomic distances 2.949 Å and 2.891 Å of N(1)–O(1) and N(1)–O(4),
respectively. The hydrogen bonded array in the crystal packing is shown in Fig. 2.
The product derived from (−)-1 and 3 was not suitable for crystal structure analysis. Elemental analysis
of the product of (+)-2 and 3 indicated that it was a 1:1 complex. Unfortunately, this compound also failed
13
to give crystals suitable for X-ray analysis.
The chiral dicarboxylic acid 1 has been used to prepare chiral phosphines and chiral diols for
1
4
15
applications in palladium and titanium catalysed reactions. The chiral dicarboxylic acid 2 has been
16
17
used to prepare C -chiral diamines for osmylation and organometallic addition reactions. Therefore,
2
the operationally simple and convenient procedures for the resolution of 1 and 2 described here should
be useful for synthetic applications involving these chiral ligands.

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C. R. Ramanathan, M. Periasamy / Tetrahedron: Asymmetry 9 (1998) 2651–2656
Fig. 1. ORTEP diagram for 1:1 complex of 1 and 3
Fig. 2. Molecular packing diagram
3. Experimental section
8
10
The racemic 1 and 2 were prepared following reported procedures. (S)-Proline supplied by Aldrich
USA) was used. Enantiomeric excesses were calculated based on the previously reported [α] values.
(
D
Optical rotations were measured on an Autopol-II automatic polarimeter. Elemental analyses were
performed on a Perkin–Elmer elemental analyser model 240C. The methanol, ethanol and acetone
18
solvents were distilled as recommended.
3.1. Resolution of 9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboxylic acid 1
The racemic 9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboxylic acid 1 (28.4 g, 96.6 mmol) and
(S)-proline (11.5 g, 100 mmol) were dissolved in methanol (300 ml) in a 500 ml round-bottomed flask by
gentle heating over a water bath. The flask was closed with a glass stopper and allowed to stand at room
temperature. After 4 h the crystalline material formed was filtered and washed with cold methanol (50

C. R. Ramanathan, M. Periasamy / Tetrahedron: Asymmetry 9 (1998) 2651–2656
2655
ml). The precipitate (mp 231–232°C) was decomposed by stirring with a mixture of diethyl ether (100
ml) and water (100 ml). The organic layer was separated and the aqueous layer was extracted with ether
(
3×90 ml). The combined organic extract was washed with brine, dried over anhydrous MgSO , filtered
4
and evaporated to obtain (11S,12S)-(−)-9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboxylic acid 1,
8
a
27
7
.2 g (25% yield, 96ꢀ2% ee) (mp 225–226°C, lit. mp 226–227°C); [α] =−7.62ꢀ0.15 (c 1.574,
D
8
a
27
CH OH), lit. [α] =+7.9 (c 0.795, CH OH). The dimethyl ester of (11S,12S)-(−)-1 had [α] =−21.33
3
D
3
D
8
a
(c 0.1476, CH OH), [lit. [α] =+21.7 (c 0.1476, CH OH), for (11R,12R)-(+)-1]. The filtrate was
3
D
3
evaporated to dryness and redissolved in fresh methanol (200 ml) and allowed to crystallise. After 12
h at room temperature, the colourless crystals formed were filtered. This complex (mp 237–238°C) on
decomposition followed by work-up with ether (90 ml) and water (90 ml) as mentioned above gave
(
11R,12R)-(+)-dihydro-9,10-ethanoanthracene-11,12-dicarboxylic acid 1, 5.3 g (19% yield, 97ꢀ2% ee)
8
a
27
(
mp 225–226°C, lit. mp 226–227°C), mp (ꢀ)-1 240–242°C; [α] =+7.73ꢀ0.15 (c 1.164, CH OH),
D
3
8
a
27
8a
lit. [α] =+7.9 (c 0.795, CH OH). Its dimethyl ester showed [α] =+21.19 (c 0.378, CH OH), lit.
D
3
D
3
[α] =+21.7 (c 0.1476, CH OH). The filtrate obtained after removal of the (+)-1 and 3 complex, after
D
3
evaporation of methanol and usual work-up as mentioned earlier gave the (11R,12R)-(+)-9,10-dihydro-
,10-ethanoanthracene-11,12-dicarboxylic acid 1, 14.77 g (52% yield, 5% ee). Anal. calcd for the 1:1
9
complex of (−)-1 and 3 (C H NO ): C 67.48%; H 5.62%; N 3.42%. Found: C 67.47%; H 5.73%; N
23
23
6
3
.43% and for the complex of (+)-1 and 3 (C H NO ) found: C 67.83%; H 5.77%; N 3.69%.
23 23 6
3.2. Resolution of 2,3-diphenylsuccinic acid 2
The racemic 2,3-diphenylsuccinic acid 2 (2.7 g, 10 mmol) and (S)-proline (1.15 g, 10 mmol) were
dissolved in 30 ml of methanol. The flask was closed and allowed to stand at room temperature for 12 h.
The precipitated material was filtered. The filtrate was concentrated to dryness and decomposed with a
mixture of ether (40 ml) and water (40 ml). The organic layer was separated and the aqueous layer was
extracted with ether (3×25 ml). The combined organic extracts were washed with brine solution, dried
over anhydrous MgSO , filtered and then evaporated to obtain (2R,3R)-(−)-2,3-diphenylsuccinic acid 2,
4
2
7
11
13
1
.72 g (64% yield, 17% ee); [α] =−62 (c 0.322, ethanol), lit. [α] =−368.9 (c 2.33, ethanol). The
D
D
precipitate fraction on decomposition with an ether/water mixture, extraction and evaporation gave the
2
7
11
(
[
2S,3S)-(+)-2,3-diphenylsuccinic acid 2, 0.58 g (24% yield, 68% ee); [α] =+254 (c 0.26, ethanol), lit.
α] =+369.5 (c 1.49, ethanol).
D
1
5
D
3.3. Enrichment of partially resolved (+)-2,3-diphenylsuccinic acid 2
The (2S,3S)-(+)-2 (68% ee, 0.42 g, 1.6 mmol) and (S)-proline (0.2 g, 1.7 mmol) were dissolved in 6
ml of methanol and kept for crystallisation for 5 h. The precipitated material was filtered. The filtrate
on evaporation followed by decomposition with a mixture of ether (20 ml) and water (20 ml) and usual
2
7
work-up gave the (2S,3S)-(+)-2,3-diphenylsuccinic acid 2, 0.138 g (32% yield, 43% ee); [α] =+159
D
(c 0.088, ethanol). The precipitate after treatment with a mixture of ether (20 ml) and water (20 ml)
for 1–2 h, work-up and evaporation gave (2S,3S)-(+)-2,3-diphenylsuccinic acid 2, 0.28 g (66% yield,
1
1
9
[
3% ee) (mp 183–185°C, lit. mp 183°C) [mp (ꢀ)-2 183°C, solidifies and remelts at 220–221°C];
27 27
11
α] =+343 (c 0.108, ethanol), lit. [α] =+369.5 (c 1.49, ethanol). The corresponding dimethyl ester
D D
2
7
11
27
showed [α] =+333.3 (c 0.105, acetone), lit. [α] =+341.9 (c 1.082, acetone). Anal. calcd for the 1:1
D
D
complex of (+)-2 and 3 (C H NO ): C 65.45%; H 5.97%; N 3.64%. Found: C 64.03%; H 5.50%; N
21
23
6
2.86%.

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C. R. Ramanathan, M. Periasamy / Tetrahedron: Asymmetry 9 (1998) 2651–2656
Acknowledgements
We are thankful to the UGC, New Delhi for support under the Special Assistance Programme. C.R.R.
thanks UGC, New Delhi for financial support. We thank Dr. S. Pal and Dr. K. C. Kumaraswamy for their
help in crystal structure analysis. We also thank Professor P. S. Zacharias for providing National Single
Crystal X-Ray Facility funded by DST, New Delhi.
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1
6 w 1 1 1
:1 in the unit cell; empirical formula, C23H23NO (f 409.42); space group P2 2 2 ; a=8.436(8) Å, b=18.9881(12)
3
3
Å, c=12.6937(11) Å; V=2033(2) Å , Dcalc=1.337 Mg/m ; α=β=γ=90°; Mo-Kα radiation (0.71073 Å) at 293 K; 3998
reflections were collected, with 2043 independent reflections; refinement method full-matrix least squares of F ; GOF
on F =1.040. Final R indices [I>2σ(I)], R1=0.0507, wR2=0.1237; R indices (all data)=0.0606, wR2=0.1330; absolute
2
2
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