New exo/endo selectivity observed in monohydrolysis of dialkyl bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylates

Article abstract of DOI:10.1016/j.tetlet.2003.09.131

New monohydrolysis reactions of several exo or endo dimethyl or diethyl bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylates showed higher selectivity toward monohydrolyses of exo-carboalkoxy groups, although the reaction centers are located away from the norborne

Full text of DOI:10.1016/j.tetlet.2003.09.131

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8567–8570
New exo/endo selectivity observed in monohydrolysis of dialkyl
bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylates
Satomi Niwayama* and Yoshikazu Hiraga†
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA
Received 23 August 2003; revised 16 September 2003; accepted 16 September 2003
Abstract—New monohydrolysis reactions of several exo or endo dimethyl or diethyl bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylates
showed higher selectivity toward monohydrolyses of exo-carboalkoxy groups, although the reaction centers are located away from
the norbornene rings.
© 2003 Elsevier Ltd. All rights reserved.
carbons that are next to the norbornane ring,3 although
the other olefinic ends are still on the strained bicyclic
ring.
The exo/endo facial selectivities of electrophilic or
nucleophilic additions as well as cyclic additions to
norbornene or 2-norbornanone derivatives have been
extensively studied for several decades both experimen-
tally and theoretically.1 The general exo selectivities
observed during these reactions have been explained,
for example, by torsional effects and/or stereoelectronic
effects based on the distorted sp2-trigonal centers of the
olefin or the carbonyl group on the C2 and/or C3
positions within the uniquely strained bicyclic structure.
Here we report unexpectedly high exo-facial selectivi-
ties observed during monohydrolysis reactions of sev-
eral exo and/or endo dialkyl bicyclo[2.2.1]hept-5-
ene-2,3-dicarboxylates.
Earlier, Niwayama reported a highly efficient selective
monohydrolysis of a series of symmetric diesters apply-
ing THF and aqueous NaOH solution at 0°C. In
contrast to classical saponification, this reaction is quite
clean and produces the corresponding half-esters in
near-quantitative to modestly high yields for a series of
symmetric diesters (Scheme 1).4
However, with respect to the reactions that occur on
the sp2 carbons attached to these C2 or C3 positions,
examples for exo/endo facial selectivities are quite rare,
since the characteristic trigonal distortions are no
longer expected due to the distance from the strained
norbornene ring. The stereochemical effects from meth-
ano and ethano bridges are also expected to be negligi-
ble. Only a few examples have been reported in
enzymatic hydrolysis reactions, where the mechanisms
are not understood.2 The bottom-face preference in
Diels–Alder cycloadditions toward isodicyclopentadi-
ene may be an intriguing example where the new car-
bonꢀcarbon bond formations occur at the olefinic
Scheme 1.
* Corresponding author. E-mail: niwayama@biochem.okstate.edu
† On leave from the Department of Chemistry, Hiroshima University, Japan.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.131

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S. Niwayama, Y. Hiraga / Tetrahedron Letters 44 (2003) 8567–8570
Table 1.
Starting diester
Reaction time (h)
Yield (%) of half-ester
Recovered diester (%)
1a
2a
1a
2a
1b
2b
1b
2b
1
1
5
24
24
24
72
72
4a 31.7
5a 21.2
4a 88.4
5a 93.7
4b 51.7
5b 53.7
4b 83.8
5b 82.9
1a 61.9
2a 76.9
1a 8.7
2a 4.7
1b 40.1
2b 45.5
1b 2.9
2b 8.3
Table 2.
Starting diester
Reaction time (h)
Yield (%) of half-ester
Ratio of 6:7
Recovered diester (%)
3a
3b
0.5
6
6a+7a 81.6
6b+7b 69.2
87:13
87:13
3a 9.5
3b 9.8
We applied this reaction to monohydrolyses of a series
of dimethyl and diethyl bicyclo[2.2.1]hept-5-ene-2,3-
dicarboxylates 1a,b–3a,b which possess two carbo-
methoxy or carboethoxy groups in (exo, exo)-, (endo,
endo)-, or (exo, endo)-positions. All of these diesters
were readily obtained in high yields by following
reported procedures.5
observation, due to the lower solubility of the diethyl
esters in the reaction mixture caused by the higher
hydrophobicity.4,8
Interestingly, when the reactivities between endo and
exo ester groups are compared applying the same
equivalent of aqueous NaOH solution, judging from
the reaction times and conversions, the (exo, exo)-
diesters showed higher reactivities than the correspond-
ing (endo, endo)-diesters, despite the fact that the
reaction center is located next to the norbornene ring
rather than within the ring. This tendency appears to be
especially prominent for dimethyl esters, 1a and 2a.9 In
order to confirm this stereoselectivity, we pitted an exo
carboalkoxy group against an endo carboalkoxy group
in the same molecule as in 3a and 3b, and these two
diesters were monohydrolyzed under the same condi-
tions (Table 2).
Table 1 summarizes the results of monohydrolyses of
the cis-diesters, 1a,b and 2a,b, applying the same condi-
tions Niwayama reported earlier.4 All the reactions
were repeated at least two times and therefore the
results were reproducible.
As can be seen from Table 1, the monohydrolysis
successfully desymmetrized all the symmetric dimethyl
and diethyl esters for both (exo, exo)- and (endo, endo)-
stereochemistries,6 although reactivities of these diesters
appeared to be lower and monohydrolyses of these
diesters required a longer time than those reported
earlier, probably due to the low solubility of these
diesters in the reaction mixture.7 Under the reaction
conditions, no changes in the stereochemistry of the
compounds were observed in any of the reactions. The
somewhat lower reactivities observed for diethyl esters
than for dimethyl esters are consistent with our earlier
As expected from the above results, the exo ester
groups in both 3a and 3b predominantly produced
half-esters where the exo carboalkoxy group was mono-
hydrolyzed (6a and 6b). The product ratios of 6a and
7a as well as 6b and 7b were determined to be 87:13 in
both cases from the relative intensities of the integral

S. Niwayama, Y. Hiraga / Tetrahedron Letters 44 (2003) 8567–8570
8569
1
curves of the methyl or ethyl signals in the H NMR
1707, 1735, 2950–3000; HRMS(EI) calcd for C10H12O4:
196.0736, found 196.0736.
spectra. The structures of half-esters, 6a, 6b, 7a, and 7b
were determined based on H-1H COSY and HMBC
1
1
Half-ester (5a); white solid (mp 71–72°C), H NMR (500
MHz, CDCl3): l 6.27 (1H, dd, J=3.0. 5.5), 6.17 (1H, dd,
J=3.0, 5.5), 3.55 (3H, s), 3.29 (1H, dd, J=3.2, 10.3), 3.25
(1H, dd, J=3.2, 10.3), 3.15 (1H, m), 3.12 (1H, m), 1.45
(1H, br.d, J=8.7), 1.30 (1H, br.d, J=8.7); 13C NMR
(125 MHz, CDCl3): l 178.5, 172.8, 135.5. 134.3, 51.4,
48.7, 48.2, 48.0, 46.5, 46.0; IR (neat, cm−1): 1711, 1739,
2950–3000; HRMS(EI) calcd for C10H12O4: 196.0736,
found 196.0735.
analyses as well as differential NOE experiments, after
separation and purification of these half-esters.10 In
1
particular, the H NMR and 13C NMR data of half-
esters, 6b and 7b, were found to be identical to those
reported.11 These diesters, 3a and 3b showed higher
reactivity than exo-cis diesters, 1a and 1b, probably due
to the less crowded trans stereochemistry.
Half-ester (4b); colorless oil, 1H NMR (500 MHz,
CDCl3): l 6.20 (2H, m), 4.09 (2H, q, J=7.1), 3.09 (2H,
m), 2.61 (2H, m), 2.09 (1H, br.d, J=9.2), 1.47 (1H, br.d,
J=9.2), 1.21 (3H, t, J=7.1); 13C NMR (125 MHz,
CDCl3): l 179.1, 173.3, 138.1, 137.9, 60.8, 47.5, 47.2,
45.8, 45.5, 45.4, 14.0; IR (neat, cm−1): 1708, 1735, 2950–
3000; HRMS(EI) calcd for C11H14O4: 210.0892, found
210.0891.
From these data, we safely conclude that the character-
istic exo-facial selectivity applies to the carbonyl car-
bons that are attached on the norbornene skeleton in
our new monohydrolysis of a series of exo- and/or endo
norbornene diesters, despite the fact that the reaction
sites are one covalent bond from the norbornene ring.
To our knowledge, among non-enzymatic reactions,
these reactions are the first examples of such unique exo
selectivities.
Half-ester (5b); colorless oil, 1H NMR (500 MHz,
CDCl3): l 6.28 (1H, dd, J=3.0, 5.5), 6.20 (1H, dd,
J=3.0, 5.5), 4.03 (2H, m), 3.30 (1H, dd, J=3.2, 10.3),
3.25 (1H, dd, J=3.2, 10.3), 3.16 (1H, m), 3.14 (1H, m),
1.46 (1H, br.d, J=8.7), 1.31 (br. d, J=8.7), 1.19 (3H, t,
J=7.1); 13C NMR (125 MHz, CDCl3): l 177.9, 172.3,
135.4. 134.4, 60.4, 48.7, 48.5, 48.0, 46.6, 46.2, 14.0; IR
(neat, cm−1): 1711, 1737, 2950–3000; HRMS(EI) calcd for
C11H14O4: 210.0892, found 210.0892.
Acknowledgements
This work is supported by the National Science Foun-
dation-CAREER (CHE-0239527) and the Elsa U.
Pardee Foundation. S. N. thanks Banyu Pharmaceuti-
cal Co. Ltd. for the Banyu Award in Synthetic Organic
Chemistry.
7. Formation of a small amount of dicarboxylic acids was
occasionally observed due to this prolonged reaction
time.
8. Niwayama, S. Tetrahedron Lett. 2000, 41, 10163–10166.
9. The somewhat smaller difference in the yields for mono-
hydrolyses of 1b and 2b than those of 1a and 2a may be
attributed to the differences in their solubilities in this
reaction mixture.
10. The spectral data for these products are as follows:
Half-ester (6a); white solid (mp 121–122°C), 1H NMR
(500 MHz, CDCl3): l 6.28 (1H, dd, J=3.2, 5.5), 6.07
(1H, dd, J=2.8, 5.5), 3.64 (3H, s), 3.36 (1H, dd, J=3.7,
4.6), 3.26 (1H, m), 3.19 (1H, m), 2.71 (1H, dd, J=1.6,
4.6), 1.60 (1H, br.d, J=8.9), 1.47 (1H, dq, J=1.6, 8.9);
13C NMR (125 MHz, CDCl3): l 179.0, 173.6, 137.5.
135.3, 51.9, 47.8, 47.6, 47.4, 47.1, 45.6; IR (neat, cm−1):
1696, 1724, 2950–3000; HRMS(EI) calcd for C10H12O4:
196.0736, found 196.0735.
References
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K. J. Am. Chem. Soc. 1976, 98, 4054–4061; (b) Schleyer,
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2. (a) Klunder, A. J. H.; van Gastel, F. J. C.; Zwanenburg,
B. Tetrahedron Lett. 1988, 29, 2697–2700; (b) Van der
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Chem. Commun. 1989, 306–308; (c) Van Gastel, F. J. C.;
Klunder, A. J. H.; Zwanenburg, B. Recueil des Travaux
Chimiques des Pay-Bas 1991, 110, 175–184.
Half-ester (7a); colorless oil, 1H NMR (500 MHz,
CDCl3): l 6.28 (1H, dd, J=3.2, 5.5), 6.12 (1H, dd,
J=2.8, 5.5), 3.71 (3H, s), 3.41 (1H, dd, J=3.7, 4.6), 3.28
(1H, m), 3.13 (1H, m), 2.64 (1H, dd, J=1.6, 4.6), 1.59
(1H, br.d, J=8.7), 1.47 (1H, dq, J=1.6, 8.7); 13C NMR
(125 MHz, CDCl3): l 177.2, 174.7, 137.8. 135.2, 52.2,
47.6, 47.6, 47.5, 47.1, 45.6; IR (neat, cm−1): 1696, 1724,
2950–3000; HRMS(EI) calcd for C10H12O4: 196.0736,
found 196.0735.
3. For example, see: (a) Gleiter, R.; Paquette, L. A. Acc.
Chem. Res. 1983, 16, 328–334; (b) Kobuke, Y.; Sugimoto,
T.; Furukawa, J. J. Org. Chem. 1976, 41, 1457–1459; (c)
Brown, F. K.; Houk, K. N. J. Am. Chem. Soc. 1984, 107,
1971–1978.
Half-ester (6b); colorless oil, 1H NMR (500 MHz,
CDCl3): l 6.27 (1H, dd, J=3.2, 5.5), 6.06 (1H, dd,
J=2.6, 5.5), 4.08 (2H, m), 3.34 (1H, dd, J=3.7, 4.6), 3.25
(1H, m), 3.18 (1H, m), 2.71 (1H, dd, J=1.6, 4.6), 1.60
(1H, br.d, J=8.9), 1.46 (1H, dd, J=1.6, 8.9), 1.22 (3H, t,
J=7.1); 13C NMR (125 MHz, CDCl3): l 180.0, 173.1,
137.5. 135.2, 60.7, 47.9, 47.7, 47.3, 47.2, 45.7, 14.2; IR
(neat, cm−1): 1704, 1732, 2950–3000; HRMS(EI) calcd for
C11H14O4: 210.0892, found 210.0892.
4. Niwayama, S. J. Org. Chem. 2000, 65, 5834–5836.
5. Craig, D. J. Am. Chem. Soc. 1951, 73, 4889–4892 and
references cited therein.
6. The spectral data for these products are as follows:
Half-ester (4a); colorless oil, 1H NMR (500 MHz,
CDCl3): l 6.18 (2H, m), 3.62 (3H, s), 3.08 (2H, m), 2.61
(2H, m), 2.06 (1H, br.d, J=9.2), 1.47 (1H, br.d, J=9.2);
13C NMR (125 MHz, CDCl3): l 179.8, 173.8, 138.0.
137.9, 51.8, 47.4, 47.3, 45.7, 45.4, 45.3; IR (neat, cm−1):

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S. Niwayama, Y. Hiraga / Tetrahedron Letters 44 (2003) 8567–8570
Half-ester (7b); colorless oil, 1H NMR (500 MHz,
CDCl3): l 6.28 (1H, dd, J=3.2, 5.5), 6.11 (1H, dd,
J=2.8, 5.5), 4.15 (2H, q, J=7.1), 3.42 (1H, dd, J=3.7,
4.6), 3.3 (1H, m), 3.1 (1H, m), 2.62 (1H, dd, J=1.6,
4.6), 1.59 (1H, br.d, J=8.7), 1.45 (1H, dq, J=1.6, 8.7),
1.25 (3H, t, J=7.1); 13C NMR (125 MHz, CDCl3): l
177.9, 174.2, 137.8, 135.2, 61.0, 47.7, 47.6, 47.4, 47.3,
45.6, 14.2; IR (neat, cm−1): 1704, 1732, 2950-3000;
HRMS(EI) calcd for C11H14O4: 210.0892, found
210.0892.
11. Clapham, G.; Shipman, M. Tetrahedron 2000, 56,
1127–1134.