A synthesis of (-)- cis -2-aminomethylcyclopropanecarboxylic acid [(-)-CAMP]

Article abstract of DOI:10.1055/s-0032-1317802

An enantioselective synthesis of (-)-cis-2- aminomethylcyclopropanecarboxylic acid [(-)-CAMP] has been achieved in 2.5% total yield over ten steps starting from 2-furaldehyde. The synthesis features diastereoselective cyclopropane formation via diazene, followed by oxime formation and the reduction, for construction of the γ-aminobutyric acid (GABA) motif. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317802

886▌
LETTER
lAetteSr ynthesis of (–)-cis-2-Aminomethylcyclopropanecarboxylic Acid
[(–)-CAMP]
Synthesis of GABA Analogue
Masato Oikawa,* Yuka Sugeno, Yuichi Ishikawa, Hideyuki Tukada
Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan
Fax +81(45)7872403; E-mail: moikawa@yokohama-cu.ac.jp
Received: 29.01.2013; Accepted after revision: 04.03.2013
that will be capable of producing both enantiomers of
CAMP with high enantiomeric purity. Here, we describe
our preliminary results to reach the goal.
Abstract: An enantioselective synthesis of (–)-cis-2-aminomethyl-
cyclopropanecarboxylic acid [(–)-CAMP] has been achieved in
2.5% total yield over ten steps starting from 2-furaldehyde. The
synthesis features diastereoselective cyclopropane formation via di-
azene, followed by oxime formation and the reduction, for construc-
tion of the γ-aminobutyric acid (GABA) motif.
We decided to employ chiral auxiliary assisted organic
synthesis for the preparation of highly enantiopure CAMP
that will be used for precise biological studies. In 1994,
Feringa’s group reported the diastereoselective synthesis
of cyclopropane (enantiomer of 2, see Scheme 1) using L-
menthol as a chiral auxiliary.8 However, they did not iso-
late the cyclopropane ent-2, and synthetic details were not
described in the paper probably due to the lability of ent-
2 and/or the diazene precursor (see below), which causes
poor reproducibility. In the present study, we reinvestigat-
ed the synthesis of the cyclopropane 2 (Scheme 1) and
successfully established the isolation procedure. Eventu-
ally, we achieved the synthesis of (–)-CAMP (1) by using
the cyclopropane 2 as a synthetic intermediate as dis-
cussed below.
Key words: amino acids, cycloaddition, photochemistry, ring con-
traction, stereoselective synthesis
Inhibitory neurotransmission in the mammalian central
nervous system is mediated by γ-aminobutyric acid
(GABA) receptors.1 Deactivation of GABA receptors, for
example, by decreasing the concentration of GABA,
causes seizures, because of an imbalance to the concentra-
tion of excitatory neurotransmitter, glutamate. Decrease
of the inhibitory neurotransmission causes not only epi-
lepsy, but also other neuronal disorders such as Alzheim-
er’s disease, Huntington’s disease, Parkinson's disease,
and drug addiction.1c Selective ligands for GABA recep-
tors are thus important as a tool for understanding the bi-
ological functions of the receptors, as well as a possible
candidate for treatment of such neuronal diseases associ-
ated with GABA receptors. In 1980, cis-2-aminomethyl-
cyclopropanecarboxylic acid (CAMP) was synthesized in
the racemic form and introduced to neurochemistry by Al-
lan et al. as a conformationally restricted analogue of GA-
BA.2 After twenty years, (+)-CAMP and (–)-CAMP were
characterized by the same research group as a full agonist
and an antagonist for GABAc receptor, respectively.3 Be-
cause of the intriguingly diverse neuroactivities, several
practical methods have been reported to date for the enan-
tioselective synthesis of (+)- and (–)-CAMP. In 1997, Ga-
leazzi et al. reported a ten-step synthesis using
phenylethylamine as a chiral auxiliary.4 Duke et al. em-
ployed the resolution of racemic CAMP by esterification
with chiral alcohol in 1998.5 In 2002, Baxendale et al. re-
ported an eight-step synthesis using polymer-supported
reagents while the enantiomeric purity was low (90% ee).6
Rodríguez–Soria et al. achieved a six-step synthesis em-
ploying radical reaction in 2008.7 Some of them4,5,7 dem-
onstrated the enantioselective synthesis of subgram
quantities of CAMP. We also started our own study to de-
velop an easy, practical, and promising synthetic entry
–OOC
O
O
O
+NH3
(–)-CAMP (1)
2
Scheme 1 Our synthetic plan toward (–)-CAMP (1) using D-menthol
as a chiral auxiliary
The synthesis started with butenolide 3, known as (5S)-(D-
menthyloxy)-2(5H)-furanone9 and readily prepared in
20% yield in two steps from 2-furaldehyde (Scheme 2).
1,3-Dipolar cycloaddition of diazomethane to butenolide
3 proceeded slowly but cleanly in Et2O at –40 °C over two
days to give rise to diazene 410 in 66% isolated yield. The
purification was carefully performed by flash column
chromatography using neutral silica gel 60N, because di-
azene 4 was unstable under both acidic and alkaline con-
ditions. Even under neutral conditions, diazene 4 should
not be stored and used immediately, since 4 gradually de-
composes into a complex mixture. In the 1,3-dipolar cy-
cloaddition, diastereomer of 4 (structure not shown) was
also generated in ca. 25% yield as judged from 1H NMR.
The structures were determined on the basis of 2D NMR
experiments (COSY, NOESY). The selectivity was com-
parable to that reported by Feringa;8 however, the present
study is the first demonstration that diastereomerically
pure diazene 4 is isolated and characterized. The major
isomer 4 was then subjected to photoirradiation (high-
SYNLETT , 201324, 0886–0888
Advanced online publication: 15.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317802; Art ID: ST-2013-U0097-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of GABA Analogue
887
pressure mercury lamp, benzophenone, benzene) to in- ylcyclopropanecarboxylic acid [(–)-CAMP, 1] employing
duce cyclopropane formation with concomitant elimina- d-menthol as the chiral auxiliary. Starting from 2-furalde-
tion of nitrogen. While small amounts of by-products such hyde, the synthesis was performed in 2.5% yield over ten
as undesired 3-methylbutenolide (structure not shown)8 steps. In addition to the efficient cyclopropane formation,
were observed, the desired cyclopropane 211 was cleanly adoption of hydrophobic and nonvolatile intermediates is
provided in 71% yield.
apparently worthy of note in our successful synthesis of
such a hydrophilic molecule of low molecular weight. Ef-
forts are currently directed toward the large-scale synthe-
sis of the antipode [(+)-CAMP], a potent agonist for
GABAc receptor,3 using l-menthol as the chiral auxiliary
to prove the synthetic practicality of our methodology.
The next challenge also includes successful reduction of
oxime ether 5 to deliver (–)-CAMP (1) directly without
sacrificing the cyclopropane ring, which greatly shortens
the synthesis to six steps.
1) hν rose bengal
MeOH
O
O
O
CHO
2) D-menthol, CSA
benzene, reflux
O
2-furaldehyde
20% (2 steps)
3
N
N
hν
Ph2CO
CH2N2
O
O
O
O
O
benzene
71%
O
Et2O
dark, –40 °C
66%
Acknowledgment
This work was supported by the grant for 2010-2012 Strategic Re-
search Promotion (Nos. T2202, T2309, T2401) of Yokohama City
University, Japan.
4
2
BnONH2⋅HCl
TMSCHN2
NaOH
MeO2C
HO2C
MeOH
94%
EtOH, H2O
88%
N
N
References and Notes
OBn
OBn
OBn
5
6
(1) (a) Johnston, G. A. R. Curr. Top. Med. Chem. 2002, 2, 903.
(b) Ordóñez, M.; Cativiela, C. Tetrahedron: Asymmetry
2007, 18, 3. (c) Silverman, R. B. Angew. Chem. Int. Ed.
2008, 47, 3500. (d) Levandovskiy, I. A.; Sharapa, D. I.;
Shamota, T. V.; Rodionov, V. N.; Shubina, T. E. Future
Med. Chem. 2011, 3, 223.
Boc2O
Et3N
NaBH3CN
MeO2C
MeO2C
AcOH
44%
MeOH
89%
BocN
HN
OBn
7
8
(2) Allan, R. D.; Curtis, D. R.; Headley, P. M.; Johnston, G. A.
R.; Lodge, D.; Twitchin, B. J. Neurochem. 1980, 34, 652.
(3) Duke, R. K.; Chebib, M.; Balcar, V. J.; Allan, R. D.; Mewett,
K. N.; Johnston, G. A. R. J. Neurochem. 2000, 75, 2602.
(4) Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron:
Asymmetry 1997, 8, 133.
(5) Duke, R. K.; Allan, R. D.; Chebib, M.; Greenwood, J. R.;
Johnston, G. A. R. Tetrahedron: Asymmetry 1998, 9, 2533.
(6) Baxendale, I. R.; Ernst, M.; Krahnert, W.-R.; Ley, S. V.
Synlett 2002, 1641.
Raney-Ni
(W-7)
6 M
HCl
EtO2C
+
NH3
–OOC
(–)-CAMP (1)
90 °C
100%
EtOH
85%
BocN
H
9
Scheme 2 Ten-step enantioselective synthesis of (–)-CAMP (1)
With cyclopropane 2 in hand, we then investigated the in-
troduction of nitrogen functionality. After several experi-
ments, treatment of 2 with benzyloxyamine was found to
be convenient, furnishing oxime ether 5 in an excellent
yield (88%). After esterification (TMSCHN2), efficient
conditions were explored for reduction of the oxime ether
to generate amine directly. The earlier attempts were,
however, discouraging. For example, hydrogenation (H2,
10% Pd/C, EtOH)12 of 6 (and also the precursor 5) in-
duced cleavage of the cyclopropane ring predominantly.
We therefore screened mild conditions, and finally found
that stepwise reductions [NaBH3CN, AcOH; Boc2O,
Et3N; Raney-Ni (W-7, EtOH]13 cleanly realize the desired
transformation to furnish N-Boc amine 9 in 33% yield.
Global deprotection under acidic conditions (6 M hydro-
chloric acid, 90 °C) successfully delivered the desired (–)-
CAMP (1) with high enantiomeric purity (100% ee) in
quantitative yield.14 Spectroscopic data including the [α]D
value were in good agreement with those reported.4–7
(7) Rodríguez-Soria, V.; Quintero, L.; Sartillo-Piscil, F.
Tetrahedron 2008, 64, 2750.
(8) Rispens, M. T.; Keller, E.; de Lange, B.; Zijlstra, R. W. J.;
Feringa, B. L. Tetrahedron: Asymmetry 1994, 5, 607.
(9) Moradei, O. M.; Paquette, L. A. Org. Synth. 2003, 80, 66.
(10) Spectroscopic data for diazene 4: [α]D20.1 –57.2 (c = 0.94,
CHCl3). 1H NMR (400 MHz, C6D6): δ = 5.05 (d, J = 6.8 Hz,
1 H), 4.41 (d, J = 2.0 Hz, 1 H), 3.95 (m, 1 H), 3.79 (m, 1 H),
3.35 (td, J = 10.6, 4.3 Hz, 1 H), 2.34 (m, 1 H), 1.95 (m, 1 H),
1.70 (m, 1 H), 1.52–1.57 (m, 2 H), 1.25 (m, 1 H), 1.10 (br, 1
H), 0.99–1.01 (m, 6 H), 0.85–0.95 (m, 4 H), 0.69–0.79 (m, 2
H). 13C NMR (100 MHz, C6D6): δ = 167.0, 104.3, 93.5, 83.1,
77.7, 48.1, 39.9, 39.1, 34.3, 31.3, 25.7, 23.2, 22.3, 21.0, 15.9.
(11) Spectroscopic data for cyclopropane 2: [α]D20.3 +137.0 (c =
1.07, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 5.41 (s, 1 H),
3.53 (td, J = 10.8, 4.11 Hz, 1 H), 2.01–2.19 (m, 4 H), 1.61–
1.66 (m, 2 H), 1.37 (m, 1 H), 1.15–1.25 (m, 2 H), 0.77–1.04
(m, 13 H). 13C NMR (100 MHz, CDCl3): δ = 175.4, 99.8,
77.5, 47.7, 40.2, 34.2, 31.4, 25.3, 23.1 (2 ×), 22.1, 20.9, 17.1,
15.6, 11.8.
(12) Gannett, P. M.; Nagel, D. L.; Reilly, P. J.; Lawson, T.;
Sharpe, J.; Toth, B. J. Org. Chem. 1988, 53, 1064.
In conclusion, we have successfully developed a new en-
try for enantioselective synthesis of cis-(–)-2-aminometh-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2003, 2013, 886–888

888
M. Oikawa et al.
LETTER
(13) (a) Ueda, M.; Miyabe, H.; Sugino, H.; Miyata, O.; Naito, T.
Angew. Chem. Int. Ed. 2005, 44, 6190. (b) Sukhorukov, A.
Y.; Ioffe, S. L. Chem. Rev. 2011, 111, 5004.
(14) A suspension of protected CAMP 9 (13.0 mg, 0.053 mmol)
in hydrochloric acid (6 M, 0.200 mL) was stirred at 90 °C for
8 h. The reaction mixture was then concentrated under
reduced pressure and subjected to ion-exchange
chromatography (Dowex 1-X8, 1.0 × 5 cm, H2O) to give (–)-
CAMP hydrochloride (8.2 mg, 100%) as a colorless solid;
[α]D20.3 –35.9 (c = 0.50, H2O). IR (KBr): 3430, 3105, 1706,
1600, 1428, 1194, 861 cm–1. 1H NMR (400 MHz, D2O): δ =
3.08–3.19 (m, 2 H), 1.80 (m 1 H), 1.53 (m, 1 H), 1.20 (m, 1
H), 0.94 (m, 1 H). 13C NMR (100 MHz, D2O): δ = 176.5,
37.9, 17.7, 17.4, 12.8.
Synlett 2003, 2013, 886–888
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