Remote Exo/Endo selectivity in selective monohydrolysis of dialkyl bicyclo[2.2.1]heptane-2,3-dicarboxylate derivatives

Article abstract of DOI:10.1021/jo100564e

Figure presented High exo-facial selectivity was observed in the selective monohydrolysis of a series of near-symmetric diesters that possess an exo-ester group and an endo-ester group attached on a norbornane or norbornene skeleton. The selectivities were found to be clear-cut, although the reaction center in these reactions is one covalent bond distant from the norbornane or norbornene ring, where the difference of the environment between the exo face and endo face is therefore expected to be negligible. The effect of the co-solvent we studied earlier for the selective monohydrolysis reaction was also confirmed and contributed to improvement of the yields of the half-esters.

Full text of DOI:10.1021/jo100564e

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Remote Exo/Endo Selectivity in Selective Monohydrolysis of Dialkyl
Bicyclo[2.2.1]heptane-2,3-dicarboxylate Derivatives
Satomi Niwayama,*,† Hanjoung Cho,† Masoud Zabet-Moghaddam,†,‡ and
Bruce R. Whittlesey§,†
†Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, and
‡Center for Biotechnology and Genomics, Texas Tech University, Lubbock, Texas 79409-3132
satomi.niwayama@ttu.edu
Received March 24, 2010
High exo-facial selectivity was observed in the selective monohydrolysis of a series of near-symmetric
diesters that possess an exo-ester group and an endo-ester group attached on a norbornane or
norbornene skeleton. The selectivities were found to be clear-cut, although the reaction center in
these reactions is one covalent bond distant from the norbornane or norbornene ring, where the
difference of the environment between the exo face and endo face is therefore expected to be
negligible. The effect of the co-solvent we studied earlier for the selective monohydrolysis reaction
was also confirmed and contributed to improvement of the yields of the half-esters.
Introduction
the pyramidalized sp2 carbons,3 and nonequivalent orbital
extension caused by the mixing of σ orbitals and π orbitals,
inducing higher exo reactivity.4 Since norbornene, norbor-
nadiene, or norbornanone and their derivatives are versatile
synthetic building blocks for further skeletal conversions, the
high exo selectivity has been applied to development of a
variety of useful stereospecific or stereoselective reactions in
organic synthesis such as epoxidation and hydroboration.
However, for the sp2 carbons that are one covalent bond
away from the norbornane skeleton, such exo/endo-facial
selectivities are not systematically studied, because the dif-
ferences of the reported steric effects are anticipated to be too
small, and the torsional effects considered within the nor-
bornane ring are not expected. Electrophilic additions to
2-methylenenornornene are still known to show the pre-
dominant exo selectivity due to the fact that C2 carbon is
part of the norbornane ring. The Diels-Alder reactions
toward isodicyclopentadiene, showing the bottom-face se-
lectivity with a variety of dienophiles, are interesting excep-
tions in which the new bond forms on the sp2 carbons next to
It has been well documented that norbornene, norborna-
diene, or norbornanone systems in general show high exo-
facial selectivity in the electrophilic, nucleophilic, or cyclic
additions. Many research groups have reported extensive
studies to explain the exo-facial selectivity from theoretical
and experimental points of view. These explanations include
steric effects due to the fact that the ethano bridge is larger
than the methano bridge,1 a torsional effect that is relieved
by exo attack but increased by endo attack in the transition
state,2 pyramidalization of the sp2 carbons toward the endo
directions leading to the favored attack on the convex face of
§ The author to whom correspondence regarding X-ray crystallographic analysis
should be directed.
(1) (a) Brown, H. C.; Kawakami, J. H. J. Am. Chem. Soc. 1970, 92, 1990–
1995. (b) Brown, H. C.; Hammar, W. J.; Kawakami, J. H.; Rothberg, I.;
Vander Jugt, D. L. J. Am. Chem. Soc. 1967, 104, 6381–6382. (c) Brown, H. C.;
Kawakami, J. H.; Liu, K.-T. J. Am. Chem. Soc. 1973, 95, 2209–2216.
(2) Schleyer, P. v. R. J. Am. Chem. Soc. 1967, 89, 701–703.
(3) (a) Rondan, N. G.; Paddon-Row, M. N.; Caramella, P.; Houk, K. N.
J. Am. Chem. Soc. 1981, 103, 2436–2438. (b) Rondan, N. G.; Paddon-Row,
M. N.; Caramella, P.; Mareda, J.; Mueller, P. H.; Houk, K. N. J. Am. Chem.
Soc. 1982, 104, 4974–4976.
(4) Inagaki, S.; Fujimoto, H.; Fukui, K. J. Am. Chem. Soc. 1976, 98,
4054–4061.
DOI: 10.1021/jo100564e
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Published on Web 05/05/2010
J. Org. Chem. 2010, 75, 3775–3780 3775
2010 American Chemical Society

Niwayama et al.
JOCArticle
the C2 and C3 sp2 carbons of the norbornane ring.5 For these
reactions, as the olefinic ends are still within the strained
norbornane ring, the selectivity is explained by the out-of-
plane bending of groups at C2 and C3 on the ring, although it
appears that the steric bulkiness of the dienophile also affects
the selectivity.6 Therefore, the only studies reported as remote
exo/endo-facial selectivity away from the norbornane or nor-
bornene ring were enzyme reactions, for which the mecha-
nisms of selectivity are not understood.7
To this end, we previously observed unusually prominent
exo-facial selectivity on the sp2 carbons that are one covalent
bond distant from the norbornene ring in the selective mono-
hydrolysis reactions we reported earlier.8 We attempted
selective monohydrolysis of (exo, exo), (endo, endo), and
(exo, endo)-dimethyl and diethyl esters attached to the
norbornene skeleton and observed enhanced reactivity on
hydrolysis of the exo esters in all cases, perhaps due to the
mild reaction conditions. Here we report the fuller details of
this unusually prominent exo-facial selectivity observed during
the selective monohydrolysis.
Earlier, we reported the highly selective monohydrolysis
of symmetric diesters that monohydrolyzes a series of sym-
metric diesters with high selectivity and reactivity, yielding
half-esters in a racemic form (Scheme 1).9 This reaction is
particularly powerful when it is necessary to hydrolyze only
one of the two identical ester groups. However, we find that
this reaction can recognize subtle steric differences and can
also selectively hydrolyze one of the two ester groups in near-
symmetrical diesters, and therefore, this reaction can selec-
tively monohydrolyze the ester group of the exo position in
exo,endo-dimethyl- and -diethylbicyclo[2.2.1]hept-5-ene-2,3-
dicarboxylates, 1a and 1b (Scheme 1).8
and higher selectivity, while protic solvents are not as
effective.10 KOH is often more effective than NaOH as a base,
perhaps due to the enhanced electropositive character of the
countercation, while LiOH tends to be inferior to NaOH.11
Our current hypothesis for the high selectivity for mono-
hydrolysis of only one of the two ester groups is that once one
of the ester groups is monohydrolyzed, in water the inter-
mediary monocarboxylate will form aggregates in which the
remaining hydrophobic portions point inside and the hydro-
-
philic CO2 groups point outside, thus prohibiting further
hydrolysis. The solvent effects we have observed thus far are
consistent with this hypothesis.
The selectivity was initially observed to be especially high
when the two ester groups possess the stereochemistry of
“cis”. We explained the potential reasons based on the
electrostatic attractive interaction due to the two closely
located carbonyl groups before formation of the potential
aggregate above.9,12 However, applying the conditions we
found later based on the information obtained from these
basic studies, we have also been successful in selectively
monohydrolyzing linear diesters13 or those with “trans”
stereochemistry as in this study.
Results and Discussion
We first tried selective monohydrolysis of exo,endo-di-
methyl- and -diethylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxy-
lates, 1a and 1b, both of which we reported earlier, in order to
improve the reaction conditions. We first changed the type of
base (Table 1) for dimethyl ester 1a and found that all bases
predominantly produced half-ester 2a in which the exo-
carbomethoxy group was monohydrolyzed. The product
ratios of 2a and 3a and 2b and 3b were determined from
the relative intensities of the integral curves of the methyl or
ethyl signal in the reaction mixture of the 1H NMR spectra.
SCHEME 1. Selective Monohydrolysis of Symmetric Diesters
1
The structures of half-esters were determined from the H
NMR and 13C NMR data we reported. Among these bases,
KOH produced the highest yields (97%). This enhanced
reactivity by KOH is also consistent with the results we
reported earlier.11,13 The amount of the base was also slightly
reduced because of the stereochemistry of the starting di-
ester, which appears to have helped improve the yield for this
particular diester. Therefore, for selective monohydrolysis
of the corresponding diethyl ester, 1b, only this KOH was
applied. Since it was anticipated that the hydrolysis of diethyl
ester would require more time than the corresponding
dimethyl ester due to the increased hydrophobicity, the co-
solvent was changed to acetonitrile from THF according to
our previous study about solvent effects.10 As a result, the
yield of the half-ester also significantly improved to 96%
in 7.5 h, while we found that the use of 1.7 equiv of base is
preferable to 1.2 equiv. These ratios for exo-carboxylic acid
and endo-carboxylic acid are comparable to those we re-
ported earlier,8 while the yields improved significantly, with-
out production of the corresponding diacid despite the fact
that the stereochemistry of these diesters is “trans”.
Initially, we applied THF as a co-solvent, 10 times the
volume of water, and aqueous NaOH solution for the
selective monohydrolysis reaction. This practical reaction
was found to monohydrolyze all the diesters thus far tried,
forming a clean reaction mixture leading to straightforward
purification unlike the classical saponification. Later, we
reported additional studies on solvent effects, types of base,
and steric effects and found conditions that improve the
selectivity and reactivity. For example, polar aprotic solvents
are in general appropriate for an accelerated reaction rate
(5) (a) Sugimoto, T.; Kobuke, Y.; Furukawa, J. J. Org. Chem. 1976, 41,
1457–1459. (b) Paquette, L. A.; Kravetz, T. M.; Boehm, M. C.; Gleiter, R.
J. Org. Chem. 1983, 48, 1250–1257. (c) Subramanyam, R.; Bartlett, P. D.;
Iglesias, G. Y. M.; Watson, W. H.; Galloy, J. J. Org. Chem. 1982, 47, 4491–
4498. (d) Avenati, M.; Vogel, P. Helv. Chim. Acta 1983, 66, 1279–1287.
(6) Brown, F. K.; Houk, K. N. J. Am. Chem. Soc. 1985, 107, 1971–1978.
(7) (a) Klunder, A. J. H.; van Gastel, F. J. C.; Zwanenburg, B. Tetra-
hedron Lett. 1988, 29, 2697–2700. (b) Van der Eycken, J.; Vandewalle, M.;
Heinemann, G.; Laumen, K.; Schneider, M. P; Kredel, J.; Sauer, J. J. Chem.
Soc., Chem. Commun. 1989, 306–308. (c) Van Gastel, F. J. C.; Klunder,
A. J. H.; Zwanenburg, B. Recl. Trav. Chim. Pays-Bas 1991, 110, 175–184.
(8) Niwayama, S.; Hiraga, Y. Tetrahedron Lett. 2003, 44, 8567–8570.
(9) (a) Niwayama, S. J. Org. Chem. 2000, 65, 5834–5836. (b) Niwayama,
S. J. Synth. Org. Chem., Jpn. 2008, 66, 983–994.
(10) Niwayama, S.; Wang, H.; Hiraga, Y.; Clayton, J. C. Tetrahedron
Lett. 2007, 48, 8508–8510.
(11) Niwayama, S.; Rimkus, A. Bull. Chem. Soc. Jpn. 2005, 78, 498–500.
(12) Cho, H.; Niwayama, S. 238th American Chemical Society National
Meeting, Washington, DC, August 2009, ORGN 516
(13) (a) Niwayama, S.; Cho, H.; Lin, C. Tetrahedron Lett. 2008, 49, 4434–
4436. (b) Niwayama, S.; Cho, H. Chem. Pharm. Bull. 2009, 57, 508–510.
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TABLE 1. Selective Monohydrolysis of 1a and 1b
TABLE 2. Selective Monohydrolysis of 4a and 4b
run diester cosolvent base base (equiv) time yielda (%) ratio (5:6)
base
run diester cosolvent base (equiv) (h)
time yielda
(%)
ratio
(2:3)
1
2
3
4
5
6
4a
4a
4a
4a
4b
4b
THF
THF
THF
THF
CH3CN KOH
DMSO KOH
LiOH
NaOH
KOH
CsOH
1.7
1.7
1.7
1.7
2.0
1.7
2.5 h 96 (4)
97:3
91:9
95:5
92:8
96:4
97:3
2 h
2 h
>99
>99
1
2
3
4
5
6
7
1a
1a
1a
1a
1b
1b
1b
THF
THF
THF
THF
THF
LiOH
NaOH
KOH
CsOH
KOH
1.2
1.2
1.2
1.2
1.7
1.7
1.2
1
1
1
1
7
77 (22)
93 (4)
97 (2)
87 (11)
91 (2)
82:18
80:20
82:18
80:20
87:13
87:13
86:14
2 h
12 h
11 h
>99
73 (17)
91 (0)
aIsolated yield of the half-ester. The recovered diesteris shown in
parentheses (%).
CH3CN KOH
CH3CN KOH
7.5 96 (0)
65 (34)
6
aIsolated yield of the half-ester. The recovered diester is shown in
parentheses (%).
effect we studied earlier again contributed to the increase in
reactivity, as DMSO is a polar aprotic solvent, and improved
the yield of this selective monohydrolysis of 4b (run 6).9b,10
From these results, it was obvious that the most respon-
sible factor that governs these remote exo-facial selectivities
is the enhanced steric hindrance by the C5-C6 bridges
compared to the C7 bridge. Therefore, it was assumed that
further modification of the C5-C6 bridge would lead to
more exclusive selectivity. We next examined diesters 7a and
7b, in which the exo positions of the C5-C6 positions are
blocked by bulkier 1,2-O-isopropylidene. These diesters
were synthesized by osmium-catalyzed dihydroxylation of
1a and 1b and subsequent protection of the formed diols as
acetonides.16 The selective monohydrolysis was conducted
on these diesters with the use of aqueous KOH. The results
are summarized in Table 3.
The ratios for half-esters 8/9 are 98:2 for both methyl and
ethyl esters, due to the enhanced steric hindrance on the exo
direction of the C5-C6 bond, showing higher exo-facial
selectivity than monohydrolysis of 4a or 4b. We also exam-
ined the effects of the co-solvent and again found that the
polar aprotic solvents, CH3CN and DMSO, in particular
DMSO, improved the yield (run 3). Therefore, only DMSO
was applied for selective monohydrolysis of diethyl ester 7b,
which led to high yields of the half-esters (run 4).
Since the reaction center is not on the norbornene ring, we
hypothesize that this remote exo-facial selectivity was in-
duced by the difference of the steric bulkiness of the methano
bridge and the etheno bridge on the C5-C6 carbons. There-
fore, for close assessment of the exo/endo-facial selectivity
on this carbon, selective monohydrolysis reactions were
applied to structural variants of the C5-C6 positions.
Diesters 4a and 4b were synthesized by hydrogenation of
diesters 1a and 1b, respectively. The selective monohydro-
lyses of these diesters were conducted, and the results are
summarized in Table 2.
From these results, this exo-selectivity was found to be
more prominent when selective monohydrolysis was con-
ducted with diesters 4a and 4b, in which the double bond in
1a and 1b is hydrogenated to introduce two additional
hydrogens on the C5-C6 positions. The exo selectivities
are increased by more than 10% for both diesters 4a and 4b.
Interestingly, the extent of the enhancement is comparable
to that observed in the addition of ethyl bromoacetate to
2-norbornenone (90% exo) versus 2-norbornanone (100% exo)
in the Reformatsky reaction,14 even though in our selective
monohydrolysis, the nucleophile, OH-, is far smaller than
ethyl bromoacetate and thus may appear less influenced by
the steric environment, especially in this remote position. It is
also noteworthy that sodium borohydride reduction of the
carbonyl of 2-norbornenone and 2-norbornanone showed
slightly enhanced exo-selectivity in the reduction of 2-norbor-
nenone (95% exo) than of 2-norbornanone (86% exo). The
reasons are perhaps due to the enhanced ring strain by
introduction of the olefinic bond within the ring and the small
size of the nucleophile, H- in this case,15 although the extent
of the enhancement of the selectivity is again comparable to
our results in 4a and 4b.
Next, we examined the steric effect of the endo positions of
the C5-C6 bond, as we expected that blocking the endo
position would most effectively lead to the high exo selectivity.
We synthesized endo,endo-dimethyl-substituted diesters
10a and 10b by the Diels-Alder reaction of 2,3-dimethyl-
cyclopentadiene prepared in situ17 with dimethyl fumarate
and subsequent hydrogenation. The selective monohydro-
lyses of both of these dimethyl and diethyl esters were
conducted with the use of aqueous KOH, and the results
are shown in Table 4.
As can shown in Table 4, even though the methyl groups
are far smaller than the O-isopropylidene, only the ester
groups on the exo position were hydrolyzed exclusively
for both dimethyl and diethyl esters, demonstrating the im-
portance of the steric effects toward the endo directions.
The structures of these half-esters, 5a, 6a, 5b, and 6b, were
determined by the matching of 1H and 13C NMR data of the
authentic 5a, 6a, 5b, and 6b, synthesized by hydrogenation of
the purified major and minor half-esters 2a, 3a, 2b, and 3b
above. For monohydrolysis of diethyl ester 4b, the solvent
(14) Lauria, F.; Vecchietti, V.; Logemann, W.; Tosolini, G.; Dradi, E.
Tetrahedron 1969, 25, 3989–3998.
(15) Brown, H. C.; Muzzio, J. J. Am. Chem. Soc. 1966, 88, 2811–2822.
(16) Moreno-Vargas, A. J.; Schutz, C.; Scopelliti, R.; Vogel, P. J. Org.
Chem. 2003, 68, 5632–5640.
(17) Maruyama, K.; Tamiaki, H. J. Org. Chem. 1986, 51, 602–606.
J. Org. Chem. Vol. 75, No. 11, 2010 3777

Niwayama et al.
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TABLE 3. Selective Monohydrolysis of 7a and 7b
are among those examples.18 The initial bromonium cation is
expected to form on the exo position, but the second bromide
ion mayattack eitherfrom theendoorexo face, formingtrans-
or cis-dibromide, respectively. Interestingly, it appears that
the selectivity toward formation of the cis-dibromide/trans-
dibromide from cis-exo,exo-5,6-dicyanonorbornene in acetic
acid is not necessarily high (11% cis, 89% trans). Bromination
of trans-5,6-dichloro- or -dicyanonorbornene is reported to
form a considerable extent of the trans dibromide depending
on the reaction conditions (33-100%), even though these
functional groups are not as bulky as O-isopropylidene.
Although the cis-endo,endo-5,6-dichloro- or -dicyanonorbor-
nenes appear to retard the reaction rate of bromination more
than the corresponding trans- or cis-exo,exo-5,6-dichloro-
or -dicyanonorbornene, the order of reaction rate for epoxidation
on the same norbornene derivatives appears to be the oppo-
site, while that for addition of diazomethane was the same.19
Therefore, our reaction demonstrates unique examples for
distinguishing the exo and endo selectivity by the C5 and C6
functional groups in a clear-cut manner.
equivalent time yielda
ratio
(8:9)
run diester cosolvent base
of base
(h)
(%)
1
2
3
4
7a
7a
7a
7b
THF KOH
CH3CN KOH
1.7
1.7
1.7
1.7
3
3
3
6
83 (5)
87 (4)
89 (3)
92 (3)
98:2
98:2
98:2
98:2
DMSO
DMSO
KOH
KOH
aIsolated yield of the half-ester. The recovered diester is shown in
parentheses (%).
Conclusions
In summary, while the exo-/endo-facial selectivities are
perceived as negligible for the carbons that are one covalent
bond distant from the norbornane ring, we have demon-
strated that such carbons can be successfully distinguished
by our selective monohydrolysis reaction with high exo-
facial selectivity. We have shown that the selectivity is
controllable in a predictable manner based on the steric
effect on the C5-C6 ethano bridge. In particular, introduc-
tion of the smallest alkyl groups, methyl groups, on the endo
positions of the C5-C6 bonds leads to the exclusive exo
selectivity.
The structure was confirmed by X-ray crystal analysis of the
half-ester 11a. Therefore, we conclude that the most critical
factor appears to be the steric effect that blocked approach of
the nucleophile OH- from the endo direction on the C5-C6
bridge.
The results in Table 4 also demonstrate effects of the co-
solvents, indicating that polar aprotic solvents improve the
reactivity. DMSO was the most efficient solvent in these
reactions as well. In particular, the yield of the half-ester for
the methyl ester, 11a, was near-quantitative (runs 2 and 3).
To our knowledge, these results are the first examples of
systematic studies for remote exo-facial selectivities that occur
one covalent bond away from the norbornyl system. Since
norbornyl systems with various endo and exo functional
groups are often applied to synthesis of polymers with different
physical properties,20 our new finding is expected to expand
the scope of exo/endo-facial selectivity observed in the nor-
bornyl systems with the use of this selective monohydrolysis
reaction, in particular on dimethyl and diethyl esters.
In addition, it has become more apparent that a polar
aprotic cosolvent significantly improves the reactivity and
selectivity of the selective monohydrolysis of diesters, con-
firming results of our previous studies about the influence of
cosolvents in the monohydrolyses of other diesters. This
solvent effect is expected to improve yields of half-esters by
selective monohydrolysis of other diesters.
TABLE 4. Selective Monohydrolysis of 10a and 10b
equivalent
of base
yielda
time (%)
ratio
(11:12)
run diester cosolvent base
1
2
3
4
5
10a
10a
10a
10b
10b
THF
KOH
1.7
1.7
1.7
1.7
2.5
9 h 63 (26)
9 h 99
8 h 49
1 d 79 (18)
2 d 79 (16)
100:0
100:0
100:0
100:0
100:0
CH3CN KOH
DMSO KOH
DMSO KOH
DMSO KOH
Experimental Section
General Methods. The melting points are uncorrected. 1H
aIsolated yield of the half-ester. The recovered diester is shown in
parentheses (%).
NMR at 300 MHz and 13C NMR at 75 MHz spectra were
There have been very few systematic studies reported
about the effects of substituents on C5 and/or C6 positions
of norbornene or norbornanone on the exo/endo-facial select-
ivities, perhaps because the effects of substituents on such
positions have been perceived as too remote even for the
reactions that occur on the norbornene or norbornanone ring,
and the reported selectivities are rather complicated. Studies
about addition of Br2 to several 5,6-disubstituted norbornenes
(18) (a) Kikkawa, S.; Nomura, M.; Uno, Y.; Matsubara, M.; Yanagida,
Y. Bull. Chem. Soc. Jpn. 1972, 45, 2523–2527. (b) Yanagida, Y.; Shigesato,
H.; Nomura, M.; Kikkawa, S. Bull. Chem. Soc. Jpn. 1974, 47, 677–680.
(19) (a) Yanagida, Y.; Shigesato, H.; Nomura, M.; Kikkawa, S. Nihon
Kagaku Kaishi 1975, 4, 657–660. (b) Yanagida, Y.; Yokota, T.; Nomura, M.;
Kikkawa, S. Nihon Kagaku Kaishi 1975, 4, 652–656.
(20) Forexample,see: (a)Nishihara, Y.;Inoue,Y.;Nakayama,Y.;Shiono,T.;
Takagi, K. Macromolecules 2006, 39, 7458–7460. (b) Delaude, L.; Demonceau, A.;
Noels, A. F. Macromolecules 2003, 36, 1446–1456. (c) Pollino, J. M.; Stubbs, L. P.;
Weck, M. Macromolecules 2003, 36, 2230–2234.
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measured as solutions in CDCl3 with tetramethylsilane (TMS)
as an internal standard. The IR spectra were recorded on an
FTIR instrument.
J = 4.5 Hz), 3.26 (1H, t, J = 5.1 Hz), 3.70 (3H, s), 4.01 (1H, d,
J = 5.1 Hz), 4.13 (1H, d J = 5.1 Hz), 7.82 (1H, br); 13C NMR
(500 MHz, CDCl3) δ = 24.1, 25.3, 29.7, 43.4, 43.4, 44.9, 45.2,
52.4, 78.3, 80.9, 109.8, 173.9, 177.7.
General Procedures for Selective Monohydrolysis. A diester
(1.2 mmol) was dissolved in 2 mL of a co-solvent, and 20 mL of
water was added. The reaction mixture was cooled to 0 °C in an
ice-water bath. To this mixture was added dropwise with stirring
0.25 M KOH aqueous solution in the amount indicated in
Tables 1-4 (1.2, 1.7, 2.0, or 2.5 equiv). The reaction mixture was
stirred until the consumption of the starting diester was observed
by TLC, acidified with 1 M HCl at 0 °C, saturated with NaCl,
extracted with ethyl acetate (ꢀ4), and dried over sodium sulfate.
This extract was concentrated in vacuo and purified by silica gel
column chromatography. The product ratios of the two diastero-
meric half-esters were determined from the relative intensities of
the integral curves of the methyl or ethyl protons or protons
attached on C2 in the reaction mixture of 1H NMR spectra.
The separation of the two half-esters was performed by a
combination of HPLC and preparative TLC for 2a and 3a, 2b
and 3b, 8a and 9a, and 8b and 9b. The authentic samples for 5a,
6a, 5b, and 6b were prepared by hydrogenation of 2a, 3a, 2b, and
3b, respectively.
endo-3-Methoxycarbonyl-endo,endo-5,6-dimethylbicyclo-
[2.2.1]heptane-exo-2-carboxylic acid (11a): white solid. 1H
NMR (300 MHz, CDCl3) δ = 0.73 (3H, d, J = 7.5 Hz), 0.93
(3H, d, J = 6.9 Hz), 1.42 (1H, dd, J = 9.9 Hz, 1.5 Hz), 1.53 (1H,
dt, J = 9.9 Hz, 1.8 Hz), 2.13 (2H, m), 2.46 (1H, d, J = 2.4 Hz),
2.62 (1H, m), 3.11 (1H, m), 3.22 (1H, dd, J = 6.6 Hz, 1.5 Hz), 3.65
(3H, s); 13C NMR (300 MHz, CDCl3) δ = 11.2, 11.8, 34.8, 35.0,
39.7, 40.6, 46.5, 47.0, 48.6, 51.6, 174.5, 181.3; IR (neat, cm-1
)
1704, 1714, 2850-3400;mp 75-76 °C. Anal. Calcdfor C12H18O4:
C, 63.70; H, 8.02. Found: C, 63.74; H,7.58.
˚
Crystal data for 11a: space group P1h, No. 2; a = 6.9411(8) A,
o
˚
˚
b = 9.2660(11) A, c = 10.4142(12) A, R = 98.810(1) , β =
o
o
3
˚
101.150(1) , γ = 109.229(1) , V = 603.26(12) A , Z = 2, M =
226.26 for C12H18O4, density (calcd) = 1.246 g cm-3, T =
293(2) K, μ = 0.093 mm-1 for Mo KR radiation (λ = 0.71073 A,
˚
fine-focus sealed tube). Measured reflections = 6879, unique
reflections =2643 (merging R for equivalents = 0.0161), unique
reflections with I > 2σ(I) = 2058. Final R factors (all data, 150
parameters refined): R = 0.0636, Rw = 0.1544. For I > 2σ(I):
R = 0.0504, Rw = 0.1428, Gof = 1.056.
endo-3-Methoxycarbonylbicyclo[2.2.1]hept-2-ene-2-exo-car-
boxylic acid (2a): white solid; 1H NMR (300 MHz, CDCl3) δ =
1.47 (1H, dq, J = 1.6, 8.9 Hz), 1.60 (1H, br. d, J = 8.9 Hz), 2.71
(1H, dd, J = 1.5, 4.7 Hz), 3.19 (1H, m), 3.26 (1H, m), 3.36 (1H,
t, J = 4.0 Hz), 3.64 (3H, s), 6.07 (1H, dd, J = 2.8, 5.7 Hz), 6.28
(1H, dd, J = 3.2, 5.6 Hz), 11.41 (1H, br); 13C NMR (300 MHz,
CDCl3) δ = 45.6, 47.1, 47.4, 47.6, 47.8, 51.9, 135.3, 137.5,
173.6, 178.8; IR (neat, cm-1) 1696, 1724, 2950-3000; mp 121-
122 °C (lit.8 mp 121-122 °C); HRMS calcd for C10H13O4
[M þ H]þ 197.0813, found 197.0817.
endo-3-Ethoxycarbonylbicyclo[2.2.1]hept-2-ene-2-exo-carboxylic
acid (2b): colorless oil; 1H NMR (300 MHz, CDCl3) δ = 1.21 (3H,
t, J = 7.0 Hz), 1.46 (1H, dd, J = 1.6, 8.9 Hz), 1.60 (1H, br d, J =
8.9 Hz), 2.71 (1H, dd, J = 1.5, 4.5 Hz), 3.18 (1H, m), 3.26 (1H, m),
3.40 (1H, t, J = 4.0 Hz), 4.08 (2H, m), 6.06 (1H, dd, J = 2.8,
5.7 Hz), 6.28 (1H, dd, J = 3.2, 5.6 Hz), 11.0 (1H, br); 13C NMR
(300 MHz, CDCl3) δ = 14.2, 45.6, 47.1, 47.4, 47.7, 47.9, 60.7,
135.2, 137.5, 173.1, 180.0; IR (neat, cm-1) 1704, 1732, 2950-3000;
HRMS calcd for C11H15O4 [M þ H]þ 211.0970, found 211.0961.
exo-3-Ethoxycarbonylbicyclo[2.2.1]hept-2-ene-endo-2-car-
boxylic acid (3b): colorless oil; 1H NMR (300 MHz, CDCl3) δ =
1.26 (3H, t, J = 7.0 Hz), 1.47 (1H, dd, J = 1.6, 8.7 Hz), 1.61 (1H,
br d, J = 8.7 Hz), 2.63 (1H, dd, J = 1.6, 4.4 Hz), 3.12 (1H, m),
3.28 (1H, m), 3.43 (1H, t, J = 4.0 Hz), 4.16 (2H, q, J = 7.1 Hz),
6.12 (1H, dd, J = 2.9, 5.6 Hz), 6.28 (1H, dd, J = 3.2, 5.6 Hz), 11.0
(1H, br); 13C NMR (300 MHz, CDCl3) δ = 14.2, 45.6, 47.2, 47.4,
47.6, 47.7, 61.0, 135.1, 137.8, 174.2, 177.5; IR (neat, cm-1) 1704,
1732, 2950-3000; HRMS calcd for C11H15O4 [M þ H]þ
211.0970, found 211.0960.
exo-3-Methoxycarbonylbicyclo[2.2.1]hept-2-ene-endo-2-car-
boxylic acid (3a): colorless oil; 1H NMR (300 MHz, CDCl3) δ =
1.45 (1H, dq, J = 1.6, 8.9 Hz), 1.60 (1H, br. d, J = 8.9 Hz), 2.64
(1H, dd, J = 1.6, 4.4 Hz), 3.12 (1H, m), 3.28 (1H, m), 3.41 (1H, t,
J = 4.0 Hz), 3.71 (3H, s), 6.12 (1H, dd, J = 2.9, 5.6 Hz), 6.28 (1H,
dd, J = 3.2, 5.6Hz), 10.44 (1H, br);13C NMR(300 MHz, CDCl3)
δ = 45.6, 47.0, 47.4, 47.6, 47.7, 52.2, 135.1, 137.8, 174.7, 177.9; IR
(neat, cm-1) 1696, 1724, 2950-3000; HRMS calcd for C10H13O4
[M þ H]þ 197.0813, found 197.0820.
endo-3-Methoxycarbonylbicyclo[2.2.1]heptane-2-exo-carboxylic
acid (5a): white solid; 1H NMR (300 MHz, CDCl3) δ = 1.60-1.22
(6H, m), 2.62 (2H, t, J = 1.5 Hz), 2.85 (1H, d, J = 5.4 Hz), 3.17
(1H, t, J = 4.5 Hz), 3.69 (3H, s); 13C NMR (300 MHz, CDCl3)
δ = 24.2, 28.8, 38.2, 40.2, 41.7, 48.4, 49.4, 51.9, 173.8, 178.8; IR
(neat, cm-1) 1693, 1704, 2880-3550; mp 81-82 °C; HRMS calcd
for C10H14O4Na [M þ Na]þ 221.0790, found 221.0801.
endo-3-Ethoxycarbonylbicyclo[2.2.1]heptane-2-exo-carboxylic
acid (5b): colorless oil; 1H NMR (300 MHz, CDCl3) δ=1.60-1.23
(9H, m), 2.62 (2H, t, J= 1.5 Hz), 2.86 (1H, d, J=5.1Hz), 3.15(1H,
t, J = 0.9 Hz), 4.15 (2H, q, J = 7.2 Hz); 13C NMR (500 MHz,
CDCl3) δ = 14.3, 24.1, 28.8, 38.2, 40.2, 41.6, 48.3, 49.4, 60.7, 173.4,
178.7; IR (neat, cm-1) 1695, 1730, 2880-3400; HRMS calcd for
C11H16O4Na [M þ Na]þ 235.0946, found 235.0935.
exo-3-Methoxycarbonylbicyclo[2.2.1]heptane-2-endo-carboxylic
acid (6a): white solid; 1H NMR (300 MHz, CDCl3) δ = 1.61-1.23
(6H, m), 2.57 (1H, t, J = 3.6 Hz), 2.67 (1H, s), 2.76 (1H, d, J =
5.1Hz), 3.25(1H, t,J=4.5Hz), 3.67(3H, s);13C NMR (500 MHz,
CDCl3) δ = 24.2, 28.8, 38.2, 40.1, 41.6, 48.4, 49.1, 52.1, 175.0,
177.4; IR (neat, cm-1) 1698, 1720, 2880-3500; mp 79 °C; HRMS
calcd for C10H14O4Na [M þ Na]þ 221.0790, found 221.0780.
endo-3-Methoxycarbonyl-exo,exo-5,6-isopropylidenedioxybicyclo-
exo-3-Ethoxycarbonylbicyclo[2.2.1]heptane-2-endo-carboxylic
acid (6b): colorless oil; 1H NMR (300 MHz, CDCl3) δ =
1.60-1.23 (9H, m), 2.56 (1H, d, J = 4.8 Hz), 2.67(1H, m),
2.74 (1H, d, J = 5.1 Hz), 3.26 (1H, t, J = 0.9 Hz), 4.12 (2H, q,
J = 7.2 Hz); 13C NMR (500 MHz, CDCl3) δ = 14.2, 24.2, 28.9,
38.1, 40.2, 41.8, 48.7, 48.9, 60.8, 174.5, 177.3; IR (neat, cm-1):
1695, 1730, 2880-3400; HRMS calcd for C11H17O4 [M þ H]þ
213.1126, found 213.1130.
1
[2.2.1]heptane-exo-2-carboxylic acid (8a): colorless oil; H NMR
(300 MHz, CDCl3) δ = 1.26 (3H, s), 1.36 (1H, d, J = 11.1 Hz),
1.42 (3H, s), 1.80 (1H, d, J = 11.1 Hz), 2.65 (2H, s), 2.70 (1H, d,
J = 4.5 Hz), 3.19 (1H, t, J = 5.1 Hz), 3.71 (3H, s), 4.01 (1H, d,
J = 5.1 Hz), 4.15 (1H, d, J = 5.1 Hz); 13C NMR (500 MHz,
CDCl3) δ = 24.1, 25.3, 31.5, 43.4, 43.4, 45.0, 45.1, 52.3, 78.2, 80.9,
109.6, 172.7, 177.2; IR (neat, cm-1) 1700, 1733, 2937-3389; HRMS
calcd for C13H18O6Na [M þ Na]þ 293.1001, found 293.1003.
exo-3-Methoxycarbonyl-exo,exo-5,6-isopropylidenedioxybicyclo-
[2.2.1]heptane-endo-2-carboxylic acid (9a): colorless oil; 1H NMR
(500 MHz, CDCl3) δ = 1.26 (3H, s), 1.36 (1H, d, J = 11.1 Hz),
1.42 (3H, s), 1.80 (1H, d, J = 11.1 Hz), 2.59 (2H, s), 2.70 (1H, d,
endo-3-Ethoxycarbonyl-exo,exo-5,6-isopropylidenedioxybicyclo-
[2.2.1]heptane-exo-2-carboxylic acid (8b): white solid; H NMR
1
(300 MHz, CDCl3) δ = 1.29-1.24 (6H, m), 1.35 (1H, d, J =
11.1 Hz), 1.42 (3H, s), 1.81 (1H, d, J = 11.1 Hz), 2.65 (2H, s), 2.71
(1H, d, J = 0.9 Hz), 3.17 (1H, t, J = 5.1 Hz), 4.02 (1H, d, J =
5.4 Hz), 4.19-4.12 (3H, m); 13C NMR (500 MHz, CDCl3) δ= 14.2,
24.1, 25.3, 31.5, 43.4, 43.4, 45.1, 45.3, 61.2, 78.2, 80.9, 109.5,
172.2, 178.5; IR (neat, cm-1) 1720, 1730, 2935-3473; mp 64-
66 °C; HRMS calcd for C14H20O6Na [M þ Na]þ 307.1158, found
307.1143.
J. Org. Chem. Vol. 75, No. 11, 2010 3779

Niwayama et al.
JOCArticle
exo-3-Ethoxycarbonyl-exo,exo-5,6-isopropylidenedioxybicyclo-
[2.2.1]heptane-endo-2-carboxylic acid (9b): white solid; 1H NMR
(300 MHz, CDCl3) δ = 1.29-1.24 (6H, m), 1.35 (1H, m, J = 11.1
Hz), 1.42 (3H, s), 1.81 (1H, d, J = 11.1 Hz), 2.65 (2H, s), 2.71 (1H,
d, J = 0.9 Hz), 3.26 (1H, t, J = 5.1 Hz), 4.02 (1H, d, J = 5.4 Hz),
4.19-4.12 (3H, m).
endo-3-Ethoxycarbonyl-endo,endo-5,6-dimethylbicyclo[2.2.1]-
heptane-exo-2-carboxylic acid (11b): colorless oil; 1H NMR
(300 MHz, CDCl3) δ = 0.75 (3H, d, J = 7.5 Hz), 0.93 (3H,
d, J = 6.9 Hz), 1.27 (3H, m), 1.42 (1H, dd, J = 9.9, 1.5 Hz), 1.53
(1H, dt, J = 9.9, 1.8 Hz), 2.13 (2H, m), 2.45 (1H, d, J = 2.4 Hz),
2.63 (1H, s), 3.11 (1H, m), 3.12 (1H, dd, J = 6.6, 1.5 Hz),
4.12 (2H, m); 13C NMR (300 MHz, CDCl3) δ = 11.2, 12.0,
14.0, 35.0, 35.1, 39.7, 40.5, 46.5, 47.4, 48.6, 60.6, 174.1,
180.9; IR (neat, cm-1) 1705, 1715, 2932-3400; mp 75-76 °C.
Anal. Calcd for C13H20O4: C, 64.98; H, 8.39. Found: C, 65.24;
H, 8.49.
Acknowledgment. This work is supported by the National
Science Foundation-CAREER grant (CHE-0443265) and in
part by the Texas Tech University-Texas Tech University
Health Sciences Center Joint Initiative Grant.
Supporting Information Available: Crystal structure of com-
pound 11a (CIF). The synthetic procedure for diesters 1a, 1b, 4a, 4b,
7a, 7b, 10a, and 10b, and the NMR spectra for the new compounds.
They are available free of charge via the Internet at http://pubs.acs.org.
3780 J. Org. Chem. Vol. 75, No. 11, 2010