Formal synthesis of FPA, a kainoid amino acid, via ketyl radical cyclization

Article abstract of DOI:10.3987/com-01-s(k)54

The formal synthesis of FPA, a kainoid amino acid, was performed through the SmI₂ induced ketyl radical cyclization as the key step. The stereoselectivity was inverted in the presence or absence of the proton source.

Full text of DOI:10.3987/com-01-s(k)54

HETEROCYCLES, Vol. 56, 2002, pp. 105-111, Received, 27th July, 2001
FORMAL SYNTHESIS OF FPA, A KAINOID AMINO ACID, VIA KETYL
RADICAL CYCLIZATION
Mitsuru Kamabe, Takayuki Miyazaki, Kimiko Hashimoto*2, and Haruhisa
Shirahama*1
School of Science, Kwansei Gakuin University, Uegahara Nishinomiya, 662-8501,
Japan
e-mail (H.S.): shiraham@sci.hokudai.ac.jp; (K. H.) kimikoh@postman.riken.go.jp
Abstract - The formal synthesis of FPA, a kainoid amino acid, was performed
through the SmI2 induced ketyl radical cyclization as the key step. The
stereoselectivity was inverted in the presence or absence of the proton source.
Kainoid amino acids, such as kainic acid (1), domoic acid (2), acromelic acids A and B (3, 4), MFPA (5),
and FPA (6), show potent neuroexcitatory activity in mammalian central nervous systems.1 Due to their
activity, they are useful probes in the neuroscience fields. Recently, a shortage of kainic acid, which has
H
HO2C
N
O
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
N
H
N
H
N
H
HO2C
H
Kainic acid (1)
Domoic acid (2)
Acromelic acid A (3)
H
N
O
CO2H
OMe
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
N
H
N
H
N
H
Acromelic acid B (4)
MFPA (5)
FPA (6)
†Dedicated to Professor James P. Kutney in celebration of his 70th birthday.

Figure 1
O
O
CO2H
CO2H
4
3
2
N
H
N
CO2Me
Boc
6
7
CO2Me
O
N
H2N
OTBDPS
H
O
OTBDPS
Boc
8
9
10
been long supplied from natural sources, began to limit the progress in neuroscience.2 However it is
again being supplied by chemical synthesis.3 The aromatic kainoids show more potent depolarizing
activity than 1 and some of them exhibit a different selectivity to the receptor subtypes.4 Accordingly,
the development of a new synthetic scheme for the kainoids is now required.5 We now describe the
formal synthesis of FPA (6) using SmI2 mediated radical cyclization as the key step,6 and also show the
preliminary results for the cyclization of a pyiridine derivative.
The retrosynthetic scheme is outlined in Figure 1. FPA (6) has been previously prepared7 from lactone
(7)7(b) through hydrogenation with inversion of the configuration8 at C4. Accordingly, synthesis of
lactone (7) should be a formal synthesis of 6. The key reaction is the intramolecular ketyl radical
cyclization of 8. The precursor (8) would be synthesized from styrene oxide (9) and the vinylglycinol
derivative (10).
The known vinylglycinol (11) was prepared according to a previous report.9 The hydroxy group of 11
was protected as the TBDPS ether and the Boc protective group was removed to give the amine (10)
(Figure 2). The amine was coupled with the epoxide (9) using LiClO4 as a catalyst in MeCN10 to afford
the desired coupling product (12) as the major product along with trace amounts of 13 and 14. The
regioselectivity could be explained by the steric bulkiness of the nucleophilic amine (10). The
inseparable mixture of 12 and 10 was separated after treatment with Boc2O and the Swern oxidation,
giving the pure ketone (15). The olefin group of 15 was cleaved by ozonolysis and the resulting
hemiacetal11 was directly exposed to the Horner-Emmons reaction without purification to give the
unsaturated ester (16) as a mixture of geometric isomers (E : Z = 4 : 1). The mixture was treated with
SmI2 (10 equiv.) in THF-HMPA (20 : 1) at -78 °C to produce 18 as the sole product. On the other hand,
the cyclization reaction was performed in the presence of MeOH (the same amount with HMPA) as a
proton donor to give a mixture of 17 and 18 in a ratio of 2.5 : 1, with the desirable stereoisomer as the

1
major product. The structure of 17 was confirmed by comparing the H NMR spectral data and the
optical rotation after conversion to the known (7).7(b) On the other hand, the stereochemistry of 18 was
tentatively estimated from the previous synthetic studies.12
Figure 2
1) TBDPSCl
imidazole
O
9
OH
BocHN
H N
2
92%
LiClO / MeCN
4
H
H
N
H
OH
OTBDPS
2) 20% TFA-CH Cl
2
2
50°C
OTBDPS
92%
11
10
12
OH
N
HO
N
H
HO
OTBDPS
OTBDPS
13
14
CO Me
2
1) Boc O
2
1) O / MeOH
3
O
N
O
KHCO aq
3
then DMS
12
2) Swern ox
2) (MeO) P(O)CH CO Me
N
2
2
2
Boc
Boc
NaH / THF
OTBDPS
OTBDPS
66% (3 steps)
62% (2 steps)
E :Z = 4 : 1
15
16
1) TBAF 2) Jones' ox 3) CH N (74%, 3 steps)
2
2
O
O
O
OH
O
CO Me
SmI - HMPA
2
2
proton donor / THF
-78°C
N
Boc
N
Boc
N
Boc
CO Me
2
OTBDPS
OTBDPS
17
18
7
ref 5 (a)
proton donor
yield (%)
17 : 18
6
-----
MeOH
64
51
<1 : 99
2.5 : 1
During the radical cyclization reaction13 of 16, the stereoselectivity was inverted depending on the
presence or the absence of MeOH. The radical addition reaction to the intramolecular olefin should be a
reversible reaction due to the lower electrophilicity of the benzyl radical.14 Accordingly, the product
(18) should be a thermodynamic product in the absence of MeOH due to the steric repulsion between the
-OSmI2 and the methoxycarbonylmethyl groups of A, the precursor of 17, compared with B, the precursor

of 18 (Figure 3). On the other hand, in the presence of MeOH, the free hydroxy group would be
produced in the reaction mixture by proton exchange with MeOH. In this case, there exists less steric
repulsion between the -OH and the methoxycarbonylmethyl groups in C than that between the phenyl and
methoxycarbonylmethy group in 18.
Figure 3
Ar
O
O
SmI2
H
H
BocN
RO
BocN
RO
SmI2
Ar
CO2Me
CO2Me
[A]
[B]
Ar
O
H
H
H
BocN
RO
BocN
RO
O
H
Ar
CO2Me
CO2Me
[C]
18
The same strategy was applied to a pyridine derivative (Figure 4). The lithiation of 2-methoxypyridine
(19) was performed using α-ethoxyvinyllithium15 and the resulting anion was trapped with acetaldehyde
to give the alcohol (20). Dehydration of 20 through mesylation followed by elimination gave the
ethylene derivative (21) which was then oxidized to the epoxide (22). The epoxide (22) was then coupled
with the amine (10) in the same manner as above to afford the amine (23). The amino group of 23 was
protected by Boc group and then the alcohol was oxidized to the ketone. The resulting ketone (24) was
exposed to ozonolysis and then the Horner-Emmons reaction to afford the precursor (25) for the radical
cyclization as a mixture of geometric isomers (E : Z = 2 : 1). The ketyl radical cyclization in the
presence of MeOH produced 26 and 27 in a ratio of 1 : 1. The stereochemistry of these products was
estimated from the comparison of the 1H NMR spectra with those of the phenyl derivatives (17 and 18).
REFERENCES AND NOTES
*1 Present address: 2-16, Minami 18 Nishi 8, Chuo-ku, Sapporo, 064-0918, Japan
*2 To whom correspondence should be addressed. Present address: Lab. of Biochemical Resources,
Plant Science Center, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan
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Figure
N
4
N
OMe
OH
OMe
N
OMe
N
OMe
O
CH3CHO
1) MsCl, Et3N
mCPBA
EVL•HMPA
THF
CH2Cl2
46%
0.5 M NaHCO3aq
CH2Cl2
19
20
21
22
2) t-BuOK / DMSO
62%
53%
91%
EVL = α-ethoxyvinyllithium
N
OMe
N
OMe
O
OH
22 / LiClO4
1) Boc2O / KHCO3
H2N
N
H
N
Boc
CH3CN
OTBDPS
H2O - dioxane
2) Swern ox
H
OTBDPS
OTBDPS
60°C
10
23
24
57% (3 steps)
O
N
OMe
O
OMe
OMe
OH
CO2Me
O
1) O3 / MeOH
SmI2
N
N
CO2Me
then DMS
MeOH
N
Boc
N
Boc
N
Boc
HMPA - THF
2) (MeO)2P(O)CH2CO2Me
OTBDPS
OTBDPS
OTBDPS
-78°C to rt
NaH / THF
25
26
27
1 : 1
65% (2 steps)
E : Z= 2 : 1
70%
N
OMe
CO2H
CO2H
N
H
28
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1
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