A simple method for resolution of endo-/exo-monoesters of trans-norborn-5-ene-2,3-dicarboxylic acids into their enantiomers

Article abstract of DOI:10.1002/chir.22404

Separation of optical isomers obtainable from trans-norborn-5-ene-2,3-dicarboxylic acid methyl and tert-butyl monoesters was performed by crystallization of the respective salts prepared with (R)- and (S)-1-phenylethylamine. Starting from racemic endo-monomethyl ester of trans-norborn-5-ene-2,3-dicarboxylic acid, prepared by partial hydrolysis of the cyclopentadiene-dimethyl fumarate adduct, the corresponding (2R, 3R)-endo-monoester was isolated in 97% enantiomeric excess (ee) yield after seven repeated crystallizations from tetrachloromethane. Starting from exo-mono-tert-butyl ester of the same acid, prepared by alcoholysis of the cyclopentadiene-maleic anhydride adduct followed by isomerization, (2R, 3R)-exo-monoester was isolated in >98% ee yield after four repeated crystallizations from ethanol. Crystallization of the acids from the mother liquor yielded products with inverse stereochemical configuration.

Full text of DOI:10.1002/chir.22404

CHIRALITY (2014)
A Simple Method for Resolution of Endo-/Exo-Monoesters of Trans-
Norborn-5-Ene-2,3-Dicarboxylic Acids Into Their Enantiomers
VITALY N. KOVALENKO,* AND YURII YU. KOZYRKOV*
Department of Organic Chemistry, Belarusian State University, Minsk, Belarus
ABSTRACT
Separation of optical isomers obtainable from trans-norborn-5-ene-2,3-dicarboxylic
acid methyl and tert-butyl monoesters was performed by crystallization of the respective salts
prepared with (R)- and (S)-1-phenylethylamine. Starting from racemic endo-monomethyl ester of
trans-norborn-5-ene-2,3-dicarboxylic acid, prepared by partial hydrolysis of the cyclopentadiene-
dimethyl fumarate adduct, the corresponding (2R,3R)-endo-monoester was isolated in 97%
enantiomeric excess (ee) yield after seven repeated crystallizations from tetrachloromethane.
Starting from exo-mono-tert-butyl ester of the same acid, prepared by alcoholysis of the
cyclopentadiene-maleic anhydride adduct followed by isomerization, (2R,3R)-exo-monoester was
isolated in >98% ee yield after four repeated crystallizations from ethanol. Crystallization of the
acids from the mother liquor containing (S)-1-phenylethylamine yielded products with inverse
stereochemical configuration. Chirality 00:000–000, 2014. © 2014 Wiley Periodicals, Inc.
KEY WORDS: enantiomer separation; recrystallization; 1-phenylethylamine; norbornene; Diels-
Alder reaction
INTRODUCTION
Ethanol was dried over anhydrous CuSO
using standard procedures.
4
. Other solvents were dried
Bicyclo[2.2.1]heptene (norbornene) derivatives form an
important compound group because of their occurrence in
structures of numerous compounds of natural origin, as well
as their frequent use as building blocks to perform targeted
organic synthesis. They were used in the syntheses of a great
number of organic compounds of various classes. To build
up norbornene structures, the Diels-Alder reaction is
However, the number examples of
successful introduction of derivatized fumaric and maleic
acids in this reaction known so far is limited and, as a rule,
endo-3-(Methoxycarbonyl)bicyclo[2.2.1]hept-5-en-exo-2-carboxylic
1
9
acid [(±)-endo-3]. Diester (±)-2 (15.0 g, 71.35 mmol) was dissolved in
THF (120 mL) and water (1200 mL) was added to the stirred mixture. To
the mixture cooled to 0°C, a solution of KOH (4.87 g, 87.0 mmol) in water
1
–6
(330 mL) was added dropwise under stirring. The stirring of the reaction
7
–9
mixture was continued at 0°C for ~2 h. Then 2M HCl (100 mL) was added,
and the mixture was saturated with NaCl, filtered, and extracted with ethyl
acetate (4 × 150 mL). The combined organic extracts were washed with
frequently used.
brine (50 mL), dried over Na
pressure. The residue was dissolved in CCl
2
SO
4
and evaporated under reduced
(15 mL) under heating, then
1
0,11
it requires the use of chiral modifiers or catalysts.
4
Preparation of optically pure substances by resolving
racemates combined with readily available chiral compounds
using repeated crystallization is still a procedure widely used
in practice, since it ensures high purity of the products and
petroleum ether (150 mL) was added, and the mixture was cooled in
refrigerator (+4°C). The precipitate was separated by filtration, and twice
crystallized from a water/methanol mixture (4/1) to give pure monoester
(±)-endo-3 as white crystals (mp 119–121°C). Yield 7.95 g (57%). The IR
and NMR spectra of (±)-endo-3 were similar to those described in the
1
2–15
good reproducibility of results.
Several examples of
1
9
literature.
resolving racemic trans-norborn-5-ene-2,3-dicarboxylic acid
by repeated crystallization with chiral amines have been
described,1
6–18
but no similar examples pertaining to its
exo-3-(Methoxycarbonyl)bicyclo[2.2.1]hept-5-en-endo-2-carboxylic
acid [(±)-exo-6a]. Anhydride 5 (2.0 g, 12.2 mmol) was added
portionwise under reflux to a stirred solution of sodium methoxide
in methanol prepared from sodium (0.57 g, 24.8 mmol) and methanol
(20 mL). The reaction mixture was additionally stirred and refluxed for
monoesters were reported. At the same time, the presence
of diversified groups in organic compounds opens the way
for its selective transformation that has importance for
organic synthesis.
20
1
h and then cooled to room temperature (rt). Most of the solvent was
evaporated under reduced pressure and the residue was treated with 3M
HCl (20 mL) and brine (20 mL). After separation of the organic layer, the
aqueous phase was additionally extracted with ethyl acetate (5 × 10 mL).
The combined organic extracts were washed with brine (20 mL), dried over
MATERIALS AND METHODS
Melting points were determined with a capillary apparatus. Thin-layer
chromatography (TLC) was performed on aluminum-backed plates
coated with silica gel 60; the chromatograms were visualized by staining
with Ce/Mo reagent and subsequent heating. Column chromatography
2 4
Na SO and evaporated under reduced pressure. The monoester (±)-exo-6a
was obtained in a yield of 2.02 g (85%) as white crystals (mp 81–87°C), and
used without purification. The IR and NMR spectra of (±)-exo-6a were
1
13
19
similar to those described in the literature.
was performed using Merck 60 silica gel (70–230 mesh). H and
C
NMR spectra were obtained with a Bruker AC 400 spectrometer at 400
1
and 100 MHz, respectively, in CDCl
3
(CHCl
at δ = 77.0 ppm for C NMR as internal standard). For
NMR spectra recorded in CD OD, chemical shifts are given relative to
3
at δ = 7.26 ppm for
H
*Correspondence to: Vitaly N. Kovalenko or Yurii Yu. Kozyrkov, Department of
Organic Chemistry, Belarusian State University, Nezavisimosty Av. 4, Minsk,
13
NMR and CHCl
3
2
20030 Belarus. E-mail: kovalenkovn@rambler.ru or kozyrkovyu@gmail.com
3
1
13
Received for publication 17 July 2014; Accepted 19 September 2014
DOI: 10.1002/chir.22404
Published online in Wiley Online Library
(wileyonlinelibrary.com).
solvent peaks at δ = 3.32 ppm for H and δ = 49.1 ppm for C NMR. The
FT-IR spectra were recorded with a Vertex 70 spectrometer. Optical
rotations were measured at 25 ± 1°C with a polarimeter Atago AP 300.
©
2014 Wiley Periodicals, Inc.

KOVALENKO AND KOZYRKOV
exo-3-(tert-Butoxycarbonyl)bicyclo[2.2.1]hept-5-en-endo-2-carboxylic
acid [(±)-exo-6b]. Anhydride 5 (10.51 g, 64.0 mmol) was added
portionwise under reflux to a stirred solution of potassium tert-butoxide
in tert-butanol prepared from potassium (5.0 g, 128 mmol) and tert-butanol
was separated by filtration, washed with cooled CCl
lized six times from CCl as described above for the salt (2R,3R)-(–)-endo-
3•(R)-1. Salt (2S,3S)-(+)-endo-3•(S)-1 was obtained in a yield of 3.1 g
(26%) as white crystals ([α] = +69.5°, c 1.0 MeOH, mp 126–129°C). The
4
(30 mL), and recrystal-
20
4
D
(
1
110 g). The reaction mixture was additionally stirred and refluxed for
5 min and then cooled to rt. Most of the solvent was evaporated under
IR and NMR spectra were identical to those for the salt (2R,3R)-(–)-endo-
3•(R)-1.
reduced pressure and the residue was treated with 3M HCl (100 mL).
After separation of the organic layer, the aqueous phase was extracted with
(1S,2S,3S,4R)-endo-3-(Methoxycarbonyl)bicyclo[2.2.1]hept-5-en-
exo-2-carboxylic acid [(2S,3S)-(+)-endo-3]. Treatment of (2S,3S)-
(+)-endo-3•(S)-1 (2.0 g, 6.3016 mmol) in the same manner as described
above for (2R,3R)-endo-3 gave (2S,3S)-(+)-endo-3 in a yield of 1.19 g (96%)
as white crystals ([α] = +140°, c 1.0 MeOH, lit. [α] = +132.8°, c 1.0
D D
MeOH, mp 82–84°C). The spectral data were identical to those for
compound (2R,3R)-(–)-endo-3.
CH
2
Cl
2
(4 × 50 mL). The combined organic extracts were washed with
SO , and evaporated under
water (10 mL), brine (50 mL), dried over Na
2
4
reduced pressure. The residue was recrystallized from a water/methanol
2
1
mixture (2/3). The monoester (±)-exo-6b was obtained as white crystals
–
1 1
(
13.4 g, 88%, mp 84–86°C). IR (KBr): νmax = 2981, 1724, 1707 cm ;
NMR (400 MHz, CDCl ): δ 1.40–1.42 (m, 1H), 1.43 (c, 9H), 1.56–1.58
m, 1H), 2.52 (dd, J = 4.5, 1.5 Hz, 1), 3.05 (br s, 1H), 3.23 (br s, 1H), 3.36
app t, J = 4.5 Hz, 1), 6.08 (dd, J = 5.6, 3.0 Hz, 1), 6.25 (dd, J = 5.6, 3.0 Hz, 1),
H
3
(
(
1
4
(1S,2R,3R,4R)-Methyl 3-(((S)-1-phenylethyl)carbamoyl)-bicyclo[2.2.1]
1
3
22
1.4 (br s, 1H); C NMR (100 MHz, CDCl
8.2, 80.7, 135.1, 137.7, 173.3, 179.6. Anal. Calcd for C13
3
): δ 28.0, 45.5, 47.2, 47.6, 47.7,
(238.28):
hept-5-ene-2-carboxylate [(2R,3R)-4].
Compound (2R,3R)-(–)-endo-3
H O
18 4
(0.2 g, 1.02 mmol) was dissolved in oxalyl chloride (1 mL) and the
mixture was left at rt for 2 h. The reagent excess was evaporated at a
reduced pressure. Thereafter, a solution of (S)-(–)-1-phenylethylamine
C 65.53, H 7.61. Found: C 65.40, H 7.58.
Resolution of (± ±)Endo)-
2 2
((S)-1) (0.30 g, 2.5 mmol) in CH Cl (1 mL) was added and the mixture
was left at rt for 16 h. Then the reaction mixture was quenched with 2M
HCl (5 mL) and extracted with ethyl acetate (2 × 3 mL). The combined
Salt of (1R,2R,3R,4S)-endo-3-(methoxycarbonyl)-bicyclo[2.2.1]hept-
-en-exo-2-carboxylic acid and (R)-(+)-1-phenylethylamine [(2R,3R)-
–)-endo-3•(R)-1]. (R)-(+)-1-Phenylethylamine ((R)-1) (5.0 g, 41.25
mmol) was added portionwise to a hot solution of monoester (±)-endo-3
7.35 g, 37.46 mmol) in CCl (40 mL). The mixture was heated to reflux
5
(
organic extracts were successively washed with water (1 mL), NaHCO
1 mL), and brine (2 mL), and dried over Na SO . Evaporation of the
solvent under reduced pressure gave crude amide (2R,3R)-4 which was
3
(
2
4
(
4
1
analyzed without purification. H NMR (400 MHz, CDCl
m, 1H), 1.47 (d, J = 7.0 Hz, 3), 1.83–1.85 (m, 1H), 2.39 (dd, J = 4.5, 2.0 Hz, 1),
.98 (br s, 1H), 3.24 (br s, 1H), 3.29 (app t, J = 4.5 Hz, 1), 3.68 (s, 3H), 5.11
app quin, J = 7.0 Hz, 1), 6.09 (dd, J = 5.5, 3.0 Hz, 1), 6.22 (dd, J = 5.5, 3.5
3
): δ 1.43–1.46
and then slowly cooled to rt. After the main portion of crystals was formed,
the flask was transferred to a refrigerator (+4°C) for 16 h. The precipitate
was separated by filtration, washed with cooled CCl
(
2
(
4
(30 mL), and
recrystallized six times from CCl (~40 mL). While performing each of
4
Hz, 1), 6.31 (br d, J = 7.0 Hz, 1H), 7.25–7.38 (m, 5H).
the repeated crystallizations, a small amount of (R)-1 (0.12 g, 1.0 mmol)
was added to the solution. Salt (2R,3R)-(–)-endo-3•(R)-1 was obtained in
(
1R,2S,3S,4S)-Methyl 3-(((S)-1-phenylethyl)carbamoyl)-bicyclo[2.2.1]
a yield of 3.16 g, (26.5%) as white crystals ([α]
D
= –69.1°, c 1.0 MeOH,
–1 1
hept-5-ene-2-carboxylate [(2S,3S)-4]. Amide (2S,3S)-4 was prepared
mp 125–127°C). IR (KBr): νmax = 2975, 1719, 1636 cm
;
H NMR
): δ 1.34–1.37 (m, 1H), 1.52–1.54 (m, 1H), 1.68
d, J = 6.8 Hz, 3), 2.44 (br d, J = 3.5 Hz, 1), 2.85 (br s, 1H), 3.20 (br s, 1H),
.28 (app t, J = 3.5 Hz, 1), 3.71 (s, 3H), 4.39 (q, J = 6.8 Hz, 1), 6.10
dd, J = 5.5, 3.0 Hz, 1), 6.26 (dd, J = 5.5, 3.0 Hz, 1), 7.43–7.56 (m, 5H),
from monoester (2S,3S)-(+)-endo-3 in the same manner as described
(400 MHz, CDCl
3
1
above for amide (2R,3R)-4. H NMR (400 MHz, CDCl
3
): δ 1.44–1.47
(
3
(
8
(m, 1H), 1.48 (d, J = 7.1 Hz, 3), 1.82–1.84 (m, 1H), 2.39 (dd, J = 5.0, 2.0
Hz, 1), 3.06 (br s, 1H), 3.17 (app t, J = 5.0 Hz, 1), 3.21 (br s, 1H), 3.66
(s, 3H), 5.12 (app quin, J = 7.1 Hz, 1), 6.10 (dd, J = 5.5, 3.0 Hz, 1), 6.26
1
3
3
.84 (br s, 3H); C NMR (100 MHz, CDCl ): δ 21.8, 45.4, 47.3, 47.7,
(dd, J = 5.5, 3.5 Hz, 1), 6.31 (br d, J = 7.1 Hz, 1H), 7.24–7.36 (m, 5H).
4
8.3, 49.8, 50.8, 51.3, 126.3, 128.0, 128.7, 134.5, 138.1, 140.7, 174.7, 180.2.
Resolution of (± ±)exo)ꢀ6
(1R,2R,3R,4S)-endo-3-(Methoxycarbonyl)bicyclo[2.2.1]hept-5-en-
exo-2-carboxylic acid [(2R,3R)-(–)-endo-3]. The salt (2R,3R)-(–)-
endo-3•(R)-1 (2.0 g, 6.3016 mmol) was treated with 2M HCl (50 mL), then
ethyl acetate (40 mL) and brine (40 mL) were added. After separation of
the organic layer, the aqueous phase was additionally extracted with ethyl
acetate (4 × 30 mL). The combined organic extracts were washed with a
mixture of 2M HCl (10 mL) and brine (10 mL), then with brine alone
Salt of (1S,2R,3R,4R)-exo-3-(tert-butoxycarbonyl)-bicyclo[2.2.1]hept-
5-en-endo-2-carboxylic acid and (R)-(+)-1-phenylethylamine [(2R,3R)-
(–)-exo-6b•(R)-1]. (R)-(+)-1-Phenylethylamine ((R)-1) (6.55 g, 54.0 mmol)
was added portionwise to a hot solution of monoester (±)-exo-6 (12.3 g,
51.6 mmol) in ethanol (50 mL). The mixture was heated to reflux and then
slowly cooled to rt. After the main portion of crystals was formed, the flask
was transferred to a refrigerator (–20°C) for 16 h. The precipitate was
isolated by filtration, washed with cooled ethanol (80 mL), and recrystal-
lized three times from ethanol (~50 mL). Salt (2R,3R)-(–)-exo-6b•(R)-1
(
20 mL). The organic solution was dried over Na
orated under reduced pressure. Monoester (2R,3R)-(–)-endo-3 was ob-
tained in a yield of 1.18 g (95%) as white crystals ([α] = –139°, c 1.0
2 4
SO and the solvent evap-
D
MeOH, mp 81–84°C).The IR and NMR spectra of (2R,3R)-(–)-endo-3 were
D
was obtained as white crystals (3.0 g, [α] = –99°, c 1.01 MeOH, mp
similar to those described in the literature.19
146–149°C). The combined mother liquors remaining after third and
fourth crystallizations were evaporated under reduced pressure. The
residue was twice crystallized from ethanol (40 and 30 mL) to give
Salt of (1S,2S,3S,4R)-endo-3-(methoxycarbonyl)-bicyclo[2.2.1]hept-
5
-en-exo-2-carboxylic acid and (S)-(–)-1-phenylethylamine [(2S,3S)-
additional amounts of the salt (2R,3R)-(–)-exo-6b•(R)-1 (1.4 g, [α]
D
= –98°, c
(+)-endo-3•(S)-1]. The combined mother liquors remaining after
1.01 MeOH, mp 145–149°C). The total yield was 4.4 g (24%). IR (KBr):
–1 1
separation of (2R,3R)-(–)-endo-3•(R)-1 were evaporated under reduced
pressure, and the residue was treated with 2M HCl (80 mL) and ethyl
acetate (80 mL). The mixture was stirred until the residue was dissolved.
Then brine (60 mL) was added and the organic layer was separated. The
aqueous layer was additionally extracted with ethyl acetate (4 × 50 mL).
The combined extracts were washed with a mixture of 2M HCl (20 mL)
νmax = 2980, 1721, 1638 cm ; H NMR (400 MHz, CD OD): δ 1.35–1.38 (m,
3
1H), 1.47 (c, 9H), 1.56–1.58 (m, 1H), 1.62 (d, J = 6.8 Hz, 3), 2.60 (dd, J = 4.5,
1.5 Hz, 1), 2.99 (br s, 1H), 3.16 (app t, J = 4.5 Hz, 1), 3.18 (br s, 1H), 4.40
(q, J = 6.8 Hz, 1), 5.13 (br s, 3H), 6.08 (dd, J = 5.5, 3.0 Hz, 1), 6.25 (dd, J = 5.5,
13
3.0 Hz, 1), 7.37–7.49 (m, 5H); C NMR (100 MHz, CD OD): δ 21.4, 28.5,
3
47.3, 48.3, 49.2, 50.0, 51.5, 52.2, 81.2, 127.6, 129.8, 130.2, 137.0, 137.6, 140.9,
and brine (20 mL), then with brine alone (30 mL), dried over Na
evaporated under reduced pressure. The residue was dissolved in CCl
45 mL), and (S)-(–)-1-phenylethylamine ((S)-1) (3.65 g, 30.1 mmol)
was added portionwise to a hot solution. The mixture was heated to reflux
and then slowly cooled to rt. After the main portion of crystals was formed,
the flask was transferred to a refrigerator (+4°C) for 16 h. The precipitate
2
SO
4
, and
176.6, 181.1. Anal. Calcd for C21
70.30, H 8.16.
4
H29NO (359.46): C 70.17, H 8.13. Found: C
4
(
(1S,2R,3R,4R)-exo-3-(tert-Butoxycarbonyl)-bicyclo[2.2.1]hept-5-en-
endo-2-carboxylic acid [(2R,3R)-exo-6b]. The salt (2R,3R)-(–)-exo-6b•
(R)-1 (4.0 g, 11.13 mmol) was treated with 2M HCl (50 mL) and CH Cl
2 2
Chirality DOI 10.1002/chir

RESOLUTION OF ENDO-/EXO-MONOESTERS
(
50mL). The organic and aqueous layers were separated and the aqueous
layer was extracted with CH Cl (3 × 30 mL). Combined extracts were
successively washed with 2M HCl (10 mL), water (10 mL) and brine
50 mL), then dried over Na SO . The solvent was evaporated under
reduced pressure to give (2R,3R)-(–)-exo-6b in a yield of 2.64 g (99%) as
white crystals ([α] = –115°, c 1.0 MeOH, mp 59–62°C). The spectral data
RESULTS AND DISCUSSION
2
2
Due to its easy availability, 1-phenylamine is one of the
widely used amines applied for resolving racemic mixtures
of chiral acids into enantiomers. It has been used, for
(
2
4
24
example, to obtain insect pheromones, as well as some drug
D
substances2
5,15
in enantiomerically pure form. In the present
were identical to those obtained for compound (±)-exo-6b.
study, we propose a method for resolving racemic mixtures
of both endo- and exo-monoesters of trans-norborn-5-ene-2,3-
dicarboxylic acid in the form of their salts with (R)- and (S)-
Salt of (1R,2S,3S,4S)-exo-3-(tert-butoxycarbonyl)-bicyclo[2.2.1]hept-
5
-en-endo-2-carboxylic acid and (S)-(–)-1-phenylethylamine [(2S,3S)-
+)-exo-6b•(S)-1]. The combined mother liquors remaining after
separation of (2R,3R)-(–)-exo-6b•(R)-1 were evaporated under reduced
pressure. The residue was treated with 2M HCl (80 mL) and CH Cl (50
mL) and the mixture was stirred until the residue was dissolved. After sep-
aration of the organic layer, the aqueous phase was extracted with CH Cl
3 × 30 mL). The combined organic extracts were successively washed
with 2M HCl (20 mL), water (10 mL), and brine (50 mL), then dried over
Na SO and evaporated under reduced pressure. The residue was dis-
1
-phenylethylamine ((R)-1 and (S)-1).
(
To prepare the monoester (±)-endo-3, we subjected
2
2
cyclopentadiene-dimethyl fumarate adduct to partial hydroly-
19
sis under alkaline conditions. This reaction gave a mixture
of exo- and endo-esters 3 (4.5:1), which contained about 10%
of the dicarboxylic acid. We were able to isolate (±)-endo-3
in pure form by repeated crystallization of this mixture from
methanol. Separation of (±)-endo-3 into enantiomers was
conducted via their salts with (R)-1 and (S)-1 (Scheme 1).
After seven repeated crystallizations of (±)-endo-3 salt with
2
2
(
2
4
solved in ethanol (55 mL), and (S)-(–)-1-phenylethylamine ((S)-1) (5.02
g, 41.4 mmol) was added portionwise to a hot solution. The product was
recrystallized three times in the same manner as described for the
(
R)-1 from carbon tetrachloride, the (2R,3R)-(–)-endo-3•
(2R,3R)-(–)-exo-6b•(R)-1. Salt (2S,3S)-(+)-exo-6b•(S)-1 was obtained as
white crystals (4.5 g, [α] = +99°, c 1.01 MeOH, mp 146–150°C). The
D
(Rn)-1 salt was isolated in a yield of 25.6% (calculated with
respect to the racemate). Treatment of the monoester
mixture present in the mother liquor with (S)-1 followed by
seven repeated crystallizations allowed a product having
inverse stereochemistry to be isolated in a yield of 26%.
Decomposition of the obtained salts with diluted hydrochloric
acid gave the respective dicarboxylic acid monoesters,
combined mother liquors remaining after second and third crystallizations
were evaporated under reduced pressure. The residue was twice
crystallized from ethanol (35 and 30 mL) to give additional amount
of the salt (2S,3S)-(+)-exo-6b•(S)-1 (1.0 g, [α]
46–149°C). The total yield was 5.5 g (30%). The IR and NMR spectra were
identical to those for the salt (2R,3R)-(–)-exo-6b•(R)-1.
D
= +98°, c 1.01 MeOH, mp
1
(
2R,3R)-(–)- and (2S,3S)-(+)-endo-3, both with 97% enantiomeric
(
1R,2S,3S,4S)-exo-3-(tert-Butoxycarbonyl)bicyclo[2.2.1]hept-5-en-
excess (ee) purity.
endo-2-carboxylic acid [(2S,3S)-(+)-exo-6b]. Treatment of (2S,3S)-(+)-
exo-6b•(S)-1 (3.0 g, 8.346 mmol) in the same manner as described above for
(
2R,3R)-(–)-exo-6b gave (2S,3S)-(+)-exo-6b in a yield of 1.99 g (100%) as
white crystals ([α] = +116°, c 1.0 MeOH, mp 59–62°C). The spectral data
were identical to those obtained for compound (2R,3R)-(–)-exo-6b.
D
(
[
1R,2R,3R,4S)-tert-butyl 3-(((S)-1-phenylethyl)carbamoyl)-bicyclo
2.2.1]hept-5-ene-2-carboxylate [(2R,3R)-7]. Amide (2R,3R)-7 was
prepared from monoester (2R,3R)-(–)-exo-6b in the same manner as
1
described above for amide (2R,3R)-4. H NMR (400 MHz, CDCl
δ 1.44–1.46 (m, 1H), 1.45 (s, 9H), 1.46 (d, J = 7.0 Hz, 3), 1.49–1.51 (m, 1H),
.47 (dd, J = 5.0, 1.6 Hz, 1), 3.05 (dd, J = 5.0, 3.5 Hz, 1), 3.09 (br s, 1H), 3.12
3
):
2
(
(
br s, 1H), 5.05 (app quin, J = 7.0 Hz, 1), 6.14 (dd, J = 5.5, 3.0 Hz, 1), 6.21
dd, J = 5.5, 3.0 Hz, 1), 6.36 (br d, J = 7.0 Hz, 1H), 7.23–7.35 (m, 5H).
(
[
1S,2S,3S,4R)-tert-butyl 3-(((S)-1-phenylethyl)carbamoyl)-bicyclo
2.2.1]hept-5-ene-2-carboxylate [(2S,3S)-7]. Amide (2S,3S)-7 was
prepared from monoester (2S,3S)-(+)-exo-6b in the same manner as
1
described above for amide (2R,3R)-4. H NMR (400 MHz, CDCl
3
):
δ 1.44–1.46 (m, 1H), 1.45 (s, 9H), 1.46 (d, J = 7.0 Hz, 3), 1.50–1.52
(
(
m, 1H), 2.43 (dd, J = 5.2, 1.5 Hz, 1), 3.08 (dd, J = 5.2, 3.5 Hz, 1), 3.10
br s, 1H), 3.16 (br s, 1H), 5.08 (app quin, J = 7.0 Hz, 1), 6.19–6.23 (m, 2),
6
.38 (br d, J = 7.0 Hz, 1H), 7.23–7.34 (m, 5H).
(
1R,2S,3S,4S)-bicyclo[2.2.1]hept-5-ene-2,3-diyldimethanol [(–)-8].
solution of monoester (2S,3S)-(+)-exo-6b (0.50 g, 2.1 mmol) in THF
2 mL) was added dropwise to a stirred suspension of LiAlH (0.32 g, 8.4
A
(
4
mmol) in THF (5 mL). Then the reaction mixture was refluxed for 1 h,
cooled to 0°C and treated successively with 15% solution of NaOH (0.3
mL), water (1 mL) and ethyl acetate (10 mL). The mixture was filtered,
2 4
and the filtrate was dried over Na SO and concentrated under reduced
pressure. The crude product was purified by column chromatography
Scheme 1. Separation of (±)-endo-3 into enantiomers, and determination of
2
their purity. Reagents and conditions: (a) KOH, H O-THF, then aq. HCl; (b)
(
(
0
eluent – petroleum ether/ethyl acetate, 4/1–1/1). The title product
two crystallizations from MeOH-H
2
O, overall yield 57%; (c) (R)-1-phenylethyl-
, 26.5%; (d) aq. HCl, 95%; (e)
–)-8 was obtained in a yield of 0.21 g (65%) as viscous oil ([α]
3 D 3
.9 CHCl , lit [α] = –23°, c 0.8 CHCl ). The IR and NMR spectra of
D
= –22°, c
amine ((R)-1), seven crystallizations from CCl
4
1
2
aq. HCl, then (S)-1-phenylethylamine ((S)-1), seven crystallizations from
23
(–)-8 were similar to those described in the literature.
CCl
4
, 26%; (f) aq. HCl, 96%; (g) (COCl)
2
, then (S)-1-phenylethylamine ((S)-1).
Chirality DOI 10.1002/chir

KOVALENKO AND KOZYRKOV
The ee purity was assessed via converting the (2R,3R)-(–)-
and (2S,3S)-(+)-endo-3 monoesters into amides, (2R,3R)-4
and (2S,3S)-4, by reaction of the acid group with (S)-1 (see
1
experimental part). H NMR spectra of the amides revealed
the presence of well-resolved signals of one of two protons
at α-position to double bond at different chemical shift values:
δ = 2.98 ppm for (2R,3R)-(–)- and δ = 3.06 ppm for (2S,3S)-(+)-
isomer. Relative intensity of the signals allowed the ee ratio
to be determined.26 Comparing the optical rotation angle
measured for the chiral monoester (2S,3S)-(+)-endo-3 synthe-
Scheme 3. Conversion of monoesters (2S,3S)-(+)-exo-6b to known diol (–)-8.
2
1,27
sized in this work with literature data
enabled us to
with respect to the racemate) (Scheme 2). After decomposi-
tion of the salts with diluted hydrochloric acid, the respective
monocarboxylic acid esters, (2R,3R)-(–)- and (2S,3S)-(+)-exo-
6b, both with >98% ee, were isolated.
Determination of the ee ratio for the monoesters thus
obtained was performed according to the procedure similar
to that described above for the endo- isomers. 1H NMR
spectra of the amides (2R,3R)-7 and (2S,3S)-7 prepared from
(2R,3R)-(–)- and (2S,3S)-(+)-exo-6b and (S)-1 (see experimen-
tal part) revealed the presence of quite well separated signals of
protons at α-position to tert-butoxycarbonyl group at different
chemical shift values: δ =2.47 ppm for (2R,3R)-(–)- and δ =2.43
ppm for (2S,3S)-(+)-isomer, and relative intensities of these
signals in each case were used to evaluate the ee ratio.
establish the absolute configuration of their stereocenters.
A procedure for transformation of the cyclopentadiene-
maleic anhydride adduct (5) into the corresponding monoes-
ter and its isomerization to obtain trans-compound has been
2
8,29
described in the literature.
We used this method to
prepare compound (±)-exo-6a,b (Scheme 2) having the acid
and ester groups located at positions isomeric to those in
(
±)-endo-3. The ring opening in anhydride 5 was performed
with sodium methylate or potassium tert-butylate. Simulta-
neously, isomerization of the cis-monoester being formed into
3
0
its trans- form took place. (Scheme 2).
We also investigated the possibility of resolving (±)-exo-6a,b
monoesters into enantiomers by means of repeated crystalli-
zation of the respective salts with (R)-1 and (S)-1. All attempts
to obtain a crystallizable salt of monomethyl ester (±)-exo-6a
with (R)-1 failed. However, we succeeded in obtaining good
results with mono-tert-butyl ester (±)-exo-6b, which yielded
No data on mono-tert-butyl esters of trans-norborn-5-ene-2,3-
dicarboxylic acids could be found in the literature. Therefore,
in order to elucidate the stereochemistry of the compounds
under study, the acid (2S,3S)-(+)-exo-6b was converted in a
23
2
4% (with respect to the racemate) of diastereomerically pure
known diol (–)-8 (Scheme 3). Comparison of the rotation
angle value that we measured for compound (–)-8 with the
literature data confirmed that the arrangement of substituents
in this compound is consistent with that of product having
2S,3S stereochemistry.
salt of (2R,3R)-(–)-exo-6b with (R)-1 after four repeated
crystallizations of the racemate salt from ethanol. A three-fold
crystallization of the product isolated from the mother liquor
containing the racemic monoester and (S)-1 gave the salt
having inverse stereochemistry in a yield of 30% (calculated
CONCLUSION
A simple method was developed enabling endo- and exo-
monoesters of trans-norborn-5-ene-2,3-dicarboxylic acids to
be isolated in enantiomerically pure form using multiple crys-
tallization technique of the respective salts with (R)- and (S)-1-
phenylethylamines. These compounds have differentiated
carboxylic groups, which is of importance for their further
selective modification.
ACKNOWLEDGMENTS
This work was carried out with the support of the Ministry of
Education of the Republic of Belarus (GPNI project). We
thank Dr. Riabcev A.N. for help with paper writing.
SUPPORTING INFORMATION
Additional supporting information may be found in the
online version of this article at the publisher’s web-site.
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