Enzymatic kinetic resolution of aromatic substituted norbornene mono-esters using pig's liver esterase

Article abstract of DOI:10.1016/S0040-4020(01)01115-2

Pig's liver esterase (PLE) has been used as a chiral catalyst in the enzymatic kinetic resolution of aromatic substituted norbornene mono-esters, methyl 3-endo-phenylbicyclo[2.2.1]hept-5-ene-2-exo-carboxylate and its endo-counterpart, methyl 3-endo-p-nitro-phenyl-bicyclo[2.2.1]hept-5-ene-2-exo-carboxylate and methyl 3-endo-benzoylbicyclo[2.2.1]hept-5-ene-2-exo-carboxylate. In this study a range of low to high enantioselectivities (83% ee) was observed. The effect of co-solvents has also been examined.

Full text of DOI:10.1016/S0040-4020(01)01115-2

TETRAHEDRON
Pergamon
Tetrahedron 58 "2002) 147±151
Enzymatic kinetic resolution of aromatic substituted norbornene
mono-esters using pig's liver esterase
M. Mamaghanip
Department of Chemistry, Faculty of Science, Guilan University, P.O. Box 1914, Rasht, Iran
Received 6 May 2001; revised 17 October 2001; accepted 8 November 2001
AbstractÐPig's liver esterase "PLE) has been used as a chiral catalyst in the enzymatic kinetic resolution of aromatic substituted
norbornene mono-esters, methyl 3-endo-phenylbicyclo[2.2.1]hept-5-ene-2-exo-carboxylate and its endo-counterpart, methyl 3-endo-p-
nitro-phenyl-bicyclo[2.2.1]hept-5-ene-2-exo-carboxylate and methyl 3-endo-benzoylbicyclo[2.2.1]hept-5-ene-2-exo-carboxylate. In this
study a range of low to high enantioselectivities "83% ee) was observed. The effect of co-solvents has also been examined. q 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Substrates 1 and 4 were prepared using Diels±Alder
methodology by re¯uxing methylcinnamate and cyclo-
pentadiene. The mixture was distilled under reduced
pressure to provide the desired adducts "exo/endo ratio
47:53, by GC) contaminated with 16% methylcinnamate
which could not be removed by distillation. The mixture
was puri®ed by PLE, which preferably hydrolyzed methyl-
cinnamate, to provide the adducts 1 and 4 as a ,1:1 exo/
endo mixture "by GC). The adducts were hydrolyzed "KOH/
MeOH) and separated by iodolactonization8 which
furnished the related acid products. Samples of pure
3-endo-phenylbicyclo[2.2.1]hept-5-ene-2-exo-carboxylic
acid and 3-exo-phenylbicyclo[2.2.1]hept-5-ene-2-endo-
carboxylic acid were methylated by diazomethane to give
pure esters 1 and 4 "yields.98%). The adduct 1 was
subjected to PLE hydrolysis "0.1 M phosphate buffer,
pHˆ7.8, room temperature) "Scheme 1). The reaction was
stopped at 50% conversion "12 days) and the products were
puri®ed by column chromatography "hexane/EtAc 5:1)
which provided "2)-1 and "1)-5 with ees of 59.5 and
61.5% respectively, Eˆ8.
Enzymes as biocatalysts have captured an important place
in organic synthesis. In particular hydrolases are effective
catalysts and the large majority of esterase catalyzed
reactions have been performed by pig liver esterase
"PLE). The great potential of this enzyme has been utilized
in asymmetric synthesis,1 separation of stereoisomers,2,3
hydrolysis of ester functions contained in hydrolytically
sensitive compounds4 and in the kinetic resolution of
racemates.5
Following our continued studies of the kinetic resolution of
norbornene type esters,6,7 in order to examine the effect of
aromatic substituents in the resolution of these systems by
PLE, substrates 1±4 "Fig. 1) were synthesized and subjected
to PLE hydrolysis.
A sample of rac-1 was also subjected to PLE hydrolysis in
the presence of 10% acetone as a co-solvent using identical
conditions as for the earlier reaction. At 50% conversion
"4 days), the reaction provided "2)-1, in 40% yield,
20
[a]D ˆ2183.02 "c 0.67, in MeOH), eeˆ62.2%, and "1)-
20
Figure 1.
5, in 47% yield, which was methylated by CH2N2, to give
the related methyl ester, [a]D ˆ1118 "c 0.7, in MeOH),
eeˆ42%.
The endo-isomer rac-4 was hydrolyzed slowly "14 days)
with almost no enantioselectivity. Enantiomeric excesses
of the acid product "1)-8 and the remaining ester "2)-4
Keywords: kinetic resolution; aromatic substitution; pig's liver esterase.
E-mail: m-chem41@cd.gu.ac.ir
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020"01)01115-2

148
M. Mamaghani / Tetrahedron 58 -2002) 147±151
Scheme 1.
Scheme 2.
calculated as 1 and 2.6%, respectively, E,1. A sample of
"1)-8 was transformed to the related methyl ester "1)-4 by
ethereal CH2N2 and the ee% of endo-acid "1)-8 was calcu-
lated on the basis of enantiomeric excess of methyl ester
"1)-4 "Scheme 2).
The resolution of methyl 3-endo-p-nitro- phenyl-
bicyclo[2.2.1]hept-5-ene-2-exo-carboxylate 2 was also con-
ducted by PLE in the presence of 10% acetone as a
co-solvent. The reaction was stopped at 10% conversion"7
days) to provide "1)3-endo-p-nitro-phenylbicyclo[2.2.1]-
hept-5-ene-2-exo-carboxylic acid "1)-6 in 9.8% yield,
20
In order to evaluate the possible effect of the nitro group in
the PLE hydrolysis of cinnamic acid/cyclopentadiene
adducts, a mixture of 3-endo-p-nitro-phenylbicyclo[2.2.1]-
hept-5-ene-2-exo-carboxylic acid "6) and 3-endo-p-nitro-
[a]D ˆ134.2 "c 0.25, in MeOH), eeˆ17% and "2)-methyl
20
3-endo-p-nitro-phenylbicyclo[2.2.1]hept-5-ene-2-exo-car-
boxylate "2)-2, [a]D ˆ21.05 "c 0.29, in MeOH),
ee,1%.
phenylbicyclo[2.2.1]-hept-5-ene-2-endo-carboxylic acid
"9) "ratio of exo/endo isomers 64:36, by H NMR) "Fig. 2)
1
In order to further substantiate the effect of benzoyl group
on the ef®ciency of PLE hydrolysis in the norbornene
system, racemic bicyclo[2.2.1]heptene ketone 3 was investi-
gated. This new adduct along with the related endo-isomer
was prepared from the reaction of methylbenzoylacrylate
and freshly distilled cyclopentadiene in 98% yield "the
ratio of endo/exo isomers ,1:1 by 1H NMR and GC)
"Scheme 3). A sample of mixed ester adducts were
hydrolyzed by methanolic potassium hydroxide and
subjected to iodolactonization. The reaction gave crystalline
3-exo-benzoylbicyclo [2.2.1] heptanecarbolactone 12 and
interestingly a ketal 11, which also provides a convenient
method for the protection of ole®nic bond and keto group
for further elaboration to the substrate 7 "Scheme 3). The
ketal and lactone 12 on treatment with Zn/AcOH "room
temperature), produced the desired 3-endo-benzoyl-
bicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid 7 and 3-
endo-benzoylbicyclo[2.2.1]hept-5-ene-2-exo-carboxylic
acid 13 in 95.5 and 82% yield, respectively. A sample of the
exo-acid 7 was transformed to the related methyl ester by
ethereal solution of diazomethane and subjected to PLE
hydrolysis "0.1 M phosphate buffer solution/5% CH3CN,
room temperature, pHˆ7.8) "Scheme 1). The reaction was
stopped at 20% conversion "7 days), to provide unreacted
"1)-methyl 3-endo-benzoylbicyclo[2.2.1]hept-5-ene-2-exo-
were prepared and separated according to the literature.8
A sample of racemic 3-endo-p-nitro-phenylbicyclo[2.2.1]-
hept-5-ene-2-exo-carboxylic acid 6 was transformed to the
related methyl ester 2 by diazomethane and subjected to
PLE hydrolysis, applying the procedure used in the resolu-
tion of 1. Due to a longer reaction time "16 days), the
reaction was stopped at 33% conversion to provide "1)-3-
endo-p-nitro-phenylbicyclo[2.2.1]hept-5-ene-2-exo-car-
20
boxylic acid "1)-6 in 31.6% yield, [a]D ˆ121.4 "c 0.51, in
20
MeOH), eeˆ10.7% "Eˆ1.5) and the unreacted methyl ester
in 77.3% yield, [a]D ˆ211.71 "c 0.64, in MeOH),
eeˆ4.5% "Scheme 1).
A sample of "1)-3-endo-p-nitro-phenylbicyclo[2.2.1]hept-
5-ene-2-exo-carboxylic acid "1)-6 was transformed to the
related methyl ester using an ethereal solution of diazo-
methane to provide "1)-2 in 97% yield, mp 59±608C,
20
[a]D ˆ127.85 "c 0.45, in MeOH), eeˆ10.7%.
20
carboxylate "1)-3, in 79.3% yield, [a]D ˆ139.6 "c 0.82,
in MeOH), eeˆ19% and "2)-3-endo-benzoylbicyclo-
20
[2.2.1]hept-5-ene-2-exo-carboxylic acid "2)-7 in 19.2%
yield, [a]D ˆ2157 "c 1, in MeOH), eeˆ83%, Eˆ13.
Figure 2.

M. Mamaghani / Tetrahedron 58 -2002) 147±151
149
Scheme 3.
A sample of "2)-exo-acid 7 was methylated by CH2N2 to
give "2)-methyl 3-endo-benzoylbicyclo[2.2.1]hept-5-ene-
cone column "25 m). Flash chromatography was carried out
at a pressure of ca. 1.5 bar, a column length of 15±25 cm
and a column diameter of 1±4 cm, using Merck Kieselgel
60 H, unless stated otherwise. All solvents used were dried
and distilled following standard procedures.
20
2-exo-carboxylate "2)-3, [a]D ˆ2171.3 "c 0.44, in
MeOH), eeˆ83%. The kinetic resolution of adduct 3 was
also conducted in the absence of co-solvent which due to the
high insolubility of the substrate and longer reaction time
we did not pursue. No attempt was made to assess the reso-
lution of the related methyl ester of endo-acid 13 by PLE,
since endo-isomers in these systems are usually hydrolyzed
much more slowely.6,7
3.2. Preparation of methyl 3-endo-phenylbicyclo[2.2.1]-
hept-5-ene-2-exo-carboxylate and methyl 3-exo-phenyl-
bicyclo[2.2.1]hept-5-ene-2-endo-carboxylate/1 and 4)
To a solution of trans-methylcinnamate "25 g, 154 mmol) in
benzene "74 ml), freshly distilled cyclopentadiene "11 g,
167 mmol) was added. The reaction mixture was re¯uxed
at 958C and every 5 h freshly distilled cyclopentadiene
"167 mmol) was added. After 21 h re¯ux, the reaction
mixture was distilled under reduced pressure, using a
short path distillation unit, to provide a 1:1 ratio of mixed
adducts and methylcinnamate "21.17 g), bpˆ127/
1.5 mmHg. The mixture was redistilled, bpˆ728/
0.06 mmHg, bath temperature ,1258C "distillation at
higher temperature led to the retro Diels±Alder reaction),
in order to separate most of the methylcinnamate. The resi-
due "11.1 g) was analyzed by GC which showed a 84:16
ratio of adducts and methylcinnamate. The adducts were
puri®ed by PLE and hydrolyzed by methanolic potassium
hydroxide to provide the related endo- and exo-acid adducts,
which were separated by iodolactonization.8 The adducts
The result of this research leads to the conclusion that the
presence of aromatic substituents trans to the methyl-ester
function in these systems, make them poor substrates for
PLE. However the best result is obtained with the pheny1
group. The effect of co-solvent on the reaction time is
impressive with no appreciable effect on the ees. These
results are also entirely consistent with results obtained
for the corresponding norbornene esters6,9 and again nicely
®t Tamm's PLE substrate model.10 The optical purity of all
the products were measured by 1H NMR spectroscopic
analysis "400 MHz) using Eu"hfc)3 as chiral shift reagent.
3. Experimental
3.1. General remarks
11
were methylated using an ethereal solution of CH2N2 to
give the related methyl esters 1 and 4 "yield, 98%). The
structures of these products were con®rmed by comparison
of their spectroscopic data with those in the literature.11
Melting points were measured with a Reichert Thermo pan
microscope and are uncorrected. IR spectra were taken on
Perkin±Elmer 298 infrared spectrophotometer. H NMR
1
spectra were recorded on a Bruker AM-400, using TMS
as an internal standard. For mass spectra a Bruker double
focusing VG 7070 E mass spectrometer was used. Capillary
GC analyses were performed using a Hewlett±Packard 5890
A gas chromatograph, containing a cross-linked methyl sili-
3.3. General procedure for PLE catalyzed hydrolysis of
the ester adducts
The ester adduct as a substrate was suspended in a 0.1 M

150
M. Mamaghani / Tetrahedron 58 -2002) 147±151
phosphate buffer solution "10 ml/mmol substrate) at
pHˆ7.8 and incubated with PLE "50 ml/mmol) at room
temperature. The pH was maintained by continuous addition
of 0.25 M NaOH using an auto-burette. After reaching an
appropriate reaction conversion the reaction was stopped by
adding aqueous sodium carbonate until pHˆ10. The
aqueous reaction mixture was extracted with ether and the
combined ether extracts were dried "MgSO4) and evapo-
rated to give the unreacted ester product.
of 3-exo-phenylbicyclo[2.2.1]hept-5-ene-2-endo-carboxylic
acid "0.15 g, 0.67 mmol) was transformed to the related
methyl ester using ethereal diazomethane,11 yield 99.5%;
[a]D ˆ13.48 "c 0.58, in MeOH); eeˆ1%.
20
3.4.3. PLE catalyzed hydrolysis of methyl 3-endo-p-
nitrophenylbicyclo[2.2.1]hept-5-ene-2-exo-carboxylate
2. Methyl 3-endo-p-nitro-phenylbicyclo[2.2.1]hept-5-ene-
2-exo-carboxylate "1.0 g, 3.66 mmol) "prepared according
to the literature)8 was subjected to PLE hydrolysis, using
the general procedure, reaction time 16 days "every 4 days
fresh PLE, 100 ml, was added). The hydrolysis reaction was
stopped at 33% conversion, to provide "2)-methyl 3-endo-
p-nitro-phenylbicyclo[2.2.1]hept-5-ene-2-exo-carboxylate
"2)-2 "0.67 g, 2.83 mmol); yield 77.3%; mp 58±598C;
The remaining aqueous layer was acidi®ed by dilute H2SO4
to pHˆ3 and extracted with ether. The combined ether
extracts were dried "MgSO4) and evaporated to give the
related acid product.
[a]D ˆ211.71 "c 0.64, in MeOH); eeˆ4.5% "the 1H
20
3.4. Large scale puri®cation of methylcinnamate adducts
/1 and 4) by use of PLE
NMR and IR were the same as starting racemate methyl
ester) and "1)-3-endo-p-nitro-phenylbicyclo[2.2.1]hept-5-
ene-2-exo-carboxylic acid "1)-6 "0.30 g, 1.15 mmol);
Methyl cinnamate/cyclopentadiene adducts"1 and 4) "8 g),
contaminated with methylcinnamate "ca. 16%), were
suspended in 0.1 M phosphate buffer solution "100 ml) at
pHˆ7.8 and incubated with PLE "300 ml) at room tempera-
ture. Following the general procedure and stopping the
reaction after consumption of 44 ml NaOH, the reaction
provided the mixed-ester adducts "exo/endo ratio 47:53 by
GC) "5.5 g) with no trace of methyl cinnamate "1H NMR
and GC analysis).
20
yield 31.6%; mp 176±1778C; [a]D ˆ121.4 "c 0.51, in
1
MeOH); eeˆ10.7%; Eˆ1.5. The H NMR and IR were
the same as racemic exo-acid. A sample of exo-acid was
transformed to the related methyl ester by ethereal solution
of
diazomethane
"yield
97%),
mp
59±608C;
20
[a]D ˆ127.85 "c 0.45, in MeOH); eeˆ10.7%.
3.4.4. Preparation of methyl 3-endo-benzoylbicyclo-
[2.2.1]hept-5-ene-2-exo-carboxylate and 3-exo-benzoyl
bicyclo[2.2.1]hept-5-ene-2-endo-carboxylic acid 3 and
13. To a magnetically stirred solution of methyl benzoyl-
acrylate12 "5 g, 26.31 mmol) in benzene "13 ml), freshly
distilled cyclopentadiene "1.87 g, 28.3 mmol) in benzene
"5 ml) was added slowly. An immediate exothermic reac-
tion occurred. The reaction mixture was stirred for 2 h and
the solvent was removed under vacuum to provide the
desired adducts "6.6 g, 25.8 mmol) in 98% yield, as a
viscous liquid. It was shown by 1H NMR to be ,1:1 mixture
of endo/exo isomers "Scheme 3).
3.4.1. PLE catalyzed hydrolysis of methyl 3-endo-phenyl-
bicyclo[2.2.1]hept-5-ene-2-exo-carboxylate 1. Methyl
3-endo-phenylbicyclo[2.2.1]hept-5-ene-2-exo-carboxylate
"1.14 g, 5 mmol), was subjected to PLE hydrolysis using the
general procedure. After 12 days "50% conversion) the
reaction gave: -2)-methyl 3-endo-phenylbicyclo[2.2.1]-
hept-5-ene-2-exo-carboxylate -2)-1 "0.53 g, 2.33 mmol);
20
yield 46.7%; mp 40±428C; [a]D ˆ2175.758 "c 0.85, in
MeOH); eeˆ59.5% "after puri®cation by column chromato-
1
graphy; hexane/EtOAc, 5:1; Eˆ8; the H NMR and IR of
this product was the same as starting methyl ester) and "1)-
3-endo-phenylbicyclo[2.2.1]hept-5-ene-2-exo-carboxylic
acid "1)-5 "0.42 g, 1.95 mmol); yield 39% "after puri®ca-
tion by column chromatography; hexane/EtOAc, 3:2); mp
A sample of the adduct mixture "5.8 g, 22.6 mmol) was
hydrolyzed by methanolic potassium hydroxide "10 g
KOH in 75 ml MeOH) at room temperature, reaction time
5 h, to give the related acid adducts 13/7 "5.1 g, 20.9 mmol),
yield 92.5%. The mixture was subjected to iodolactoniza-
tion8 to provide: 3-exo-benzoylbicyclo[2.2.1]heptane
carbolactone 12 "3.1 g, 8.42 mmol) in 40.3% yield as a
brown solid; mp 157±1588C "recrystalized from acetone/
ethanol); nmax "KBr) 1760, 1660 "CvO stretch), 1590,
1575, 1440 "CvC stretch of arom. ring) cm21; dH
"400 MHz, CDCl3) 7.98 "2H, m, arom. H), 7.57 "3H, m,
arom. H), 5.20 "1H, t, Jˆ5.1 Hz, H6), 4.08 "1H, d,
Jˆ2.5 Hz, H5), 3.71 "1H, s, H1), 3.22 "2H, m, H2, H3),
2.96 "1H, s, H4), 2.30 "1H, d, Jˆ9.5 Hz, H7), 1.8 "1H, d,
Jˆ9.5 Hz, H7); m/z "EI) "0.97, M1, 0.30, M11), 242 "13.3),
241 "77.9), 127 "1.2), 105 "100%); HRMS: M1, found
367.99098^0.00073. C16H13IO3 requires 367.99095 and
ketal 11 "2.8 g, 7 mmol) in 33.5% yield, as a white solid,
mp 185±1868C "recrystalized from methanol); nmax
"CH2Cl2) 3500±2500"O±H stretch), 1705 "CvO
stretch) cm21; dH "400 MHz, CDCl3), 7.38 "5H, m, arom.
H), 4.91 "1H, d, Jˆ5.0 Hz, H5), 3.81 "1H, d, Jˆ2.5 Hz, H6),
3.25 "1H, m, H1), 3.05 "1H, t, Jˆ4.8 Hz, H3), 2.93 "3H, s,
OMe), 2.75 "1H, s, H4), 2.2 "1H, d, Jˆ4.8 Hz, H2), 2.04 "1H,
20
90±928C; [a]D ˆ1172 "c 0.63, in MeOH), eeˆ61.5%. The
1H NMR and IR spectra of this product were also the same
as racemic exo-acid. A sample of this optically active acid
was transformed to the related methyl ester using diazo-
methane,11 mp 40±438C; [a]D ˆ1172.7 "c 0.55, in
20
MeOH); eeˆ61.5%.
3.4.2. PLE catalyzed hydrolysis of methyl 3-exo-phenyl-
bicyclo[2.2.1]hept-5-ene-2-endo-carboxylate 4. Using the
general procedure, racemic methyl 3-exo-phenylbicyclo-
[2.2.1]hept-5-ene-2-endo-carboxylate "0.5 g, 2.19 mmol)
was hydrolyzed by PLE "105 ml), reaction time 14 days
"after 11 days 30 ml fresh PLE was added), 50% conversion,
to provide: -2)-methyl 3-exo-phenylbicyclo[2.2.1]hept-5-
ene-2-endo-carboxylate -1)-4 "0.25 g, 1.09 mmol), yield
20
1
50%; [a]D ˆ23.54 "c 1, in MeOH); eeˆ2.6% "the H
NMR and IR were the same as racemic starting ester) and
"1)-3-exo-phenylbicyclo[2.2.1]hept-5-ene-2-endo-carboxylic
20
acid "1)-8 "0.2 g, 0.93 mmol), yield 42.5%; [a]D ˆ12.98
1
"c 0.97, in MeOH), eeˆ1%; E,1; mp 107±1088C; the H
NMR and IR were the same as racemic endo-acid. A sample

M. Mamaghani / Tetrahedron 58 -2002) 147±151
151
br s, H7), 1.85 "1H, d, Jˆ9.3 Hz, H7); m/z "EI) "100,
M±OMe), 370 "16.7), 273 "0.2), 197 "7.8), 242 "0.7), 241
"2.3), 127 "4.3), 105 "30.0%); HRMS: "M±OMe), found
368.99871^0.00073. C15H14IO3 requires 368.99817.
as a co-solvent, using the general procedure. The reaction
was stopped at 20% conversion, reaction time 7 days "after 6
days 113 ml fresh PLE was added), to give the unreacted
"1)-methyl 3-endo-benzoylbicyclo[2.2.1]hept-5-ene-2-exo-
carboxylate "1)-3 "0.22 g, 0.85 mmol), puri®ed by column
chromatography "hexane/EtOH, 10:1); yield 79.4%;
The ketal 11 "0.97 g, 2.42 mmol) was treated with zinc
"1.14 g) and glacial acetic acid "8 ml) and stirred magneti-
cally at room temperature for 48 h. The reaction mixture
was ®ltered and the residue was washed with hot water
and ether. The ®ltrate was extracted with ether "3£70 ml),
the combined ether extracts were dried "MgSO4) and evapo-
rated in a rotatory evaporator to give 3-endo-benzoyl-
bicyclo[2.2.1] hept-5-ene-2-exo-carboxylic acid 7 "0.56 g,
2.31 mmol) in 95.5% yield as a colorless oil; nmax
"CH2Cl2) 3500±2500 "OH stretch), 1695, 1680 "CvO
stretch) cm21; dH "400 MHz, CDCl3) 10.35 "carboxylic
H), 7.99 "2H, m, arom. H), 7.53 "3H, m, arom. H), 6.33
"1H, dd, Jˆ2.8, 5.3 Hz, H5 or H6), 5.83 "1H, dd, Jˆ2.6,
5.3 Hz, H5 or H6), 4.29 "1H, t, Jˆ4.2 Hz, H3), 3.30 "2H,
br s, H1, H4), 3.10 "1H, dd, Jˆ3.0, 4.2 Hz, H2), 1.8 "1H, d,
Jˆ8.7 Hz, H7), 1.53 "1H, m, H7); HRMS: M1, found
242.09419^0.00069. C15 H14O3 requires 242.094229.
[a]D ˆ139.60 "c 0.82, in MeOH); eeˆ19% "the 1H
20
NMR and IR of this product was the same as the starting
racemic ester) and "2)-3-endo-benzoylbicyclo[2.2.1]hept-
5-ene-2-exo-carboxylic acid "2)-7 "0.05 g, 0.20 mmol);
20
yield 19.2%; [a]D ˆ2157 "c 1, in MeOH); eeˆ83%;
1
Eˆ13. The H NMR and IR spectra of this acid were the
same as the related racemic acid. A sample of the acid "2)-7
was transformed to the related methyl ester by ethereal
20
solution of diazomethane, [a]D ˆ2171.3 "c 0.44, in
MeOH); eeˆ83%.
Acknowledgements
The author is grateful to Professor B. Zwanenburg, Dr
A. J. H. Klunder "the Netherlands) and the Research Council
of Guilan University.
A sample of 3-endo-benzoylbicyclo[2.2.1] hept-5-ene-2-
exo-carboxylic acid 7 "0.5 g, 2.06 mmol) was methylated
by an ethereal solution of diazomethane at room tempera-
ture to provide methyl 3-endo-benzoylbicyclo[2.2.1]hept-5-
ene-2-exo-carboxylate 3 "0.48 g, 1.87 mmol) in 90.5% yield
as a colorless oil; nmax "liquid ®lm) 1720, 1675 "CvO
stretch), 1595, 1580, 1445 "Aromatic CvC stretch), 1265,
1215 "C±O±C stretch)cm21; dH "400 MHz, CDCl3) 8.0
"2H, m, arom. H), 7.26 "3H, m, arom. H), 6.30 "1H, dd,
Jˆ2.8, 5.3 Hz, H5 or H6), 5.83 "1H, dd, Jˆ2.7, 5.3 Hz, H5
or H6), 4.28 "1H, t, Jˆ4.2 Hz, H3), 3.71 "3H, s, OMe), 3.31
"2H, br s, H1, H4), 3.05 "1H, dd, Jˆ3.2, 4.5 Hz, H2), 1.75
"1H, d, Jˆ8.6 Hz, H7), 1.50 "1H, m, H7); HRMS: M1, found
256.10983^0.00065. C16H16O3 requires 256.10986.
References
1. "a) Ohno, M.; Otsuka, M. Org. React. 1989, 37, 1±55.
"b) Santaniello, E.; Ferraboschi, P.; Manzocchi, A. Chem.
Rev. 1992, 92, 1071±1140. "c) Faber, K. Pure Appl. Chem.
1997, 69, 1613±1632. "d) Faber, K. Biotransformation in
Organic Chemistry, A Textbook; 3rd ed; Springer: Heidelberg,
1997. "e) Pietruszka, J.; Wilhelm, T.; Witt, A. Synlett 1999,
12, 1981±1983. "f) Athawale, V.; Manjrekar, N. Synlett 2000,
2, 225±226.
2. Eberl, M.; Egli, M.; Seebach, D. Helv. Chim. Acta. 1988, 71,
1±23.
3. Sweers, H. M.; Wong, C. J. Am. Chem. Soc. 1986, 108, 6421±
6422.
3-exo-Benzoylbicyclo[2.2.1]heptane
carbolactone
12
4. Sicic, S.; Lerroy, J.; Wakselman, C. Synthesis 1987, 155±156.
5. "a) Kozikowski, A. P.; Simoni, D.; Baraldi, P. G.; Lampronti,
I.; Manfredini, S. Bioorg. Med. Chem. Lett. 1996, 6, 4441±
4444. "b) Renold, P.; Tamm, C. Tetrahedron: Asymmetry
1993, 4 "11), 2295±2298. "c) Klunder, A. J. H.; Huizinga,
W. B.; Hulshof, A. J. M.; Zwanenburg, B. Tetrahedron Lett.
1986, 2543±2546. "d) Whitesides, G. M.; Wong, C.
Aldrichim. Acta 1983, 16, 27±32.
"1.85 g, 5.03 mmol) was treated with zinc "2.01 g) and
glacial acetic acid "14 ml) mixture at room temperature,
reaction time 5 h, to give 3-exo-benzoylbicyclo[2.2.1]-
hept-5-ene-2-endo-carboxylic acid 13 "0.95 g, 4.13 mmol)
in 82% yield as a colorless oil; nmax "CH2Cl2), 3500±2500
"OH stretch), 1700, 1675 "CvO stretch), 1596, 1580, 1447
"aromatic CvC stretch), 1370, 1020, 910, 870 cm21; dH
"400 MHz, CDCl3) 8.02 "2H, m, arom. H), 7.53 "3H, m,
arom. H), 6.43 "1H, dd, Jˆ2.9, 5.2 Hz, H5 or H6), 6.24
"1H, dd, Jˆ2.7, 5.2 Hz, H5 or H6), 3.75 "1H, t, Jˆ3.1 Hz,
H1), 3.62 "1H, dd, Jˆ3.2, 5.1 Hz, H3), 3.48 "1H, br s, H4),
3.35 "1H, br s, H2), 1.65 "1H, d, Jˆ8.5 Hz, H7), 1.42 "1H, m,
H7); m/z "EI) "6.0, M1, 1.3, M11), 224 "26.2), 197 "30.2),
178 "12.5), 177 "100), 159 "36.5), 137 "15.6), 105 "59.6%);
HRMS: M1, found 242.09419^0.00096. C15H14O3 requires
242.09429.
6. Mamaghani, M.; Namazi, A. J. Sci. I. R. Iran 1999, 10 "3),
169±173.
7. Mamaghani, M.; Klunder, A. J. H.; Zwanenburg, B. J. Sci. I.
R. Iran 2000, 11 "3), 205±212.
8. Roundestveet, Jr., C. S.; Ver Nooy, C. D. J. Am. Chem. Soc.
1955, 76, 4878±4883.
9. Zhu, L. M.; Tedford, M. C. Tetrahedron 1990, 46 "19), 6587±
6611.
10. Mohr, P.; Waespe-Sarcevic, N.; Tamm, C.; Gawronska, K.;
Gawronski, J. K. Helv. Chim. Acta. 1983, 66, 2501±2511.
11. Nicolas, L.; Beuglmans-Verrier, M.; Guilhem, J. Tetrahedron
1981, 37, 3847±3860.
3.4.5. PLE catalyzed hydrolysis of methyl 3-endo-
benzoylbicyclo[2.2.1]hept-5-ene-2-exo-carboxylate
"^)-Methyl 3-endo-benzoylbicyclo[2.2.1]hept-5-ene-2-
3.
12. Lutz, R. E. J. Am. Chem. Soc. 1930, 52, 3423±3436.
exo-carboxylate "0.275 g, 1.07 mmol) was subjected to
PLE catalyzed hydrolysis in the presence of 5% acetonitrile