Syntheses of (±)-α-isokainic acid and (±)-α- dihydroallokainic acid using a decarboxylative Ramberg-Ba?cklund reaction

Article abstract of DOI:10.1055/s-2005-868477

Total syntheses of (±)-α-isokainic acid and (±)-α-dihydroallokainic acid have been achieved via tandem radical addition-homoallylic rearrangement and a decarboxylative Ramberg-Ba?cklund reaction as the key steps.

Full text of DOI:10.1055/s-2005-868477

LETTER
1267
Syntheses of ( )-a-Isokainic Acid and ( )-a-Dihydroallokainic Acid Using a
Decarboxylative Ramberg–Bäcklund Reaction
S
ynthese
s
of Kainoa
ids vid M. Hodgson,*a Shuji Hachisu,a Mark D. Andrewsb
a
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
Fax +44(1865)275708; E-mail: david.hodgson@chem.ox.ac.uk
b
Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
Received 16 March 2005
tion–homoallylic radical rearrangement on a 7-azabi-
cyclo[2.2.1]heptadiene 5 (R = p-tolyl), followed by
oxidative cleavage of the double bond in the resulting
2-azabicyclo[2.2.1]hept-5-ene 7. A significant factor
favoring the key radical rearrangement is probably the
stabilization afforded to the resulting radical 6 by the a-
nitrogen.7
Abstract: Total syntheses of ( )-a-isokainic acid and ( )-a-dihy-
droallokainic acid have been achieved via tandem radical addition–
homoallylic rearrangement and a decarboxylative Ramberg–
Bäcklund reaction as the key steps.
Key words: total synthesis, stereoselective, kainoids, radical rear-
rangement, Ramberg–Bäcklund reaction
In seeking to develop this route towards other kainoids,
especially a-isokainic acid (3), we considered that sulfone
8 might provide a more direct way of introducing the iso-
propylidene unit at C-4 by a decarboxylative Ramberg–
Bäcklund reaction (RBR, Scheme 1).8 a-Chloro-a-isopro-
pyl sulfone 8 was anticipated to be available from a 7-
azabicycle 5 bearing an appropriate sulfone.
The kainoids are a family of non-proteinogenic amino ac-
ids that includes a-kainic acid (1), a-allokainic acid (2),
and a-isokainic acid (3, Figure 1).1 The rest of the family
of kainoids are structurally more complex versions of
these compounds in which the substituent at C-4 is varied,
such as in isodomoic acid G (4).2
The requisite 7-azabicycle 12 was prepared by [4+2]
cycloaddition9 of N-Boc pyrrole and 2-(ethynylsulfo-
nyl)propane (11) in 63% yield (Scheme 2). 2-(Ethynylsul-
fonyl)propane (11) has previously been prepared in 5
steps from acetylene, but it was synthesized more directly
by following a protocol for forming S-alkyl ynethiol
ethers from trichloroethylene, followed by oxidation with
peracetic acid in 53% yield over two steps.10 Pleasingly,
reductive radical addition of 2-iodoethanol to 7-azabicy-
cle 12 led to tandem radical addition–homoallylic radical
rearrangement to give 2-azabicycle 13 in good yield
(82%).11 Further experimentation established that it was
best if introduction of the chloro substituent for the RBR
was carried out before oxidative cleavage of the double
The kainoids are well known for their acute excitatory
neurotransmitting activity in the mammalian nervous sys-
tem.3 The total synthesis of kainoids is an active area of
research, due to the marked biological activities displayed
by this class of compounds. In particular, a-kainic acid (1)
and a-allokainic acid (2) have received much attention.
More structurally complex members, such as isodomoic
acid G (4) have also been synthesized.4 However, the syn-
thesis of a-isokainic acid (3) has received scant attention
since its first non-stereoselective synthesis in the 1950s.5
We recently reported a new strategy to access 2,3,4-
trisubstituted pyrrolidines, specifically kainoid systems
(e.g. kainic acid 1, Scheme 1).6 This strategy involved
tandem intermolecular C–C bond-forming radical addi-
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
4
3
N
H
N
H
N
H
N
H
2
1
3
4
α-kainic acid
α-allokainic acid
α-isokainic acid
isodomoic acid G
Figure 1
SYNLETT 2005, No. 8, pp 1267–1270
1
7.
0
5.
2
0
0
5
Advanced online publication: 21.04.2005
DOI: 10.1055/s-2005-868477; Art ID: D07605ST
© Georg Thieme Verlag Stuttgart · New York

1268
D. M. Hodgson et al.
LETTER
HO(CH2)2
BocN
Boc
Boc
N
N
HO(CH2)2I
Bu3SnH
13 steps6
RO2S
RO2S
1
HO(CH2)2
R = p-tolyl
SO2R
7
5
6
oxidation
R = CClMe2
O2
S
Me2ClCO2S
HO2C
CO2H
CO2H
CO2H
Cl
– HCl
– SO2
– CO2
CO2H
CO2H
CO2H
N
N
N
Boc
Boc
Boc
10
9
8
Scheme 1
bond in 2-azabicycle 13. Chlorination of 2-azabicycle 13
was achieved by deprotonation a to the sulfone with BuLi,
followed by trapping of the lithiated species using C2Cl6.12
i-PrO2S
NBoc
a,b
c
i-PrO2S
i-PrSH
53%
63%
Ozonolysis of 2-azabicycle 14 with a reductive work up
(Me2S) led cleanly to the formation of lactols 15 and 16
(15:16, 1:1 in CDCl3, Scheme 3). Simultaneous oxidation
of aldehyde and lactol (masked aldehyde and primary
alcohol) with 4-AcNH-TEMPO and Br2 under basic
conditions13 gave transient triacid 8, which after heating
cleanly led to unsaturated diacid 10 via the desired decar-
boxylative RBR. In order to assist purification, the result-
ing unsaturated diacid 10 was esterified using TMSCHN2
to form protected a-isokainic acid 17 in 72% yield from 2-
azabicycle 14.14 Protected a-isokainic acid 17 was con-
verted into a-isokainic acid (3)15 by hydrolysis of the
methyl esters (THF and aq KOH), and deprotection of the
Boc group (TFA in CH2Cl2),16 in 81% yield over two
steps.
11
12
HO(CH2)2
BocN
HO(CH2)2
BocN
d
e
82%
86%
Me2ClCO2S
14
i-PrO2S
13
Scheme 2 Reagents and conditions: (a) KH (1.5 equiv), THF,
20 °C, 17 h, then Cl2C=CHCl (1.1 equiv), cat. MeOH, –50 °C to
20 °C, 4 h, then BuLi (2.2 equiv), –70 °C to –40 °C, 1 h; (b) AcO2H
(2.8 equiv), MeOH, THF 0 °C to 20 °C, 15 h; (c) N-Boc pyrrole (3
equiv), 85 °C, 27 h; (d) HO(CH2)2I (6 equiv), Bu3SnH (6 equiv by
syringe pump over 100 min), Et3B (0.6 equiv), dry air (0.6 equiv O2
portionwise over 100 min), CH2Cl2, 20 °C, 100 min; (e) BuLi (2.2
equiv), C2Cl6 (3 equiv), THF, –78 °C to 20 °C, 150 min.
O
HO(CH2)2
HO
OHC
a
b
+
BocN
Me2ClCO2S
Me2ClCO2S
O
CHO
N
N
Me2ClCO2S
Boc
Boc
OH
16
14
15
Me2ClCO2S
HO2C
CO2H
CO2H
CO2H
CO2H
CO2Me
c
CO2Me
N
N
N
Boc
Boc
Boc
10
8
17
72% from 14
d, e
CO2H
81%
CO2H
N
H
( )-3
Scheme 3 Reagents and conditions: (a) O3/O2, then Me2S, CH2Cl2, –78 °C to 20 °C, 1 h; (b) 4-AcNH-TEMPO (0.1 equiv), Br2 (6 equiv),
KOH (added to maintain pH at 11.5), Na2S2O5 (10 equiv), MeCN–H2O (1:1), 0 °C to 95 °C, 4.5 h; (c) TMSCHN2 (14 equiv), PhMe–MeOH
(7:2), 20 °C, 16 h; (d) KOH (14 equiv), H2O, THF, 20 °C, 15 h; (e) TFA (44 equiv), CH2Cl2, 20 °C, 28 h.
Synlett 2005, No. 8, 1267–1270 © Thieme Stuttgart · New York

LETTER
Syntheses of Kainoids
1269
O
Acknowledgment
O
We thank the EPSRC and Pfizer for a CASE award (to S.H.). We
also thank the EPSRC National Mass Spectrometry Service Centre
(Swansea) for mass spectra.
CO2H
CO2H
CO2H
CO2H
HBr
+
CO2H
N
H
N
H
N
H
References
3
18
1
Equation 117
(1) (a) Parsons, A. F. Tetrahedron 1996, 52, 4149.
(b) Moloney, M. G. Nat. Prod. Rep. 2002, 19, 597.
(c) Calaf, R.; Barlatier, A.; Maillard, C.; Balansard, G.;
Garcon, D. Plant. Med. Phytother. 1989, 23, 24. (d) Calaf,
R.; Barlatier, A.; Maillard, C.; Ollivier-Vidal, E.; Garcon, D.
Plant. Med. Phytother. 1989, 23, 16.
(2) Zaman, L.; Arakawa, O.; Shimosu, A.; Onoue, Y.; Nishio,
S.; Shida, Y.; Noguchi, T. Toxicon 1997, 35, 205.
(3) Hashimoto, K.; Shirahama, H. Trends Org. Chem. 1991, 2,
1.
Due to the unavailability of NMR spectra of a-isokainic
acid (3), our synthetic sample of a-isokainic acid (3) was
compared to material obtained from treatment of (–)-a-
kainic acid (1) with HBr, which is known to give a-kainic
acid d-lactone 18 and a-isokainic acid (3, Equation 1).17
1
Pleasingly, the H NMR spectrum of this mixture of a-
kainic acid d-lactone 18 and a-isokainic acid (3) showed
peaks with identical chemical shifts and coupling con-
stants to synthetic a-isokainic acid (3).
(4) Ni, Y.; Amarasinghe, K. K. D.; Ksebati, B.; Montgomery, J.
Org. Lett. 2003, 5, 3771.
(5) (a) Honjo, M. Yakugaku Zasshi 1957, 77, 598; Chem. Abstr.
1957, 51, 90648. (b) Miyamoto, M.; Honjo, M.; Sanno, Y.;
Uchibayashi, M.; Tanaka, K.; Tatsuoka, S. Yakugaku Zasshi
1957, 77, 586; Chem. Abstr. 1957, 51, 90645.
Catalytic hydrogenation of protected a-isokainic acid 17
was examined (Scheme 4) with the aim of forming a dihy-
drokainoid structure. All possible diastereomeric forms
(excluding enantiomers) of dihydrokainoids are known,18
so hydrogenation of protected a-isokainic acid 17 would
further provide evidence of its structure. Treatment of
protected a-isokainic acid 17 with Adams’ catalyst under
an atmosphere of H2 cleanly formed protected a-dihy-
droallokainic acid 19 (98%, Scheme 4). The hydrogena-
tion occurred stereoselectively without competitive
formation of protected a-dihydrokainic acid (C-4 epimer).
Hydrolysis followed by Boc deprotection of protected a-
dihydroallokainic acid 19 gave a-dihydroallokainic acid
20 in 91% yield.19 This sequence provides further evi-
dence supporting our synthesis of a-isokainic acid (3), and
establishes an approach to a-dihydroallokainic acid 20
from common intermediate 17.
(6) Hodgson, D. M.; Hachisu, S.; Andrews, M. D. Org. Lett.
2005, 7, 815.
(7) Wayner, D. D. M.; Clark, K. B.; Rauk, A.; Yu, D.;
Armstrong, D. A. J. Am. Chem. Soc. 1997, 119, 8925.
(8) (a) Wladislaw, B.; Marzorati, L.; Torres Russo, V. F.; Zim,
M. H.; Di Vitta, C. Tetrahedron Lett. 1995, 36, 8367. (b)
For a recent review, see: Taylor, R. J. K.; Casy, G. Org.
React. 2003, 62, 357.
(9) Leung-Toung, R.; Liu, Y.; Muchowski, J. M.; Wu, Y.-L. J.
Org. Chem. 1998, 63, 3235.
(10) (a) Laba, V. I.; Polievktov, M. K.; Prilezhaeva, E. N.;
Mairanovskii, S. G. Izv. Akad. Nauk. SSSR, Ser. Khim. 1969,
2149; Chem. Abstr. 1970, 72, 54654. (b) Nebois, P.; Kann,
N.; Greene, A. E. J. Org. Chem. 1995, 60, 7690.
(11) Only a trace of the epimeric adduct (1:13) arising from
addition to the less accessible endo face of 7-azabicycle 12
was detected.
(12) Vacher, B.; Samat, A.; Allouche, A.; Laknifli, A.; Baldy, A.;
Chanon, M. Tetrahedron 1988, 44, 2925.
(13) Merbouh, N.; Bobbitt, J. M.; Brückner, C. J. Carbohydr.
Chem. 2002, 21, 65.
CO2Me
CO2Me
CO2Me
CO2H
CO2H
a
b, c
4
(14) 2-Azabicycle 14 (270 mg, 0.711 mmol) was dissolved in
CH2Cl2 (200 mL), and the temperature was lowered to
–78 °C. A mixture of O3/O2 was bubbled through the
solution until it turned blue, followed by O2 until the solution
became colorless. Then, Ar was passed through the solution
for 5 min, and Me2S (5 mL, 68 mmol) was added dropwise.
The mixture was warmed to 20 °C and stirred for 1 h. The
mixture was then concentrated in vacuo and the residue
dissolved in Et2O (50 mL, the dissolution aided by small
amount of CH2Cl2). This solution was washed with H2O (2
ꢀ 30 mL), dried (MgSO4), and concentrated in vacuo to give
a crude mixture of lactols 15 and 16 as a white foam. This
crude mixture was dissolved in MeCN–H2O (17 mL, 1:1
MeCN–H2O), and the temperature was lowered to 0 °C. 4-
Acetamido-2,2,6,6-tetramethylpiperidine-1-oxyl (14 mg,
0.066 mmol) was added, followed by aq KOH (7.5 M) until
the pH was 11.5. A mixture of Br2 (0.21 mL, 4.10 mmol) and
MeCN (6 mL) was added dropwise over 30 min, together
with aq KOH (7.5 M) to maintain the pH at 11.5. Residual
Br2 was washed into the reaction using MeCN–H2O (6 mL,
1:1 MeCN–H2O), and the reaction was further stirred at pH
11.5 and 0 °C for 2 h. Na2S2O5 (1.35 g, 7.10 mmol) was then
98%
CO2Me
91%
N
N
N
H
Boc
Boc
17
19
20
Scheme 4 Reagents and conditions: (a) PtO2 (1.4 equiv), H2 (1
atm), MeOH, 20 °C, 14 h; (b) KOH (14 equiv), H2O, THF, 20 °C, 15
h; (c) TFA (20 equiv), CH2Cl2, 20 °C, 11 h.
In summary, a new stereocontrolled divergent approach to
a-isokainic acid (3) and a-dihydroallokainic acid 20 (10
and 11 steps from commercial materials, respectively) has
been established using a tandem intermolecular C–C
bond-forming radical addition–homoallylic radical rear-
rangement sequence. These concise syntheses were facil-
itated by the multifaceted use of the sulfone moiety as the
activator of the dienophile (in the Diels–Alder reaction)
and the resulting double bond (to radical addition). The
sulfone was then finally removed constructively in a de-
carboxylative RBR to install the isopropylidene unit.
Synlett 2005, No. 8, 1267–1270 © Thieme Stuttgart · New York

1270
D. M. Hodgson et al.
LETTER
added and the mixture stirred vigorously until it turned
colorless; aq KOH (6 mL, 7.5 M, 45.0 mmol) was then added
and the temperature was raised to 95 °C for 2 h. The mixture
was cooled to 20 °C and acidified to pH 1 with aq HCl (2.0
M). The aqueous layer was extracted with EtOAc (4 ꢀ 20
mL), and the combined organic extracts were washed with
brine (100 mL), dried (MgSO4), and concentrated in vacuo.
The residue was dissolved in PhMe–MeOH (18 mL, 7:2
PhMe–MeOH), and(trimethylsilyl)diazomethane (5 mL, 2.0
M in hexane, 10.0 mmol) was added and the mixture stirred
at 20 °C for 16 h. AcOH (0.6 mL) was then added and the
mixture was concentrated in vacuo. Purification of the
residue by column chromatography (25% Et2O–pentane)
gave protected a-isokainic acid 17 (174 mg, 72% over 3
steps) as a colorless oil; Rf = 0.3 (25% Et2O–pentane). IR:
nmax = 2976, 1742, 1706, 1394, 1256, 1175, 1104, 1108, 897
cm–1. 1H NMR (400 MHz, CDCl3): d = 4.33, 4.23 [1 H, s,
C(2)H], 4.09–3.85 [2 H, m, C(5)H2], 3.67, 3.64 (3 H, s,
OMe), 3.67, 3.64 (3 H, s, OMe¢), 3.27 [1 H, dd, J = 9.4 Hz,
J = 5.5 Hz, C(3)H], 2.45–2.32 (2 H, m, CH2CO2), 1.60 (3 H,
38.5 (CH2CO2), 28.5, 28.3 (CMe3), 21.1, 21.1 (Me), 20.5,
20.5 (Me¢). MS (ES): m/z (%) = 705 (14) [2 M + Na+], 364
(100) [M + Na+], 308 (22), 242 (39) [M – Boc + H+]. Anal.
Calcd for C17H28NO6 [M]: 342.1917; found [M + H+]:
342.1927.
(15) a-Isokainic acid (3): mp 240–245 °C (dec.) [lit.5 237–240 °C
(dec.)]. IR: nmax = 2927, 2361, 2342, 1564, 1557, 1373,
1297, 1043, 859 cm–1. 1H NMR (250 MHz, D2O): d = 4.15
[1 H, d, J = 1.2 Hz, C(2)H], 4.06 [1 H, d, J = 14.9 Hz,
C(5)H], 3.94 [1 H, d, J = 14.9, C(5)H¢], 3.55 [1 H, td, J = 6.8
Hz, J = 1.2 Hz, C(3)H], 2.54 (1 H, dd, J = 14.8 Hz, J = 6.8
Hz, CHCO2), 2.46 (1 H, dd, J = 14.8 Hz, J = 6.8 Hz,
CH¢CO2), 1.71 (3 H, s, Me), 1.62 (3 H, s, Me¢). 13C NMR
(126 MHz, D2O): d = 178.1 (CO2), 174.1 (CO2), 131.0 (=C),
126.0 (=C¢), 66.7 (C2), 47.4 (C5), 42.2 (C3), 39.8 (C6), 21.2
(Me), 20.9 (Me¢). MS (ES): m/z (%) = 212 (100) [M – H+],
168 (35). Anal. Calcd for C10H16NO4 [M]: 214.1079; found:
[M + H+]: 214.1074.
(16) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 5418.
(17) Morimoto, H. Yakugaku Zasshi 1955, 75, 916; Chem. Abstr.
1956, 50, 24089.
s, Me), 1.56 (3 H, s, Me¢), 1.43, 1.37 (9 H, s, CMe3). 13
C
NMR (100 MHz, CDCl3): d = 172.5, 172.3 (CO2Me), 172.0,
171.8 (C¢O2Me), 155.1, 154.6 (NCO2), 130.0, 129.1 (=C),
126.4, 126.3 (=C¢), 80.2, 80.2 (CMe3), 64.4, 63.9 (C2), 52.4,
52.3 (OMe), 51.9, 51.9 (OMe¢), 48.6 (C5), 42.7, 41.9 (C3),
(18) Hashimoto, K.; Konno, K.; Shirahama, H. J. Org. Chem.
1996, 61, 4685.
(19) Sugawa, T. Yakugaku Zasshi 1957, 77, 332; Chem. Abstr.
1957, 51, 62288.
Synlett 2005, No. 8, 1267–1270 © Thieme Stuttgart · New York