Model studies towards kainic acid

Article abstract of DOI:10.1055/s-2002-19324

A novel photochemical approach to the kainoid ring system is presented alongside model studies to demonstrate its feasibility.

Full text of DOI:10.1055/s-2002-19324

LETTER
167
Model Studies Towards Kainic Acid
Model Studies
T
.
owards
K
ai
S
nic
A
cid . Greenwood, P. J. Parsons*
The Chemical Laboratories, School of Chemistry, Physics & Environmental Science, University of Sussex, Falmer, Brighton, East Sussex,
BN1 9QJ, UK
Fax +44(1273)677196; E-mail: P.J.Parsons@sussex.ac.uk
Received 17 October 2001
O
Abstract: A novel photochemical approach to the kainoid ring sys-
tem is presented alongside model studies to demonstrate its feasibil-
ity.
CO2H
CO2H
CO2Me
CO2R
N
H
N
P
Key words: kainic acid, photochemistry, cycloadditions, cyclobu-
tanes, natural products
1
2
O
The kainoid amino acids have attracted considerable in-
terest in the fields of biology and neurobiology due to
their pronounced insecticidal, anthelmintic and, principal-
ly, neuroexcitatory properties.1 Kainic acid 1 has demon-
strated extremely potent activity on both the vertebrate
and invertebrate glutaminergic systems, leading to specif-
ic neuronal death in the brain,2 and its pronounced neu-
roexcitatory properties have been well documented.3 The
pharmacological effects and the patterns of neuronal de-
generation observed after the injection of kainoids have
been shown to mimic the symptoms of neuronal condi-
tions such as epilepsy,4 Alzheimer’s disease and Hunting-
ton’s chorea.5 Additionally, it has been proposed that the
neuronal death induced by kainoids is a good experimen-
tal model for the neuronal cell loss observed in senile de-
mentia.2
O
O
H
O
Me
H
O
O
CO2R
N
H
P
CO2R
N
4
5
P
3
Scheme 1 Where P = protecting group, R = Me, Et, t-Bu etc.
variety of conditions produced an optimized combined
yield of 50% (Table 1).8
With the success of the photocycloaddition of Boc-3-pyr-
roline 6, a selection of other nitrogen protecting groups
was investigated. Benzyl- (8) and tosyl-3-pyrroline (10)
were generated by the action of the appropriate amine
with cis-1,4-dichlorobut-2-ene. The trifluoroacetyl com-
pound 12 was formed by standard protection of 3-pyrro-
line.9 Submission of these protected 3-pyrrolines to the
optimized photocyclization conditions gave disappointing
yields for the benzyl- and tosyl-protected pyrrolines, but
an increased combined yield for the trifluoroacetyl deriv-
ative (Table 2). The formation of the Boc- and trifluoro-
acetyl-cyclobutane systems, 7 and 13, were repeated
successfully on multi-gram scales.
Our rapid approach to the kainoid ring system is illustrat-
ed in the following retrosynthetic analysis (Scheme 1).
Kainic acid 1 could be readily elucidated from the protect-
ed ketone 2, which could be formed from the action of so-
dium methoxide in methanol on the cyclobutane 3. The
key cyclobutane 3 could be generated from the photo-
chemically induced [2+2] cycloaddition of the protected
proline derivative 4 and dioxinone 5. The dioxinone 5 is
commercially available and several literature procedures
exist for the formation of the proline derivative 4.6
In order to evaluate the feasibility of this novel, photo-
chemical approach a variety of model studies were con-
ducted. Initially, the proline derivative 4 was replaced by
the achiral Boc-3-pyrroline 6, formed by a modification of
the route of Meyers.7 Irradiation of an acetonitrile solution
of 6 and the photoreagent 5, with a 125 W medium pres-
sure mercury lamp, gave a mixture of two of the desired
cyclobutanes 7, a mixture of endo- and exo-addition prod-
ucts, which were readily separable by column chromatog-
raphy (Scheme 2). Repeating the experiment under a
O
O
4
5
7
5
7
4
6
3
6
3
O
O
O
O
2
2
O
hυ
Me
H
H
H
Me
H
H
H
O
O
N
P
8
1
8
1
see Table 1
9
9
11
11
10
10
N
N
5
P
P
P=Boc
P=Bn
6
7-endo
9-endo
11-endo
13-endo
7-exo
8
9-exo
P=Ts
10
12
11-exo
13-exo
P=COCF3
Scheme 2
Synlett 2002, No. 1, 28 12 2001. Article Identifier:
1437-2096,E;2002,0,01,0167,0169,ftx,en;D24001ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

168
E. S. Greenwood, P. J. Parsons
LETTER
To complete the model studies, methylenation of the ke-
tone functionality was examined. The use of standard
Wittig methodology10 was discounted due to the ready
epimerization of the C-4 stereocenter. Consequently, the
dimethyltitanocene (Cp2TiMe2) procedure of Petasis and
Bzowej11 was utilized. A tetrahydrofuran solution of dim-
ethyltitanocene was readily prepared from the action of
methyllithium on titanocene dichloride,12 and refluxing
this solution with the ketones 14 and 15 in the dark for 24
hours gave a good yield of the desired pyrrolidines 16 and
17, with no observable epimerization (Scheme 4).
Table 1
Bulb
strength
(W)
Solvent
Filter
Sensitizer Time Yield of Yield of
(h)
endo
exo
product product
(%)
17
(%)
0
16
125
125
125
125
400
400
400
CH3CN
CH3CN
CH3CN
CH3CN
EtOAc
CH3CN
CH3CN
CH3CN
None
None
Pyrex
Pyrex
None
None
None
None
None
None
Acetone
None
None
None
None
None
20
2.5 21
2.5 15
9
7
10
0
0
2.5 35
15
3.7
7.6
5.8
O
CO2Me
CO2Me
0.5
1.0
1.5
4.0
Cp2TiMe2
4
3
THF, reflux
4.2
4.0
N
P
N
P
P=Boc
P=COCF3
16 77%
17 68%
14
15
All photoreactions were carried out under continuous degassing with
N2, using 2 equivalents of the protected 3-pyrroline at a concentration
of 0.1 mmol/mL. The yields are of isolated products after column
chromatography.
Scheme 4
The model studies detailed (vide supra) allow the rapid
formation of the majority of the kainoid skeleton, includ-
ing the crucial C-3/C-4 cis stereochemistry. Work in the
group is now concentrating on the photocycloaddition of
dioxinone 5 to a proline derivative 2 to generate a chiral,
non-racemic cyclobutane, subsequent manipulation of
which would afford enantiopure (–)- -kainic acid 1.
Table 2
Bulb
strength
(W)
Solvent
Protecting group
Time Yield of Yield of
(h)
endo
exo
product product
(%)
0
(%)
9
125
125
125
EtOAc
EtOAc
EtOAc
Benzyl
2.5
2.5
2.5
Acknowledgement
We wish to thank the Royal Commission for the Exhibition of 1851
and Tocris Cookson Ltd. for funding this research.
Tosyl
0
0
Trifluoroacetyl
47
12
References
With reasonable quantities of the cyclobutanes 7 and 13 in
hand, studies towards the methoxide induced fragmenta-
tions were conducted. A methanolic solution of the cy-
clobutanes 7 and 13 containing a catalytic amount of
sodium methoxide was heated at reflux to yield the de-
sired, ring-opened products 14 and 15 (Scheme 3). The
endo compounds opened more cleanly and rapidly than
their exo isomers, presumably due to the increased steric
interactions driving the fragmentations.
(1) For a comprehensive review, see: Parsons, A. F.
Tetrahedron 1996, 52, 4149.
(2) (a) Shinozaki, H.; Knoishi, S. Brain Res. 1970, 368.
(b) Ishida, M.; Shinozaki, H. Brain Res 1988, 386.
(c) Shinozaki, H.; Ishida, M.; Okamoto, T. Brain Res. 1986,
395. (d) Maruyama, M.; Takeda, K. Brain Res. 1989, 328.
(e) Shinozaki, H.; Ishida, M.; Gotoh, Y.; Kwak, S. Brain
Res. 1989, 330.
(3) (a) Kainic Acid as a Tool in Neurobiology; McGeer, E. G.;
Olney, J. W.; McGeer, P. L., Eds.; Raven Press: New York,
1978. (b) Excitatory Amino Acids; Simon, R. P., Ed.;
Thieme Medical Publishers: New York, 1992. (c) Amino
Acids and Synaptic Transmissions; Wheal, H. V.; Thomson,
A. M., Eds.; Academic Press: London, 1991. (d)Watkins,J.
C.; Krogsgaard-Larsen, P.; Honori, T. Trends Pharmacol.
Sci. 1990, 11, 25.
O
O
O
O
CO2Me
NaOMe (0.1 eq.)
MeOH, reflux
Me
H
H
H
N
P
(4) Sperk, G. Prog. Neurobiol. 1994, 42, 1.
N
P
(5) (a) Coyle, J. T.; Schwarcz, R. Nature 1976, 263, 244.
(b) McGeer, E. G.; McGeer, P. L. Nature 1976, 263, 517.
(6) (a) Mayer, S. C.; Ramanjulu, J.; Vera, M. D.; Pfizenmayer,
A. J.; Joullie, M. M. J. Org. Chem. 1994, 59, 5192.
(b) Kahl, J.-U.; Wieland, T. Liebigs Ann. Chem. 1981, 1445.
(c) Sibi, M. P.; Christensen, J. W. Tetrahedron Lett. 1995,
36, 6213.
P=Boc
P=Boc
7-endo
7-exo
14 65%
14 10%
15 63%
15 23%
P=COCF3 13-endo
13-exo
P=COCF3
Scheme 3
(7) Meyers, A. I.; Warmus, J. S.; Dilley, G. J. Org. Synth. 1996,
73, 246.
Synlett 2002, No. 1, 167–169 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Model Studies Towards Kainic Acid
169
(8) A typical Procedure for the Formation of Cyclobutanes
13:
dioxinone], 143(87) [dioxinone], 85(95), 43(100)
[CH(CH3)2]; HRMS (EI) found: 308.1127, [M + H],
C13H17NO4F3 requires 308.1110.
A solution of the freshly distilled dioxinone 5 (7.10 g, 50.0
mmol)and N-trifluoroacetyl-3-pyrroline 12 (16.50 g, 100.0
mmol) in EtOAc (400 mL), under continuous degassing with
nitrogen, was irradiated with a 125 W medium pressure
mercury lamp. After 72 h TLC analysis indicated full
consumption of the dioxinone. The reaction mixture was
concentrated under reduced pressure and purified by column
chromatography (50% diethyl ether/petroleum ether eluent),
to give two cyclobutane products.
13-endo: Colourless crystals (7.27 g, 47%); TLC, (diethyl
ether) Rf = 0.20; mp 75–77 °C; IR (thin film): 2926 (s, CH3/
CH2), 1730 (s, C3=O), 1687 (s, N–C=O), 1157 (s, C–O) cm–
1; 1H NMR (300 MHz; CDCl3): = 4.46 and 4.43 (1 H, d, J
= 12.7, 9-H), 4.32 and 4.24 (1 H, 2 d, J = 12.3, 11-H), 3.52–
3.20 (3 H, m, 9-H, 11-H and 1-H) 3.08 and 3.04 (1 H, 2 dd,
J = 9.8 and 1.9, 2-H), 2.91 and 2.84 (1 H, 2 dd app 2 t, J
= 8.3, 8-H), 1.63 and 1.62 (3 H, 2 s, 7-Me), 1.56 and 1.55
(6 H, 2 s, 5-Me);13C NMR (75 MHz; CDCl3): = 165.9 and
165.6 (C-3), 155.4 (q, J = 37.4, COCF3), 115.9 (q, J = 300.6,
COCF3), 103.8 and 103.4 (C-5), 69.5 and 69.4 (C-7), 47.7
(C-8), 46.2 and 45.8 (C-9 or C-11), 44.6 (C-8), 44.5 (C-9 or
C-11), 43.5 (C-9 or C-11), 39.0 and 38.8 (C-2), 34.6 and 32.1
(C-1), 27.0, 26.9, 26.8 and 26.4 (5-Me and 7-Me);MS (EI):
m/z (%) = 308(39) [M + H], 292(8) [M–Me], 250(77) [M–
CO(CH3)2], 222(25) [M–CO2(CH3)3], 165(83) [M–
13-exo: Colourless crystals (1.80 g, 12%); TLC, (Et2O)
Rf = 0.47; mp 99–103 °C; IR (thin film): 2924 (s, CH3/CH2),
2854 (s, CH), 1735 (s, C3=O), 1689 (s, N–C=O), 1463 (s,
CH3/CH2), 1385 and 1354 (s, C(CH3)3)cm–1; 1H NMR (300
MHz; CDCl3): = 4.25 and 4.05 (1 H, 2 d, J = 14.0, 9-Hu),
4.08–3.98 (1 H, m, 11-H), 3.72–3.47 (2 H, m, 9-Hd and 11-
H), 3.29–3.00 (2 H, m, 1-H and 8-H), 2.71 and 2.62 (1 H, 2
d, J = 3.4, 2-H), 1.67–1.61 (6 H, m, 5-Me), 1.45 and 1.39
(3 H, 2 s, 7-Me); 13C NMR (75 MHz; CDCl3): = 170.0
(C-3), 155.4 (q, J = 36.7, COCF3), 116.0 (q, J = 287.3,
COCF3), 106.73 and 106.67 (C-5), 76.0 (C-7), 53.1 and 52.0
(C-11), 47.6 and 47.3 (C-9), 46.9 and 46.8 (C-8), 45.1 and
44.6 (C-2), 40.3 and 44.6 (C-1), 27.0, 29.6, 29.1 and 28.9 (5-
Me), 22.0 and 21.7 (7-Me); MS (EI): m/z (%) = 308(12) [M
+ H], 292(5) [M–Me], 250(52) [M–CO(CH3)2], 165(80) [M–
dioxinone], 143(87) [dioxinone], 69(62) [CF3], 59(49)
[(CH3)2CHO] 43(100) [CH(CH3)2]; HRMS (EI) found:
308.1128, [M + H], C13H17NO4F3 requires 308.1110.
(9) Ziegler, C. B.; Bitha, P.; Lin, Y. J. Heterocycl. Chem. 1988,
25, 719.
(10) Wittig, G.; Schoellkopf, U. Chem. Ber. 1954, 87, 1318.
(11) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112,
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(12) Claus, K.; Bestian, H. Liebigs Ann. Chem. 1962, 654, 8.
Synlett 2002, No. 1, 167–169 ISSN 0936-5214 © Thieme Stuttgart · New York