Asymmetric organocatalytic cyclopropanation on chiral menthyl acrylate for the synthesis of (-)- trans -2-aminomethylcyclopropanecarboxylic acid [(-)-tamp]

Article abstract of DOI:10.1055/s-0033-1340953

An enantioselective synthesis of (-)-trans-2- aminomethylcyclopropanecarboxylic acid [(-)-TAMP], a partial agonist for GABAc receptor, has been achieved as the hydrochloride salt in 3.9% overall yield for total eight steps from l-menthol. The synthesis fe

Full text of DOI:10.1055/s-0033-1340953

LETTER
▌987
lAettserymmetric Organocatalytic Cyclopropanation on Chiral Menthyl Acrylate
for the Synthesis of (–)-trans-2-Aminomethylcyclopropanecarboxylic Acid
[(–)-TAMP]
Synthesis of GABA Analogue
Yuka Sugeno, Yuichi Ishikawa, Masato Oikawa*
Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan
Fax +81(45)7872403; E-mail: moikawa@yokohama-cu.ac.jp
Received: 29.01.2014; Accepted after revision: 17.02.2014
Gaunt,6 and finally determined by the synthesis of a
Abstract: An enantioselective synthesis of (–)-trans-2-aminometh-
known compound [(–)-TAMP (1)] in the present study.
ylcyclopropanecarboxylic acid [(–)-TAMP], a partial agonist for
We first examined cyclopropanation mediated by an achi-
ral amine, 1,4-diazabicyclo[2.2.2]octane (DABCO), to
GABAc receptor, has been achieved as the hydrochloride salt in
3.9% overall yield for total eight steps from L-menthol. The synthe-
sis features double asymmetric cyclopropanation that employs cin- evaluate the L-menthyl group as a chiral auxiliary for
chona alkaloid derived organocatalyst and L-menthyl chiral
auxiliary.
asymmetric induction (Table 1, entry 1). Here, a mixture
of trans-cyclopropanes (R,R)-3 and (S,S)-4 was obtained
Key words: amino acids, asymmetric catalysis, carbocycles, chiral
auxiliaries, diastereoselectivity
in 35% isolated yield which was unfortunately insepara-
ble by silica gel column chromatography, and the ratio of
3/4 was determined to be 56:44 by chiral HPLC analysis
(CHIRALPAK
ID-3,
0.46 × 25
cm,
H2O–
Cyclopropanes are quite often used for conformational re- MeCN = 40:60). When quinidine derivative 56 was em-
striction of functionally interesting small molecules.1 ployed (Table 1, entry 2), the isolated yield (42%, 89%
Asymmetric synthesis has been studied as a methodology based on recovered starting material) and diastereoselec-
for the preparation of highly enantiopure cyclopropanes.2 tivity (3/4 = 75:25) were reasonably improved.7 The op-
Here, we report facile synthesis of trans-1,2-disubstituted posite and even higher diastereoselectivity was observed
cyclopropanes by double asymmetric cyclopropanation in Table 1, entry 3, where quinine derivative 66 was used.
employing L-menthyl ester as a chiral auxiliary and cin- From these observations, in conjunction with the empiri-
chona alkaloid derived organocatalyst. Furthermore, the cal rule by Gaunt,6 cyclopropanation of L-menthyl acry-
method was successfully applied to the synthesis of hy- late (2) with quinidine derivative 5 (Table 1, entry 2) is
drochloride salt of (–)-trans-2-aminomethylcyclopropane- considered to be a mismatched double asymmetric reac-
carboxylic acid [(–)-TAMP (1), Figure 1],3,4 a partial tion, whereas the reaction of 2 with quinine derivative 6
agonist for GABAc receptor.
(Table 1, entry 3) is likely stereochemically matched.8 It
has been suggested that sterically hindered acrylate is a
poorly reactive substrate in the ammonium ylide mediated
cyclopropanation.6 The low yields in Table 1 would,
therefore, be attributed to the menthyl group. On the other
hand, we attempted to reduce the steric demand of bromo-
acetate by employing benzyl bromoacetate instead of tert-
butyl bromoacetate (data not shown). However, the yield
for cyclopropanation of L-menthyl acrylate (2) with ben-
zyl bromoacetate was found to be much lower (18%) than
that in entry 2 (Table 1) because of decomposition of the
benzyl ester under these reaction conditions (amine 5,
Cs2CO3, MeCN, 80 °C). Our efforts continue to improve
the cyclopropanation yield.
(R)
(R)
–
CO2
+ NH3
(–)-TAMP (1)
Figure 1 (–)-trans-2-Aminomethylcyclopropanecarboxylic acid
[(–)-TAMP (1)] as a partial agonist for GABAc receptor3
L-Menthyl acrylate (2) was prepared from acryloyl chlo-
ride and L-menthol using Et3N in THF at 0 °C (94%
yield).5 We then examined cyclopropanation of 2 with
ammonium ylides derived from tert-butyl bromoacetate
and chiral6 or achiral amines (Table 1). The reactions were
carried out at 80 °C in MeCN. In all entries, only trans-
substituted cyclopropanes, that is, R,R-isomer (R,R)-3 and
S,S-isomer (S,S)-4, were obtained and no cis-cyclopro-
panes were detected. The structures were tentatively as-
signed on the basis of the empirical rule proposed by
We then decided to use cyclopropane (R,R)-3 (50% de,
entry 2 in Table 1) for the synthesis of (–)-TAMP (1,
Scheme 1). While 3 was obtained as an inseparable mix-
ture of diastereomers, we anticipated the S,S-isomer
(S,S)-4 should be removed later in the synthesis. Thus,
tert-butyl ester 3 was deprotected by TFA in CH2Cl2 (0 °C
to r.t.) to give carboxylic acid 7, which, in turn, was selec-
tively reduced by BH3·THF at room temperature to give
alcohol 8 in 55% yield. For this transformation, two-step
reduction via carbonic acid anhydride (ClCO2Me, Et3N,
THF; NaBH4, MeOH, –78 °C to r.t.)9 was also effective to
SYNLETT 2014, 25, 0987–0990
Advanced online publication: 14.03.2014
DOI: 10.1055/s-0033-1340953; Art ID: ST-2014-U0083-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

988
Y. Sugeno et al.
LETTER
Table 1 Ammonium Ylide Mediated Cyclopropanation on L-Menthyl Acrylate (2)
t-BuO
Br
O
L
(R)
(R)
L
(S)
(S)
L
amine
Cs2CO3, MeCN
80 °C, 16–25 h
O
t-BuO2C
O
t-BuO2C
O
O
O
O
(R,R)-3
(S,S)-4
2
Entry
1
Aminea
Yield (%)b
35 (36)
Diastereoselectivity (3/4)c
N
56:44
DABCO
N
OMe
MeO
N
2
3
42 (89)
75:25
N
quinidine derivative 5
OMe
H
N
34 (63)
7:93
OMe
N
quinine derivative 6
a Ratio of 2–bromoacetate–amine was 1.2:1:1 (entry 1) and 1.1:1:0.2 (entries 2 and 3).
b In parentheses are the yields based on recovered starting material 2.
c Diastereoselectivity determined by chiral HPLC analysis (CHIRALPAK ID-3, 0.46 × 25 cm, H2O–MeCN = 40:60).
give rise to 8 in lower yield (38% from 5). We then ex- using ammonium ylides generated from tert-butyl bromo-
plored the introduction of a nitrogen functionality which acetate and cinchona alkaloid derivatives. We have dis-
would allow purification of the R,R-isomer with concom- covered that L-menthyl acrylate (2) and quinidine
itant removal of the undesired S,S-isomer. After several derivative 56 is stereochemically mismatched, whereas
experimentations, it was found that phthalimide 9, pre- cyclopropanation of 2 with ammonium ylide from quinine
pared under Mitsunobu conditions (phthalimide, DEAD, derivative 66 is a matched double asymmetric reaction. The
Ph3P, benzene),10 is crystalline and can be readily purified cyclopropane 3 further led to neutrally active (–)-trans-2-
to >99.5% de by recrystallization from hot hexane (26% aminomethylcyclopropanecarboxylic acid [(–)-TAMP, 1]
yield), as judged from HPLC and 1H NMR analyses.11 The successfully. It should be noted that the results described
phthaloyl group was replaced with the Boc protecting herein can be efficiently applied to the synthesis of more
group (hydrazine, EtOH; Boc2O, Et3N, MeOH) via amine than subgram quantities of TAMP, and also the synthesis
10 to furnish 11 in 76% yield (two steps) after chromato- of enantiomeric (+)-TAMP has been already achieved
graphic removal of residual hydrophilic impurities. Final- (not shown here). We are currently working on improve-
ly, acid treatment for global deprotection (6 M HCl, ment of the cyclopropanation yield, as well as broad and
60 °C) provided (–)-TAMP·HCl (1·HCl) in quantitative in-depth evaluation of the biological activity of these and
yield after purification by column chromatography on re- other GABA analogues13 in the central nervous system.
versed-phase silica gel (H2O).12 Spectroscopic data for
(–)-TAMP·HCl were identical to those reported,4d,g indi-
Acknowledgment
cating the correct stereochemical assignments of the prod-
We are grateful to Mr. Ryo Kinoshita (Yokohama City University)
for his investigation during the early stage of this research. Daicel
Co. is gratefully acknowledged for HPLC analysis shown in Table
1.
ucts obtained in the asymmetric organocatalytic
cyclopropanation, which had been tentatively assigned
based on the empirical rule.6 Total yield was 3.9% for
eight steps from L-menthol, through reduction by
BH3·THF.
References and Notes
In summary, we have investigated the asymmetric or-
ganocatalytic cyclopropanation on L-menthyl acrylate (2)
(1) Reichelt, A.; Martin, S. F. Acc. Chem. Res. 2006, 39, 433.
Synlett 2014, 25, 987–990
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of GABA Analogue
989
TFA
(R)
(R)
CH2Cl2
0 °C to r.t.
t-BuO2C
O
HO2C
O
O
O
(R,R)-3 (50% de)
7
BH3⋅THF
THF, r.t.
55% (2 steps)
phthalimide
DEAD
(R)
(R)
Ph3P
benzene
92%
or
O
O
ClCOOMe
Et3N, THF;
NaBH4, MeOH
–78 °C to r.t.
38% (3 steps)
O
O
OH
NPhth
8
9 (48% de)
recrystallization
(hexane), 26%
9 (>99.5% de)
Boc2O
Et3N
NH2NH2⋅H2O
EtOH
MeOH
76% (2 steps)
O
O
O
O
NH2
NHBoc
10
11
(R)
(R)
COOH
6 M HCl
NH2⋅HCl
60 °C
quant
(–)-TAMP⋅HCl
(1⋅HCl)
Scheme 1 An enantioselective synthesis of hydrochloride salt of (–)-TAMP (1)
(2) (a) Doyle, M. P.; Protopopova, M. N. Tetrahedron 1998, 54,
7919. (b) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette,
A. B. Chem. Rev. 2003, 103, 977. (c) Pellissier, H.
(5) Sukopp, M.; Schwab, R.; Marinelli, L.; Biron, E.; Heller, M.;
Várkondi, E.; Pap, Á.; Novellino, E.; Kéri, G.; Kessler, H.
J. Med. Chem. 2005, 48, 2916.
Tetrahedron 2008, 64, 7041. (d) Nicolas, I.; Le Maux, P.;
Simonneaux, G. Coord. Chem. Rev. 2008, 252, 727.
(e) Concellon, J. M.; Rodriguez-Solla, H.; Concellon, C.; del
Amo, V. Chem. Soc. Rev. 2010, 39, 4103. (f) Chen, D. Y. K.;
Pouwer, R. H.; Richard, J.-A. Chem. Soc. Rev. 2012, 41,
4631.
(6) Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.;
Gaunt, M. J. Angew. Chem. Int. Ed. 2004, 43, 4641.
(7) To a stirred solution of quinidine derivative 5 (585 mg, 1.73
mmol) and Cs2CO3 (3.38 g, 10.4 mmol) in MeCN (20 mL)
were added a solution of tert-butyl bromoacetate (1.26 mL,
8.65 mmol) and L-menthyl acrylate (2, 2.00 g, 9.51 mmol) in
MeCN (15 mL). After stirring at 80 °C for 24 h, the reaction
mixture was poured into CH2Cl2 (20 mL) and washed with
sat. aq NH4Cl (20 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 20 mL). The combined organic layer was
washed with brine (20 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (70 g,
Et2O–hexane = 1:9) to give cyclopropane 3 (1.20 g, 42%) as
a colorless oil. Unreacted acrylate 2 was also recovered (1.13
g, 57%). Diastereomeric purity of 3 was determined to be
50% de from chiral HPLC analysis (CHIRALPAK ID-3,
0.46 × 25 cm, H2O– MeCN = 40:60).
(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) (a) Allan, R. D.; Curtis, D. R.; Headley, P. M.; Johnston, G.
A. R.; Lodge, D.; Twitchin, B. J. Neurochem. 1980, 34, 652.
(b) Kusama, T.; Spivak, C. E.; Whiting, P.; Dawson, V. L.;
Schaeffer, J. C.; Uhl, G. R. Br. J. Pharmacol. 1993, 109,
200. (c) Kusama, T.; Wang, T.-L.; Guggino, W. B.; Cutting,
G. R.; Uhl, G. R. Eur. J. Pharmacol. Mol. Pharmacol. 1993,
245, 83. (d) Duke, R. K.; Allan, R. D.; Chebib, M.;
Greenwood, J. R.; Johnston, G. A. R. Tetrahedron:
Asymmetry 1998, 9, 2533. (e) Aitken, D. J.; Bull, S. D.;
Davies, I. R.; Drouin, L.; Ollivier, J.; Peed, J. Synlett 2010,
2729. (f) Levandovskiy, I. A.; Sharapa, D. I.; Shamota, T.
V.; Rodionov, V. N.; Shubina, T. E. Future Med. Chem.
2011, 3, 223. (g) Nakada, K.; Yoshikawa, M.; Ide, S.;
Suemasa, A.; Kawamura, S.; Kobayashi, T.; Masuda, E.; Ito,
Y.; Hayakawa, W.; Katayama, T.; Yamada, S.; Arisawa, M.;
Minami, M.; Shuto, S. Bioorg. Med. Chem. 2013, 21, 4938.
Spectroscopic Data for Cyclopropane 3 (50% de)
[α]D23.2 –83.8 (c 2.43, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 4.64 (ddd, J = 12.0, 12.0, 4.4 Hz, 1 H), 2.05–2.01 (m, 2
H), 1.93 (m, 1 H), 1.82 (m, 1 H), 1.62 (m, 2 H), 1.43 (m, 1
H), 1.40 (s, 9 H), 1.36–1.26 (m, 3 H), 1.02–0.90 (m, 2 H),
0.86–0.84 (m, 7 H), 0.72–0.70 (m, 3 H). 13C NMR (100
MHz, CDCl3): δ = 171.6, 171.0, 128.4, 81.3, 47.0, 40.9,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 987–990

990
Y. Sugeno et al.
LETTER
(12) A suspension of 11 (48.8 mg, 0.138 mmol) in HCl (6 M,
34.3, 31.4, 28.1 (3×), 26.3, 23.4, 23.2, 22.3, 22.1, 20.9, 16.4,
15.4.
0.200 mL) was stirred at 60 °C for 15 h. The reaction
mixture was then concentrated under reduced pressure. The
residue was purified by column chromatography on
reversed-phase silica gel (500 mg, H2O) to give HCl salt of
(8) For recent examples, see: (a) Chen, M.; Roush, W. R. J. Am.
Chem. Soc. 2012, 134, 10947. (b) Huang, L.; Zhang, Y.;
Staples, R. J.; Huang, R. H.; Wulff, W. D. Chem. Eur. J.
2012, 18, 5302.
22.0
(–)-TAMP (1, 20.9 mg, quant.) as a colorless solid: [α]D
(9) Sui, X.; Zhu, R.; Li, G.; Ma, X.; Gu, Z. J. Am. Chem. Soc.
2013, 135, 9318.
(10) Mitsunobu, O. Synthesis 1981, 1.
–65.4 (c 0.15, 1 M HCl). 1H NMR (400 MHz, D2O): δ = 2.98
(dd, J = 12.0, 8.0 Hz, 1 H), 2.87 (dd, J = 12.0, 8.0 Hz, 1 H),
1.68–1.60 (m, 2 H), 1.23 (m, 1 H), 1.02 (m, 1 H). 13C NMR
(100 MHz, D2O): δ = 181.6, 42.8, 21.9, 17.4, 12.2.
(13) For our related studies, see: (a) Oikawa, M.; Sasaki, S.;
Sakai, M.; Sakai, R. Tetrahedron Lett. 2011, 52, 4402.
(b) Oikawa, M.; Sasaki, S.; Sakai, M.; Ishikawa, Y.; Sakai,
R. Eur. J. Org. Chem. 2012, 5789. (c) Oikawa, M.; Sugeno,
Y.; Ishikawa, Y.; Tukada, H. Synlett 2013, 24, 886.
(d) Sakai, M.; Ishikawa, Y.; Takamizawa, S.; Oikawa, M.
Tetrahedron Lett. 2013, 54, 5911.
(11) Spectroscopic Data for Phthalimide 9
[α]D23.5 –131.4 (c 0.04, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.91–7.81 (m, 2 H), 7.73–7.69 (m, 2 H), 4.56
(ddd, J = 10.8, 10.8, 4.4 Hz, 1 H), 3.61 (d, J = 4.0 Hz, 2 H),
1.92 (br, 1 H), 1.78 (m, 1 H), 1.71–1.56 (m, 5 H), 1.41 (br, 1
H), 1.28–1.16 (m, 2 H), 0.99–0.89 (m, 3 H), 0.85 (d, J = 6.4
Hz, 3 H), 0.69 (d, J = 6.8 Hz, 3 H), 0.56 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.9, 168.2 (2×), 134.1
(2×), 132.1 (2×), 123.4 (2×), 74.5, 47.0, 40.9, 40.6 34.3,
31.4, 26.4, 23.6, 22.1, 21.2, 20.6, 19.7, 16.4, 13.9.
Synlett 2014, 25, 987–990
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