New and facile synthesis of aminobicyclo[22.1]heptane-2-carboxylic acids

Article abstract of DOI:10.1055/s-0034-1378690

Abstract A facile approach for the stereoselective synthesis of a- and b-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is described. Substrate-controlled α-carboxylation of norbonene monoester delivered the asymmetric diester intermediate with high diastereoselectivity (up to 35:1). Sequential chemoselective ester cleavage, Curtius rearrangement, and hydrolysis gave the a- and b-isomers of 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid, respectively.

Full text of DOI:10.1055/s-0034-1378690

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1243–1247
letter
1243
T.-S. Kim et al.
Letter
Synlett
New and Facile Synthesis of Aminobicyclo[2.2.1]heptane-2-car-
boxylic Acids
Taek-Soo Kim
NH2
stereoselective
α-carboxylation
ClCO2R2
Seung-Yong Seo*
Dongyun Shin*
a-( )-BCH
CO2R2
CO2R1
CO2H
CO2H
NH2
CO2R1
College of Pharmacy, Gachon University, 7-45 Songdo-dong,
Yeonsu-gu, Incheon 406-799, Republic of Korea
syseo@gachon.ac.kr
up to 35:1 (exo/endo)
b-( )-BCH
dyshin@gachon.ac.kr
Received: 29.01.2015
Accepted after: 22.02.2015
Published online: 20.03.2015
DOI: 10.1055/s-0034-1378690; Art ID: st-2015-u0065-l
dehydrogenase (GDH)2 and it plays a role in the cell-mem-
brane transport system as an L-amino acid carrier inhibi-
tor.3
As shown in Figure 1, there are four stereoisomers of
BCH, called a- and b-isomers, in which a- and b- was desig-
nated by the group of Christensen according to separation
sequence. In pioneering work it was reported that for al-
losteric activators such as the L-leucine analogue, b-BCH in-
duced insulin release by activating glutamate dehydroge-
nase. Interestingly, b-(–)-BCH stimulates insulin release
from the pancreatic β-cells effectively, whereas their ste-
reoisomers are reported to have weak activity.4 Given the
unique structural features of BCH and its range of biological
activities depending on stereochemistry, we sought to de-
velop an efficient and scalable synthetic route to BCH.
Herein, we report stereoselective synthesis of a- and b-(±)-
BCH through substrate-controlled synthesis of the nor-
bonene diester.
Abstract A facile approach for the stereoselective synthesis of a- and
b-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid is described. Sub-
strate-controlled α-carboxylation of norbonene monoester delivered
the asymmetric diester intermediate with high diastereoselectivity (up
to 35:1). Sequential chemoselective ester cleavage, Curtius rearrange-
ment, and hydrolysis gave the a- and b-isomers of 2-aminobicyc-
lo[2.2.1]heptane-2-carboxylic acid, respectively.
Key words carbocycles, amino acids, bicyclic compounds, diastereo-
selectivity, carbonylation
The use of unnatural amino acids as tools for drug dis-
covery research is becoming more important because of
their interesting chemical and biological properties.1 Such
compounds have been incorporated into peptides to modify
the conformation and enhance the stability of the peptides.
Moreover, the modified amino acids and peptides can be
more biologically active than the natural analogues. They
are capable of acting as enzymatic modulators, by mimick-
ing their natural ligands, while preventing undesired enzy-
matic reaction by modifying the conformation of the pep-
tide and enhancing resistance to chemical and enzymatic
degradation. One of the representative unnatural amino
acids is 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid
(BCH), which bears a norbonane nucleus and α,α-disubsti-
tuted α-amino acid. BCH is bulker and more resistant to
metabolic enzymes than α-monosubstituted amino acid
derivatives. Thus, it is used as an unmetabolizable surrogate
for branched-chain amino acids such as valine, leucine, and
isoleucine. So far, several potentially useful effects of BCH in
biological systems have been reported. It can be used to in-
crease insulin secretion as a selective activator of glutamate
R1 R1
a-(–)-BCH
R1= NH2, R2 = CO2H
(1R,2R,4S)
a-(+)-BCH
R1 = NH2, R2 = CO2H
(1S,2S,4R)
2
2
R2
R2
b-(–)-BCH
R1 = CO2H, R2 = NH2
(1R,2S,4S)
b-(+)-BCH
R
1 = CO2H, R2 = NH2
(1S,2R,4R)
Figure 1 Structures of the four stereoisomers of BCH
Several stereoselective synthetic approaches to 2-ami-
nobicyclo[2.2.1]heptane-2-carboxylic acid and its ana-
logues have been developed. Christensen’s group developed
the synthesis of both BCH isomers by Bucherer–Berg reac-
tion and Strecker reaction of bicyclo[2.2.1]heptan-2-
one.3a,4d As evidenced by facile and efficient approaches
that have been achieved by using the Diels–Alder reaction
with N-acyl-α,β-dehydroalaninate and cyclopentadiene,5
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1243–1247

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T.-S. Kim et al.
Letter
Synlett
some groups have utilized stereoselective Diels–Alder reac-
tions using a chiral auxiliary and substrate; (i) menthyl 2-
acetamidoacrylate,6 (ii) oxazolone and hydantoin,7 and (iii)
pyrazinone and oxazolidinone8 along with enantioselective
reaction with an organocatalyst.9 However, separation of
the a- and b-isomers of BCH is challenging and the prepara-
tion of chiral auxiliaries and catalysts in the previous ap-
proaches is not straightforward. In contrast, to our knowl-
edge, fully substrate-controlled direct synthetic methods
have not been reported. We envisioned that a- and b-(±)-
BCH could be obtained by Curtius rearrangement of the
exo- and endo-acid, respectively, and finally hydrolysis. Our
plan for the synthesis of two acid intermediates would be
substrate-controlled stereoselective α-carboxylation of 5-
norbornene-2-carboxylate, followed by chemoselective hy-
drolysis of the monoester (Scheme 1).
formed into benzyl methyl diester with exo/endo adduct ra-
tio of 32:1 at –40 °C and 35:1 at –78 °C (entries 1 and 2,
respectively). The use of benzyl ester 1b led to low chemical
yield (31 and 38%; entries 3 and 4) compared with methyl
ester substrate (77 and 89%; entries 1 and 2), and tert-butyl
ester 1c showed relatively low facial selectivity and chemi-
cal yields (entries 5–8). Overall, smaller esters gave better
chemical yield than bulkier esters, and lower temperature
yielded slightly higher chemical yields and increased facial
selectivities (exo/endo ratio).
Table 1 Stereoselective Synthesis of Norbornene Diester
CO2R1
CO2R2
endo adduct
CO2R1
CO2R2
ClCO2R2
+
CO2R1
exo adduct
LDA, THF
1a R1 = Me
1b R1 = Bn
1c R1 = t-Bu
(1)
O
Bucherer–Berg
or Strecker
Entry
1
R1
R2
Temp (°C) Yield (%)a exo/endob
NH2
CO2H
CO2H
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1c
1c
Me
Bn
–40
–78
–40
–78
–40
–78
–40
–78
77
89
31
38
30
45
23
27
32:1
35:1
26:1
32:1
19:1
25:1
14:1
22:1
NH2
b-BCH
Me
Bn
a-BCH
(2)
(3)
Bn
Me
Me
Me
Me
Bn
Diels–Alder
O
Curtius
rearrangement
Bn
N
t-Bu
t-Bu
t-Bu
t-Bu
stereocontrol
CO2H
CO2R
α-carboxylation
Bn
CO2R
a Isolated yield.
b Determined by 1H NMR analysis of the total product mixture.
CO2R
exo-acid
CO2H
endo-acid
chemoselective
hydrolysis
R = Me, Bn, t-Bu
Scheme 1 Stereoselective synthetic routes to a- and b-BCH
To confirm the stereochemistries of α-carboxylation,
the major isolated diester compounds 2a (exo adduct de-
rived from 1a) and 2b (exo adduct derived from 1b) were
treated with bromine to afford lactones 3 and 4 by bromo-
lactonization.11 Based on 1H NMR assignment of the result-
ing lactones, it was concluded that electrophiles favored ap-
proach of the upper face of the norbornene enolate to give
the exo adducts (Scheme 2).
Our study commenced with the preparation of methyl,
benzyl, and tert-butyl esters 1a–c from commercially avail-
able 5-norbornene-2-carboxylic acid under conventional
esterification conditions. The resulting esters were ob-
tained as endo/exo mixtures, and these were used without
separation of the stereoisomers. Although it was reported
that anionic α-alkylation and acylation in exocyclic com-
pounds such as 5-norbornene-2-carboxylate is exo-selec-
tive,10 studies on the stereochemistry and reactivity of sub-
strate-controlled α-carboxylation in which 5-norbornene-
2,2-dicarboxylates are generated has not been performed.
To differentiate between the two esters chemically and hy-
drolyze just one ester chemoselectively, electrophiles were
selected based on the starting ester 1a–c and thus methyl
chloroformate and benzyl chloroformate were chosen as
electrophiles. All reactions were carried out by using LDA
(1.05 equiv) as base, alkyl chloroformate (1.05 equiv) and
anhydrous THF solvent under inert conditions, and two re-
action temperatures (–40 and –78 °C) were tested. The re-
sults are presented in Table 1. Methyl ester 1a was trans-
CO2Bn
CO2Bn
CO2Bn
Br
Br
Br2
O
CH2Cl2
0 °C
CO2Me
CO2Bn
O
3
O
O
2a
Me
CO2Me
CO2Me
CO2Me
Br
Br
Br2
O
CH2Cl2
0 °C
O
4
O
O
2b
stereochemistry
confirmed by NMR
Bn
Scheme 2 Stereochemistry confirmation through bromolactonization
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1243–1247

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T.-S. Kim et al.
Letter
Synlett
With diesters 2a and 2b in hand, we turned our atten-
tion to the preparation of a-(±)-BCH and b-(±)-BCH, respec-
tively. Stereoselective synthesis of a-(±)-BCH is illustrated
in Scheme 3.12 Under hydrogenation conditions, benzyl
methyl diester 2a, which was prepared through α-carboxyl-
ation of methyl ester by using benzyl chloroformate (Table
1, entry 2), was easily converted into the corresponding sat-
urated mono-ester 5a. Acyl azide 6a was generated by using
DPPA,13 followed by Curtius rearrangement14 to afford the
isocyanate intermediate, which was used in the next step
without further purification. N-Boc-protected amino ester
compound 7a was easily generated by treatment with t-
BuONa/t-BuOH in good chemical yield. Finally, hydrolysis of
the methyl ester of 7a followed by Boc-deprotection gave
the desired a-(±)-BCH compound. Similarly, b-(±)-BCH was
synthesized from 2b by using the same synthetic process
described for a-(±)-BCH (Scheme 4). The concise and scal-
able synthesis of b-(±)-BCH was thus accomplished in six
steps with 64% overall yield.
scale synthesis of BCH. Further studies on the synthesis of
BCH analogues and their biological evaluation are under-
way and the results will be reported in due course.
Acknowledgment
This research was supported by a grant from the Korea Health Tech-
nology R&D Project through the Korea Health Industry Development
Institute (KHIDI), funded by the Ministry of Health & Welfare, Repub-
lic of Korea (grant number: HI14C1135).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378690.
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References and Notes
(1) (a) Gelmi, M. L.; Pocar, D. Org. Prep. Proced. Int. 2003, 35, 141.
(b) Vogta, H.; Brase, S. Org. Biomol. Chem. 2007, 5, 406.
(c) Cativiela, C.; Mario Ordóñez, M. Tetrahedron: Asymmetry
2009, 20, 1. (d) Kotha, S.; Goyal, D.; Chavan, A. S. J. Org. Chem.
2013, 78, 12288.
CO2Bn
CO2Me
CO2H
CO2Me
CON3
CO2Me
a
b
(2) (a) Sener, A.; Malaisse, W. J. Nature 1980, 288, 187. (b) Sener, A.;
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Lee, H. C.; Lee, K. W.; Kang, Y. J. Endocrinol. 2012, 212, 307.
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Zand, R. J. Biol. Chem. 1969, 244, 1510. (b) Sebastianelli, L.;
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(4) (a) Tager, H. S.; Christensen, H. N. Biochem. Biophys. Res.
Commun. 1971, 44, 186. (b) Christensen, H. N.; Hellman, B.;
Lernmark, A.; Sehlin, J.; Tager, H. S.; Taljedal, I.-B. Biochim.
Biophys. Acta 1971, 241, 341. (c) Tager, H. S.; Christensen, H.
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1976, 13, 20.
(5) (a) Bueno, M. P.; Cativiela, C.; Finol, C.; Mayoral, J. A. Can. J.
Chem. 1987, 65, 2182. (b) Mamedov, E. G.; Klabunovskii, E. I.
Russ. J. Org. Chem. 2008, 44, 1097.
2a
5a
6a
NH2
NHBoc
c, d
e, f
CO2Me
CO2H
a-( )-BCH
7a
Scheme 3 Synthesis of a-(±)-BCH from diester 2a. Reagents and condi-
tions: (a) Pd/C, H2, EtOAc, r.t., 99%; (b) DPPA, Et3N, anhydrous CH2Cl2,
r.t., 94% (c) toluene, reflux; (d) t-BuONa, t-BuOH, r.t. 72% for two steps;
(e) KOH, H2O, reflux; (f) 4 M HCl in 1,4-dioxane, r.t., 81% for two steps.
CO2Me
CO2Bn
CO2Me
CO2H
CO2Me
CON3
a
b
2b
5b
CO2Me
6b
CO2H
e, f
c, d
NHBoc
NH2
b-( )-BCH
7b
Scheme 4 Synthesis of b-(±)-BCH from diester 2b. Reagents and condi-
tions: (a) Pd/C, H2, EtOAc, r.t., 99%; (b) DPPA, Et3N, anhydrous CH2Cl2,
r.t., 99%; (c) toluene, reflux; (d) t-BuONa, t-BuOH, r.t., 76% for two
steps; (e) KOH, H2O, reflux; (f) 4 M HCl in 1,4-dioxane, r.t., 86% for two
steps.
(6) (a) Caputo, F.; Clerici, F.; Gelmi, M. L.; Pellegrino, S.; Pocar, D.
Tetrahedron: Asymmetry 2006, 17, 1430. (b) Cativiela, C.; Lopez,
P.; Mayoral, J. A. Tetrahedron: Asymmetry 1990, 1, 379.
(c) Yamauchi, M.; Aoki, T.; Li, M. Z.; Honda, Y. Tetrahedron:
Asymmetry 2001, 12, 3113. (d) Cativiela, C.; Garcia, J. I.; Mayoral,
J. A.; Pires, E.; Royo, A. J.; Figueras, F. A. Appl. Catal., A 1995, 131,
159.
(7) (a) Pyne, S. G.; Dikic, B.; Gordon, P. A.; Skelton, B. W.; White, A.
H. Aust. J. Chem. 1993, 46, 73. (b) Avenoza, A.; Busto, J. H.; Paris,
M.; Peregrina, J. M.; Cativiela, C. J. Heterocycl. Chem. 1997, 34,
In conclusion, we have established a facile and practical
synthesis of 2-aminobicyclo[2.2.1]heptane-2-carboxylic
acid (BCH) from readily available exo-predominant (up to
exo/endo ratio 35:1) norbornene diester compounds, which
were generated by substrate-controlled stereoselective α-
carboxylation. Both high diastereoselectivity and chemical
yield make this approach a practical route for the large-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1243–1247

1246
T.-S. Kim et al.
Letter
Synlett
1099. (c) Fraile, J. M.; Lafuente, G.; Mayoral, J. A.; Pallares, A. Tet-
rahedron 2011, 67, 8639. (d) Sankhavasi, W.; Kojmoto, S.;
Yamamoto, M.; Nishio, T.; Iida, I.; Yamada, K. Bull. Chem. Soc.
Jpn. 1992, 65, 935.
5.21 (d, J = 12.6 Hz, 1 H), 5.16–5.14 (d, J = 12.6 Hz, 1 H), 3.60 (s, 3
H), 3.42–3.42 (d, J = 0.6 Hz, 1 H), 2.92 (s, 1 H) 2.14–2.12 (dd, J =
3.6, 12.6 Hz, 1 H), 2.03–2.00 (dd, J = 3.0, 12.6 Hz, 1 H), 1.65–1.64
(d, J = 9.0 Hz, 1 H), 1.52–1.51 (dd, J = 1.2, 9.0 Hz, 1 H) ppm. 13C
NMR (150 MHz, CDCl3): δ = 172.29, 171.31, 139.82, 135.71,
133.45, 128.51, 128.21, 127.84, 66.96, 60.30, 52.28, 49.80,
48.80, 48.77, 42.03, 35.86 ppm.
(8) (a) Abellan, T.; Mancheno, B.; Najera, C.; Sansano, J. M. Tetrahe-
dron 2001, 57, 6627. (b) Abellan, T.; Najera, C.; Sansano, J. M.
Tetrahedron: Asymmetry 2000, 11, 1051. (c) Chinchilla, R.;
Falvello, L. R.; Galindo, N.; Najera, C. J. Org. Chem. 2000, 65, 3034.
(9) Ishihara, K.; Nakano, K.; Akakura, M. Org. Lett. 2008, 10, 2893.
(10) For the α-enolate alkylation of norbonene, see: (a) Krapcho, A.
P.; Dundulis, E. A. J. Org. Chem. 1980, 45, 3236. (b) Ponticello, I. S.
J. Polym. Sci., Part A: Polym. Chem. 1979, 17, 3499.
2-(Methoxycarbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid
(5a)
To a solution of diester compound 2a (300 mg, 1.05 mmol) in
EtOAc (5 mL), 10% Pd/C (30 mg, 10 wt.%) was added under an
inert atmosphere and the mixture was hydrogenated at 1 atm
for 3 h. After completion of the reaction, the catalyst was
removed by filtration through a Celite pad. The filtrate was con-
centrated under reduced pressure. The residue was purified by
flash column chromatography (hexanes–EtOAc, 20:1 to 1:1) to
give desired compound 5a (205 mg, 99%) as a white solid.
1H NMR (600 MHz, CDCl3): δ = 3.75 (s, 3H), 2.86–2.84 (d, J = 3.6
Hz, 1 H), 2.31–2.29 (dd, J = 3.0, 13.2 Hz, 2 H), 1.93–1.90 (m, 1 H),
1.66–1.65 (m, 1 H), 1.56–1.46 (m, 2 H), 1.41–1.38 (m, 1 H),
1.31–1.27 (m, 1 H), 1.15–1.11 (m, 1 H). 13C NMR (150 MHz,
CDCl3): δ = 176.81, 171.50, 61.17, 52.68, 43.94, 39.40, 38.55,
36.35, 27.61, 25.23 ppm.
(11) (a) Windmon, N.; Dragojlovic, V. Beilstein J. Org. Chem. 2008, 4,
29. (b) Breder, A.; Chinigo, G. M.; Waltman, A. W.; Carreira, E. M.
Chem. Eur. J. 2011, 17, 12405.
(12) Representative procedure for the preparation of a,b-(±)-BCH.
(endo,exo)-Methyl
Bicyclo[2.2.1]hept-5-ene-2-carboxylate
(1a)
To a solution of 5-norbornene-2-carboxylic acid (50.67 mmol,
7.00 g; predominantly endo mixture) in anhydrous CH2Cl2 (150
ml), oxalyl chloride (5.2 mL, 60.80 mmol) and DMF (390 μL,
5.07 mmol) were added at 0 °C under inert conditions. The
reaction slowly warm to r.t. and stirred for 12 h at ambient tem-
perature. The resulting solution was maintained at 0 °C and
then anhydrous MeOH (4.10 mL, 101.33 mmol) and Et3N (10.6
mL, 76.00 mmol) were added at 0 °C. The reaction mixture was
allowed to ambient temperature and stirred for 6 h. After com-
pletion of the reaction, the reaction mixture was diluted with
CH2Cl2 (1000 mL), washed with H2O (700 mL), dried over
MgSO4, filtered, and the solvent was concentrated in vacuo. The
residue was purified by flash column chromatography (hex-
anes–EtOAc, 20:1) to give ester compound (5.92 g, 77%) as a col-
orless oil.
Methyl 2-(Azidocarbonyl)bicyclo[2.2.1]heptane-2-carboxyl-
ate (6a)
To a solution of acid compound 5a (205mg, 1.03 mmol) in
CH2Cl2 (5 mL), diphenylphosphoryl azide (268 μL, 1.24 mmol)
and Et3N (173 μL, 1.24 mmol) were added at ambient tempera-
ture and stirred for 12 h. After completion of the reaction, the
reaction mixture was diluted with CH2Cl2 (120 mL), washed
with H2O (80 mL), dried over MgSO4, filtered, and concentrated
in vacuo. The residue was purified by flash column chromatog-
raphy (hexanes–EtOAc, 50:1) to give the desired acyl azide 6a
(216 g, 94%) as a colorless oil.
endo-1a (major): 1H NMR (600 MHz, CDCl3): δ = 6.20–6.19 (dd, J
= 3.6, 6.0 Hz, 1 H), 5.94–5.92 (dd, J = 6.0, 3.0 Hz, 1 H), 3.63 (s, 3
H), 3.20–3.20 (d, J = 0.6 Hz, 1 H), 2.97–2.94 (td, J = 3.6, 9.6 Hz, 1
H), 2.91 (s, 1 H), 1.94–1.89 (m, 1 H), 1.44–1.41 (m, 2 H), 1.28–
1.27 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ =
175.28, 137.75, 132.37, 51.48, 49.61, 45.66, 43.17, 42.51, 29.25
ppm.
1H NMR (600 MHz, CDCl3): δ = 3.75 (s, 3 H), 2.89–2.89 (d, J = 3.0
Hz, 1 H), 2.32–2.31 (t, J = 3.9 Hz, 1 H), 2.26–2.23 (dd, J = 3.0, 13.2
Hz, 1 H), 1.83–1.80 (m, 1 H), 1.56–1.46 (m, 3 H), 1.41–1.38 (m, 1
H), 1.30–1.26 (m, 1 H), 1.13–1.09 (m, 1 H) ppm. 13C NMR (150
MHz, CDCl3): δ = 178.98, 170.74, 63.29, 52.77, 43.46, 39.49,
38.76, 36.55, 27.61, 25.09 ppm.
exo-1a (minor): 1H NMR (600 MHz, CDCl3): δ = 6.15–6.13 (dd, J
= 5.4, 5.4 Hz, 1 H), 6.11–6.10 (dd, J = 5.4, 5.4 Hz, 1 H), 3.69 (s, 3
H), 3.04–3.04 (d, J = 0.6 Hz, 1 H), 2.92 (s, 1 H), 2.24–2.22, (dd, J =
4.8, 10.8 Hz, 1 H), 1.94–1.91 (m, 1 H), 1.54–1.52 (d, J = 9 Hz, 1
H), 1.39–1.35 (m, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ =
176.76, 138.05, 135.73, 51.71, 46.57, 46.36, 42.98, 41.62, 29.25
ppm.
Methyl
tane-2-carboxylate (7a)
2-[(tert-Butoxycarbonyl)amino]bicyclo[2.2.1]hep-
The acyl azide compound 6a (202 mg, 1.02 mmol) was diluted
with anhydrous toluene (4 mL) and refluxed for 1 h. After com-
pletion of the reaction, solvent was removed under reduced
pressure. The isocyanate intermediate was used in the next step
without further purification. To a solution of isocyanate com-
pound in t-BuOH (4 mL), NaOt-Bu (147 mg, 1.53 mmol) was
added and stirred for 30 min at ambient temperature. After
completion of the reaction, the reaction mixture was quenched
with sat. NH4Cl solution, and concentrated in vacuo. The reac-
tion mixture was diluted with EtOAc (100 mL), washed with
brine (70 mL), dried over MgSO4, filtered, and the solvent was
concentrated in vacuo. The residue was purified by flash
column chromatography (hexanes–EtOAc, 10:1) to give the
desired N-Boc amino ester compound 7a (198 mg, 72% over 2
steps) as a white solid.
2-Benzyl 2-Methyl Bicyclo[2.2.1]hept-5-ene-2,2-dicarboxyl-
ate (2a)
To a solution of (endo/exo)-1a (8.39 g, 55.13 mmol) in anhy-
drous THF (150 mL), LDA (2.0 M solution in THF, 28.9 mL, 57.88
mmol) and benzyl chloroformate (8.26 mL, 57.88 mmol) was
slowly added at –78 °C and then stirred for 72 h. The reaction
mixture was quenched with sat. NH4Cl and slowly warmed to
r.t. The solvent was removed in vacuo and the residue was
diluted with EtOAc (1000 mL), washed with H2O (700 mL), dried
over MgSO4 and filtered. The residue was purified by flash
column chromatography (hexanes–EtOAc, 100:1) to give diester
compound 2a (14.02 g, 89%) as a colorless oil.
1H NMR (600 MHz, CDCl3): δ = 4.96 (s, 1 H), 3.71 (s, 3 H), 2.45–
2.42 (d, J = 12.6 Hz, 1 H), 2.34 (s, 1 H), 2.15–2.15 (d, J = 3.0 Hz, 1
H), 1.81–1.79 (m, 1 H), 1.69–1.67 (d, J = 14.4 Hz, 1 H), 1.53–1.47
(m, 1 H), 1.43–1.37 (m, 1 H), 1.40 (s, 9 H), 1.35–1.30 (m, 2 H),
1H NMR (600 MHz, CDCl3): δ = 7.38–7.30 (m, 5 H), 6.27–6.26
(dd, J = 3.0, 5.4 Hz, 1 H), 5.99–5.98 (dd, J = 3.0, 5.4 Hz, 1 H), 5.23–
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1243–1247

1247
T.-S. Kim et al.
Letter
Synlett
1.21–1.18 (m, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 173.86,
154.87, 79.91, 66.50, 52.07, 47.14, 42.82, 38.28, 37.21, 28.24,
27.23, 24.23 ppm.
(±)-2-Aminobicyclo[2.2.1]heptane-2-carboxylic acid (a-(±)-
BCH)
To a solution of amino ester compound 7a in H2O (5 mL), solid
KOH (79 mg, 1.41) was added at ambient temperature and then
heated to reflux for 12 h. After cooling the reaction mixture to
ambient temperature, the reaction mixture was concentrated in
vacuo, treated with 4 M HCl in 1,4-dioxane (5 mL), and stirred at
ambient temperature for 12 h. After completion of the reaction,
the reaction mixture was concentrated in vacuo, purified by
DOWEX®-50WX8 ion-exchange resin column chromatography
to give the desired amino acid compound a-BCH (90 mg, 81%
over 2 steps) as an ivory solid.
1H NMR (600 MHz, D2O): δ = 2.32 (s, 2 H), 2.06–2.04 (dd, J = 1.2,
13.2 Hz, 1 H), 1.59–1.57 (d, J = 10.8 Hz, 1 H), 1.48–1.35 (m, 4 H),
1.29–1.25 (m, 1 H), 1.19–1.15 (m, 1 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 175.87, 68.10, 45.55, 38.77, 37.04, 37.02, 26.15,
23.88 ppm.
(13) (a) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30,
2151. (b) Lee, E. E.; Rovis, T. Org. Lett. 2008, 10, 1231. (c) Tashiro,
T.; Shigeura, T.; Watarai, H.; Taniguchi, M.; Mori, K. Bioorg. Med.
Chem. 2012, 20, 4540.
(14) (a) Kim, S.; Ko, H.; Kim, E.; Kim, D. Org. Lett. 2002, 4, 1343.
(b) Boger, D. L.; Cassidy, K. C.; Nakahara, S. J. Am. Chem. Soc.
1993, 115, 10733.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1243–1247

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