A rigid GABA analog from a [4+3]-cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2009.02.113

A rigid GABA analog has been prepared from the adduct obtained from the [4+3]-cycloaddition of pentachloroacetone and a 2-substituted furan.

Full text of DOI:10.1016/j.tetlet.2009.02.113

Tetrahedron Letters 50 (2009) 2109–2110
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Tetrahedron Letters
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A rigid GABA analog from a [4+3]-cycloaddition
*
Paitoon Rashatasakhon, Michael Harmata
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A rigid GABA analog has been prepared from the adduct obtained from the [4+3]-cycloaddition of penta-
chloroacetone and a 2-substituted furan.
Received 8 February 2009
Revised 17 February 2009
Accepted 17 February 2009
Available online 21 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
As an extremely important inhibitory neurotransmitter in
mammalian central nervous system, gamma-aminobutyric acid or
GABA (1) has captured much attention in pharmacological re-
search.1 One of the most effective ways to prevent epilepsy is to
use GABA analogs to deactivate enzyme that degrades GABA. Sev-
eral synthetic compounds such as vigabatrin2 (2), gabapentin3 (3),
and pregabalin4 (4) have been used as anticonvulsant drugs.
Among the synthetic GABA analogs in the literature, compounds
with a restricted conformation are very desirable since the orienta-
tion of the two functional groups in three-dimensions is known.
They can provide substantial information on active conformations
of the neurotransmitter that participate in various processes such
as receptor activation, cellular uptake, or enzymatic transamina-
tion.5 Even with many advances, the design and development of
new structurally rigid GABA analogs are still very important.
tion,7 we now wish to demonstrate the utility of this methodology
by reporting the synthesis of a new GABA analog (5) from an ad-
vanced intermediate generated from this reaction.
Our retrosynthetic analysis involved a series of functional group
transformations of oxabicyclic ketones derived from cycloaddition
between oxyallyl zwitterions A and a functionalized furan (Scheme
1).
We began the synthesis by treatment of pentachloroacetone (7)
with 2-substituted furans (Scheme 2) under the conditions devel-
oped by Föhlisch.8 The intermediate oxyallyl zwitterion A reacted
with electron-rich furans to afford cycloadducts with an oxabicy-
clic framework in moderate yields. In order to simplify the follow-
ing protection–deprotection strategies, we decided to pursue the
synthesis with 2-(benzyloxymethyl)furan (6)9 even though the
reaction of 2-(dimethoxymethyl)furan10 was quite effective. It is
worth-mentioning that this reaction with furans bearing an elec-
tron-withdrawing group, such as methyl or benzyl furan-2-carbox-
ylate, resulted only in recovery of the starting diene and
decomposition of the pentachloroacetone. The reductive dehalo-
genation of the relatively unstable tetrachloroketone 8 took place
smoothly using zinc powder and copper(I) acetate in saturated
methanolic ammonium chloride solution, affording 9 in 87%
yield.11
H2N
COOH
GABA, 1
H2N
COOH
Vigabatrin, 2
NH2
With the intermediate 9 in hand, we carried out the functional
group manipulation outlined in Scheme 3. A highly stereoselective
reduction of ketone 9 was achieved using a bulky borane such as L-
COOH
NH2
Gabapentin, 3
H
COOH
Pregabalin,4
O
O
NH2
O
HOOC
The [4+3] cycloaddition reaction has long been known as a con-
venient method for the construction of compounds with a seven-
membered ring,6 especially those with rigid bicyclic frameworks.
As part of our continuous research program in the [4+3]-cycloaddi-
R
O
H
5
O-
Cl
Cl
R
+
+
Cl
Cl
A
* Corresponding author. Tel.: +1 573 882 1097; fax: +1 573 882 2754.
E-mail address: harmatam@missouri.edu (M. Harmata).
Scheme 1. Retrosynthesis of 5.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.113

2110
P. Rashatasakhon, M. Harmata / Tetrahedron Letters 50 (2009) 2109–2110
tion is known15 and a wide variety of structural possibilities exist
O
OBn
+
6
NaOCH2CF3, TFE
oC to rt, 55%
for the cycloaddition. Moreover, the [4+3]-cycloadducts can pos-
sess a variety of functional groups that are subject to elaboration.
All of these factors point to an opportunity to make diverse li-
braries of GABA analogs using this approach. Further results will
be reported in due course.
O
O
Cl
0
Cl3C
Cl
7
Cl
Cl
O
Zn, Cu(OAc)2
NH4Cl, MeOH
87%
Cl
Acknowledgment
O
O
Cl
9
OBn
OBn
8
This work was supported by the National Science Foundation to
which we are grateful.
Scheme 2. Synthesis of key [4+3]-cycloadduct.
Supplementary data
O
O
L-Selectride
THF, 90%
p-TsCl, DMAP
H
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.113.
O
CH2Cl2, 98%
OH
10
BnO
BnO
9
References and notes
O
O
H2, 80 psi
H
H
1. (a) Dutar, P.; Nicoll, R. A. Nature 1988, 332, 156; (b) Krogsgaard-Larsen, P. J.
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10% Pd/C,
OTs
11
OTs
BnO
HO
EtOAc, 97%
12
O
4. Miller, R.; Frame, B.; Corrigan, B.; Burger, P.; Bockbrader, H.; Garofalo, E.;
Lalonde, R. Clin. Pharmacol. Ther. 2003, 73, 491.
NaN3, DMF
93%
1. RuCl3-3H2O, NaIO4
CCl4/MeCN/H20
2. Cs2CO3, BnBr, DMF
80%
H
O
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Z.; Yuan, H.; Silverman, R. B. Biochemistry 2006, 45, 14513; (c) Lu, H.; Silverman,
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OTs
BnO
13
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Curr. Org. Chem. 1998, 2, 217; (c) Mann, J. Tetrahedron 1986, 42, 4611.
7. (a) Harmata, M.; Brackley, J. A., III; Barnes, C. L. Tetrahedron Lett. 2006, 47, 8151;
(b) Harmata, M.; Rashatasakhon, P.; Barnes, C. L. Can. J. Chem. 2006, 84, 145; (c)
Harmata, M.; Wacharasindhu, S. Org. Lett. 2005, 8, 2563; (d) Harmata, M.;
Bohnert, G. L. Org. Lett. 2003, 5, 59; (e) Harmata, M.; Rashatasakhon, P.
Tetrahedron Lett. 2001, 42, 5593; (f) Harmata, M.; Rashatasakhon, P. Synlett
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8. (a) Sendelbach, S.; Schwetzler-Raschke, R.; Radl, A.; Kaiser, R.; Henle, G. H.;
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O
O
H2, 80 psi
10% Pd/C,
EtOH, 90%
NH2
N3
O
O
H
H
HO
BnO
14
5
Scheme 3. Synthesis of 5.
SelectrideÒ. The analysis of the 1H NMR spectrum of a crude prod-
uct revealed that a single diastereomer was produced.12 The hydro-
xyl group in 10 was subsequently transformed into
toluenesulfonate ester. A facile removal of the benzyl group and
a hydrogenation/hydrogenolysis afforded alcohol 12 in one simple
operation.
After extensive screening, it was found that many oxidizing
conditions, especially the acidic ones, tended to give low yields
in the attempted oxidation of the primary alcohol 12 to the corre-
sponding carboxylic acid. We suspected that protonation of the oxa
bridge leading to decomposition was responsible for the inefficient
reaction. To our delight, we found that the alcohol 12 could be oxi-
dized to a corresponding carboxylic acid in nearly quantitative
yield using NaIO4 and RuCl3.13 The crude product was very clean
as characterized by both 1H and 13C NMR. Transformation of this
carboxylic acid into benzyl ester 13 was accomplished by treat-
ment with Cs2CO3 and benzyl bromide. Upon heating this with
NaN3 in DMF, the p-toluenesulfonate group in 13 was converted
into an azide group with inversion of configuration. Finally,
hydrogenolysis of the benzyl ester and reduction of the azide were
Synthesis of 8: To a 50 mL round-bottomed flask were placed 6.20 g
(26.9 mmol) of pentachloroacetone and 4.61 g (24.5 mmol) of 2-
(benzyloxymethyl)furan. The mixture was cooled in an ice bath for 5 min. A
2 M solution of sodium trifluoroethoxide in trifluoroethanol (17 mL) was added
via syringe over a period of 30 min and the ice bath was removed. The reaction
was stirred at room temperature for 2 h and 40 mL of water was added in order
to quench the reaction. The mixture was allowed to settle and the aqueous
layer was separated and extracted with CH2Cl2 (3 Â 30 mL). The combined
organic layers were dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography on silica gel using 10:1 hexanes/EtOAc as the eluent.
Compound 6 was obtained as white solid in 55% yield. 1H NMR (250 MHz,
CDCl3) d 7.38–7.26 (m, 5H), 6.52 (d, J = 6.0 Hz, 1H), 6.47 (dd, J = 6.0, 1.6 Hz, 1H),
5.24 (d, J = 1.6 Hz, 1H), 4.69 (d, J = 12.0 Hz, 1H), 4.57 (d, J = 12.0 Hz, 1H), 4.26 (d,
J = 12.0 Hz, 1H), 4.09 (d, J = 12.0 Hz, 1H); 13C NMR (62.5 MHz, CDCl3) d 184.5,
137.2, 135.9, 133.1, 128.4, 127.9, 127.6, 94.2, 87.4, 85.0, 82.1, 73.9, 67.5; IR
(KBr) 3108, 3031, 2919, 2874, 1764, 1603, 1491, 1453, 1367, 1095, 928,
874 cmÀ1. Anal. Calcd for C15H12Cl4O3: C, 47.15; H, 3.17. Found: C, 47.20; H,
3.23.
a p-
9. Arjona, O.; Iradier, F.; Manas, R. M.; Plumet, J.; Grabuleda, X.; Jaime, C.
Tetrahedron 1998, 54, 9095.
10. Gopinath, R.; Jiaul Haque, S.; Bhisma, K. P. J. Org. Chem. 2002, 67, 5842.
11. Wege, D. J. Org. Chem. 1990, 55, 1667.
12. In the reduction using NaBH4 or LiBEt3H, there were two sets of signals in the
1H NMR spectra of the crude product which indicated two isomers (exo and
endo). For the carbinol proton, the chemical shift of the exo isomer should be
more downfield since it is shielded by the olefinic p-system. When L-Selectride
(LiB(s-Bu)3H) was used, the more downfield carbinol signal completely
disappeared.
carried out in one-pot to afford
c-amino butyric acid 5 in good
yield.14
In conclusion, we have successfully synthesized a new analog of
GABA from a [4+3]-cycloaddition product. This compound has a ri-
gid skeleton with a restricted conformation about the amino and
carboxylic acid functional groups. The synthesis should serve as a
paradigm for future work, since the asymmetric [4+3]-cycloaddi-
13. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46,
3936.
14. Characterization of 5: 1H NMR (250 MHz, D2O) d 4.51–4.45 (m, 1H), 3.70–3.55
(m, 1H), 2.32 (dd, J = 12.7, 5.6 Hz, 1H), 2.20–1.50 (m, 7H); 13C NMR (62.5 MHz,
D2O) d 179.3, 83.4, 74.4, 43.2, 37.5, 34.4, 31.9, 27.9.
15. Harmata, M. Adv. Synth. Catal. 2006, 348, 2297.