A formal synthesis of (-)-α-kainic acid

Article abstract of DOI:10.1055/s-1998-1694

The formal synthesis of (-)-α-kainic acid was achieved from L-pyroglutamic acid. The C-4 substituent of the pyrrolidine ring was introduced by using a ketyl radical cyclization on an enecarbamate.

Full text of DOI:10.1055/s-1998-1694

May 1998
SYNLETT
507
A Formal Synthesis of (-)-α-Kainic Acid
Janine Cossy *, Manuel Cases, Domingo Gomez Pardo
Laboratoire de Chimie Organique, Associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05 - France.
Fax: 33.1.40.79.44.25; E-mail: janine.cossy@espci.fr
Received 9 February 1998
16
Abstract: The formal synthesis of (-)-α-kainic acid was achieved from
L-pyroglutamic acid. The C-4 substituent of the pyrrolidine ring was
introduced by using a ketyl radical cyclization on an enecarbamate.
organocupromagnesium derivative 4 in THF at -78 °C furnished the
expected C-3 alkylated pyrrolidine (-)-5 in 71% yield.
We have to point out that the addition of 4 to the N-Boc protected
17
enamide (-)-3' led to the alkylated product (-)-5' in lower yield (24%).
(-)-α-Kainic acid A, first isolated in 1953 from the marine alga Digenea
The relative trans stereochemistry of the two side-chains at C-2 and C-3
1
simplex , is the parent member of kainoids displaying potent
1
18
in (-)-5 and (-)-5' was determined by H NMR (J H -H ≈ 0 Hz).
2
2
3
anthelmintic properties and neurotransmitting activity in the central
nervous system. Among these properties, the neuroexcitatory activity is
attributed to their trans C-2/C-3: cis C-3/C-4 structure and the
functionality at the C-4 center beside the 2-carboxy and 3-
carboxymethyl functionalities. Because of its biological importance as
well as its synthetic interest, several enantiocontrolled syntheses have
been disclosed. Oppolzer’s synthesis of (-)-α-kainic acid relying on an
intramolecular ene reaction stands as the first and, as yet remains, the
most efficient approach in terms of the number of steps and overall
3
4
Scheme 3
yield. In other approaches, intramolecular Pauson-Khand reaction,
5
6
7
tandem Michael reactions, thiazolium or azomethine ylide
8
19
cycloadditions, Diels-Alder addition, retro Diels-Alder reaction of keto
Desulfonylation of (-)-5 by Na in the presence of naphthalene,
followed by tert-butoxycarbonylation [(Boc) O] afforded the carbamate
(-)-6 (yield: 83%). The requisite enecarbamate (+)-7 for the radical
cyclization was prepared by reduction of the amide (-)-6 by Dibal-H
(90%), followed by deprotection of the ketone (HCl, H O-acetone) and
9
10
dicyclopentadiene, palladium-induced cyclization, or enolate Claisen
2
11
rearrangement have been used. More recently, syntheses of several
12,
kainoids using free radical cyclization reaction have been presented.
13
We report here a procedure for the construction of (-)-α-kainic acid
2
by synthesizing the key intermediate (-)-12, using an intramolecular
dehydration of the corresponding hydroxycarbamate by quinolinium
camphorsulfonate (QCS) (overall yield for the two steps: 42%). We
20
radical cyclization of
a ketyl radical. The method allows the
introduction of the C-4 substituent on the pyrrolidine ring. The synthesis
of (-)-α-kainic acid was planned from L-pyroglutamic acid according to
the following retrosynthetic Scheme.
investigated the ketyl radical cyclization by irradiating ketone (+)-7 in
-2
21
the presence of Et N (10 equiv.) at 254 nm in CH CN (10 M). No
3
3
1
cyclized product was detected by GC-MS or by H NMR. However,
when the ketyl radical was generated by using SmI in THF in the
2
22
presence of HMPA (20 equiv.) and t-BuOH (3 equiv.) the bicyclic
amine (-)-8 was isolated in 55% yield together with the corresponding
23
product B of pinacolic coupling (32%). Transformation of the bicyclic
system into (-)-12 was realized in 5 steps.
Treatment of the tertiary alcohol (-)-8 with POCl in pyridine afforded
3
alkene (-)-9 (72% yield). This compound was then treated with RuO -
2
NaIO to produce a ketocarboxylic acid that was treated directly with
4
CH I in the presence of K CO to produce intermediate 10.
3
2
3
24
Methylenation of the methyl ketone into (-)-11 was achieved by using
non-basic conditions such as CH I , TiCl , Zn. No purification was
6
2 2
4
performed on compound 10 to avoid its epimerisation at C-4. Finally,
13, 25
the known precursor (-)-12
of the (-)-α-kainic acid was obtained by
11
treating (-)-11 with a solution of HF (40%) in THF (yield ≥ 30%).
Since the trans, cis-trisubstituted pyrrolidine (-)-12 has been converted
13
into (-)-α-kainic acid A without difficulty , the present transformation
Scheme 1
of L-pyroglutamic acid (-)-1 into (-)-12 (18 steps) constitutes a new
formal synthesis of this natural product.
L-Pyroglutamic acid (-)-1 was transformed into the protected amido
20
14
alcohol (+)-2 [m.p.= 70 °C, [α]
+ 57.1 (c 0.25, THF)] in 3 steps
D
Our work demonstrates that cis-3,4-disubstituted pyrrolidines can be
obtained with high stereoselectivity applying a 5-exo-trig radical
induced cyclization of δ,ε-unsaturated ketones.
with an overall yield of 63% (Scheme 2). Compound (+)-2 was
tosylated in the presence of LiHMDS, followed by the addition of p-
15
toluenesulfonyl chloride (yield: 98%). In order to introduce the 3-
oxobutyl side chain at C-3, the obtained tosylamide was transformed
15a
Acknowledgment. One of us (M. C.) thanks the Ministère de la
Recherche et de l'Enseignement Supérieur for a grant (MRES).
into the corresponding enamide (-)-3
via phenylselenylation
(LiHMDS, PhSeCl, -78 °C, 85%) and subsequent oxidation with H O
2
2
in ethyl acetate (yield: 75%). Conjugate addition of the

508
LETTERS
SYNLETT
Scheme 2
References and Notes
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169.
(13) (a) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 5418. (b)
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46, 7263.
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1213.

May 1998
SYNLETT
509
(19) Ji, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson,
(d), 79.2 (s), 81.0 (s), 128.0 (d), 128.1 (d), 129.8 (d), 129.9 (d),
+
W. D. J. Am. Chem. Soc. 1967, 27, 5311.
135.1 (s), 135.3 (s), 136.2 (d), 136.3 (d), 155.2 (s). MS (FAB )
+
+
m/z: 1018 (M + H), 918 (M + H - CH =C(CH ) - CO ), 900
(20) Cossy, J.; Cases, M.; Gomez Pardo, D. Synth. Commun. 1997, 27,
2
3 2
+
2
+
(M + H - CH =C(CH ) - CO - H O), 862 (M + H - 2 x
2769.
2
3 2
2
2
+
(CH =C(CH ) ) - CO ), 844 (M + H - 2 x (CH =C(CH ) ) - CO
2
(21) Belotti, D.; Cossy, J.; Pete, J.-P.; Portella, C. J. Org. Chem. 1986,
51, 4196.
2
3 2
2
2
3 2
+
- H O), 818 (M + H - 2 x (CH =C(CH ) ) - 2 x CO ).
2
2
3 2
2
20
(22) Molander, G. A.; McKie, J. A. J. Org. Chem. 1994, 59, 3186.
(23) Structure of dimer B:
(24) (-)-11: oil; [α]
-26.3 (c 0.4, CH Cl ). IR (neat): 1740, 1700
2 2
D
-1 1
cm . H NMR (300 MHz, CDCl ) δ: 1.07 (s, 9H), 1.27- 1.35 (m,
3
9H), 1.72-1.76 (m, 3H), 2.12-2.49 (m, 2H), 2.77- 3.19 (m, 2H),
3.40-3.81 (m, 8H), 4.67-4.94 (m, 2H), 7.37- 7.44 (m, 6H), 7.63-
13
7.66 (m, 4H). C NMR (75 MHz, CDCl )
3
δ: 19.0 (s), 22.4 (q), 26.7 (q), 28.3 (q), 32.8 (t), 38.6 (d), 44.7 (d),
47.9 (t), 51.4 (q), 63.2 (d), 68.0 (t), 79.4 (s), 112.3 (t), 127.5 (d),
128.6 (d), 133.1 (s), 133.2 (s), 135.4 (d), 141.7 (s), 154.1 (s),
+.
.
172.9 (s). MS (EI) m/z: 494 (M -C H ), 438 (42), 393 (31), 378
4
9
(78), 122 (64), 57 (100). HRMS calculated for C
H
NO Si
28 36
5
-1
1
Analytical data for B: oil; IR (neat): 3420, 1690, 1660 cm
. H
+.
.
(M -C H ): 494.2362, found: 494.2361.
4
9
NMR (300 MHz, toluene-d , 90 °C) δ: 1.13 (s, 3H), 1.19 (s, 9H),
1.26 (s, 9H), 1.51-1.69 (m, 3H), 2.13-2.23 (m, 1H), 2.27-2.30
(m,1H), 2.99-3.07 (m, 1H), 3.75-3.81 (m, 1H), 4.03 (s, 1H), 4.11-
8
20
13b
21
(25) (-)-12: oil; [α]
-35.0 (c 0.2, CHCl ) [Lit.
[α]
D
-38.0
D
3
-1 1
(c 0.2, CHCl )]. IR (neat): 3421, 1737, 1690, 1674, 1403 cm . H
3
NMR (300 MHz, CDCl ) δ: 1.47 (s, 9H), 1.71 (s, 3H), 2.17-2.37
4.17 (m, 1H), 4.22-4.25 (m, 1H), 7.19-7.26 (m, 6H), 7.77-7.82 (m,
3
13
(m, 2H), 2.46-2.53 (m, 1H), 2.90-2.97 (m, 1H), 3.48 (d, J = 7.7
Hz, 2H), 3.58-3.82 (m, 6H), 4.67-4.69 (m, 1H), 4.89-4.93 (m, 1H).
4H). C NMR (75 MHz, toluene-d , 90 °C) δ: 25.0 (q), 27.6 (q),
8
28.7 (q), 31.5 (t), 42.3 (t), 47.6 (d), 58.3 (d), 64.5 (d), 68.7 (t), 69.5