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The total synthesis of α-allokainic acid
Tetrahedron Letters,Vo1.24,No.33,pp Printed in Great Britain
THE TOTAL
0040-4039/83 $3.00 + .OO 01983 Pergamon Press Ltd.
3427-3430,1983
SYNTHESIS
OF cc-ALLOKAINIC
ACID
George A. Kraus* and Jon 0. Nagy Chemistry
Summary
- The aminoacid
The aminoacid Ag.'
a-allokainic
a-allokainic
Other members
isopropenyl
Department,
of this class
and the acetic
HD2CCH2
acid
Iowa State University,
acid was synthesized
Ames,
Iowa 50011
in eight steps from thiazolidine
2.
(1) was isolated from the marine algae Digenea sinlplex
include a-kainic
acid,2
an isomer of
acid groups are cis, and domoic acid.3
1 in which the
Although
1 shows
$-;
H02C 1"h N CI a-kainic
1
antihelmintic considerably elucidate
properties,
on an intramolecular We recently pyrrolidine
its potent neurophysiological
more attention.
the structure.
domoic acid
acid
Earlier syntheses
Recently,
Oppolzer
activity
in mammals4
were nonstereospecific
has communicated
has attracted
but served to
an elegant
synthesis
of 1 based
ene reaction. 5
reported
a 1,3-cycloaddition
2 and demonstrated
route that produced
that the cycloaddition
3427
the functionalized
was stereospecific.
Additionally,
the
3428
3 Et3N
Et02C
CH3CN COCH3 H2CH20H
H3C
2
300 MHz proton NMR spectrum 1O:l.
The relative
stereochemistry
natural products
we undertook
mixtures
of products.
potassium
t-butoxide
The vinylogous in the presence
o-silylation
of
by x-ray
of pyrrolidine-based
1. The successful outcome of our efforts is
cyanoborohydride
by acid hydrolysis
Hydrogenolysis
(HCl, anhyd
5 with Jones
by NMR absorptions
followed
followed
sequence
from 5 affords
6.
of 2 with
with hydroof
a reaction
of the resulting
and DBU epimerization
has been streamlined
by use of a
of tributyltin
a hemiketal
A Wittig
hydride"
of the aminoketone. which
reaction
The structure
at 1.69 6 (brs) and 3.67(s).
we
complex
However,
r.t.) and protectionll
(r.t., 15 min.).
Initially,
for the reduction
by reduction
with one equivalent
EtOH',
reagent
by reaction
protection
(H2, Pd/C, 18 psi) produces
nBuLi, THF, O'C) on the ester derived is supported
in ethanol,
the synthetic
produced
and aminoalcohols.
triflate'
desulfurization
of the benzyl group
to ketoacid
of aminoketones
with trimethylsilyl
involving
iodide8
1.
by the reaction
Common procedures
(r.t., 3h).
Recently
in ammonia
amide 3 could be prepared of methyl
mixtures
4 in good yield.
two step procedure
oxidized
ethanol
amides afforded
iminium salt with sodium
followed
the synthesis
agents such as RaNi or lithium
chloric acid in anhydrous
furnished
was determined
of 2 (R = CH2CH20CH2Ph) 7 into 1 is shown in Scheme
found that desulfurization
involving
of 2 (R = CH2CH20Bn)
was greater than
of this paper.
The transformation
vinylogous
that the ratio of endo- to exo-adducts
In order to exploit this strategy for the synthesis
crystallography.
the subject
indicated
in turn is
(Ph3PCH31,
of this intermediate
Ester hydrolysis
(KOH, CH30H)
3429
and removal of the protecting structure.
We initially
hydrolysis.
However,
group I2 produces
anticipated
an isomer of 1 as evidenced
that epimerization
no epimerization
was observed.
would occur
in 11% yield.
We intend to use this strategy
acid and other alkaloids
The synthesis
Drs. R. A. Jacobson
starting
Scheme
for the synthesis
the pyrrolidine
and J. Benson
for a generous
of 1 from 2 proceeds
of dolomic acid,
cc-kainic
subunit.
- We thank the Alfred P. Sloan Foundation
Acknowledgement
1, Dr. Ohfune
containing
during ester to 1 did occur when the
Epimerization
acid was heated with an excess of base for lh at 155“C.
by the x-ray
for partial
for the x-ray structures,
sample of 1 and Marie Ahking
Professor
support Oppolzer
of this work, for spectra
and Jim Delano for preparation
of
materials.
1
1) tBuOK,tBuOH,CH31 >
2 2) HCl,EtOH
3
\
1) TMSOTf,
1) Bu3SnH
NaBH3CN
2) HCl, EtOH 3) tBuOC02C02tBu
il
2) tBuOC02C02tBu
.
3) DBu
67%
0
X
/ \ '
1) H2, Pd/C C02tBu
2) Jones 48% from 4
1) KOH/MeOH
1
2) CF3C02H
-
3) aq. NaOH
4 1) CH2N2 2) Ph3P=CH2 57%
5 R=H, X=0 __j 6, R=CH3.
X=CH2
of
3430
REFERENCES
1.
Murakami,
S.; Takemoto,
Morimoto,
H. Ibid.,
Takagi,
N.
T.; Shimizu, 37.
1955,2,
Ibid., 1955,2,
Z.
Murakami,
For a recent synthesis,
see Oppolzer,
3.
For a recent synthesis,
see Ohfune,
4.
Biscoe, J. J.; Evans, R. H.; Headly, McGeer,
166.
E. G.; McGeer,
5.
Oppolzer,
W.; Andres,
6.
Kraus, G. A.; Nagy, J. 0.
7.
The structure
needed
of the appropriate yield.
the assigned
45,
1
G.; Kober, W.
10. Gutierrez,
P. L.
Nature
Lett.
ylid
Helv. Chim. Acta.
M.; Watkins,
1976,263,
1979, 62, 1982,104,
J. C.
Nature
2282. 3511.
1975,
517.
1978, 3397.
Lett.
1981,22,
2727.
acid synthesis
was prepared
from the reaction
(see ref. 6) with 6-benzyloxy-3-hexen-2-one
by a Wittig reaction
in 65%
on 3-benzyloxy-propionaldehyde.
PMR, CMR, IR and high resolution
All
mass spec data in accord with
structures.
Brain, E. G.; Mcmillan,
Simchen,
1026.
T.; Tei, Z.; Daigo, K.;
J. Am. Chem. Sot.
P. M.; Martin,
Tetrahedron
thiazolim
H.
Y.; Tomita, M.
for the a-allokainic
exhibited
Sot. Perkin Trans. 9.
W.; Andres,
Tetrahedron
The enone was prepared
intermediates
8.
H.
S.; Takemoto,
1953,73,
1252.
2.
255,
J. Pharm. Sot. Japan
C. G.;
I.; Nayler, J.H.C.;
Southgate,
R.; To-liday,
P. J.
J. Chem.
1975, 562. Synthesis
Stringham,
1976, 259.
R. A.; Nitasaka,
T.; Glasscock,
K. G.
J. Org. Chem.
1980,
3393.
11. Pope, B. M.; Yamamoto, 12. Schnabel,
Y.; Tarbell,
E.; Klostermeyer,
(Received
D. S.
H.; Berndt, H.
in USA 25 April
1983)
Proc. Nat. Acad. Sci. USA Ann.
1971, 749,
90.
1972, 69, 730.
THE TOTAL
0040-4039/83 $3.00 + .OO 01983 Pergamon Press Ltd.
3427-3430,1983
SYNTHESIS
OF cc-ALLOKAINIC
ACID
George A. Kraus* and Jon 0. Nagy Chemistry
Summary
- The aminoacid
The aminoacid Ag.'
a-allokainic
a-allokainic
Other members
isopropenyl
Department,
of this class
and the acetic
HD2CCH2
acid
Iowa State University,
acid was synthesized
Ames,
Iowa 50011
in eight steps from thiazolidine
2.
(1) was isolated from the marine algae Digenea sinlplex
include a-kainic
acid,2
an isomer of
acid groups are cis, and domoic acid.3
1 in which the
Although
1 shows
$-;
H02C 1"h N CI a-kainic
1
antihelmintic considerably elucidate
properties,
on an intramolecular We recently pyrrolidine
its potent neurophysiological
more attention.
the structure.
domoic acid
acid
Earlier syntheses
Recently,
Oppolzer
activity
in mammals4
were nonstereospecific
has communicated
has attracted
but served to
an elegant
synthesis
of 1 based
ene reaction. 5
reported
a 1,3-cycloaddition
2 and demonstrated
route that produced
that the cycloaddition
3427
the functionalized
was stereospecific.
Additionally,
the
3428
3 Et3N
Et02C
CH3CN COCH3 H2CH20H
H3C
2
300 MHz proton NMR spectrum 1O:l.
The relative
stereochemistry
natural products
we undertook
mixtures
of products.
potassium
t-butoxide
The vinylogous in the presence
o-silylation
of
by x-ray
of pyrrolidine-based
1. The successful outcome of our efforts is
cyanoborohydride
by acid hydrolysis
Hydrogenolysis
(HCl, anhyd
5 with Jones
by NMR absorptions
followed
followed
sequence
from 5 affords
6.
of 2 with
with hydroof
a reaction
of the resulting
and DBU epimerization
has been streamlined
by use of a
of tributyltin
a hemiketal
A Wittig
hydride"
of the aminoketone. which
reaction
The structure
at 1.69 6 (brs) and 3.67(s).
we
complex
However,
r.t.) and protectionll
(r.t., 15 min.).
Initially,
for the reduction
by reduction
with one equivalent
EtOH',
reagent
by reaction
protection
(H2, Pd/C, 18 psi) produces
nBuLi, THF, O'C) on the ester derived is supported
in ethanol,
the synthetic
produced
and aminoalcohols.
triflate'
desulfurization
of the benzyl group
to ketoacid
of aminoketones
with trimethylsilyl
involving
iodide8
1.
by the reaction
Common procedures
(r.t., 3h).
Recently
in ammonia
amide 3 could be prepared of methyl
mixtures
4 in good yield.
two step procedure
oxidized
ethanol
amides afforded
iminium salt with sodium
followed
the synthesis
agents such as RaNi or lithium
chloric acid in anhydrous
furnished
was determined
of 2 (R = CH2CH20CH2Ph) 7 into 1 is shown in Scheme
found that desulfurization
involving
of 2 (R = CH2CH20Bn)
was greater than
of this paper.
The transformation
vinylogous
that the ratio of endo- to exo-adducts
In order to exploit this strategy for the synthesis
crystallography.
the subject
indicated
in turn is
(Ph3PCH31,
of this intermediate
Ester hydrolysis
(KOH, CH30H)
3429
and removal of the protecting structure.
We initially
hydrolysis.
However,
group I2 produces
anticipated
an isomer of 1 as evidenced
that epimerization
no epimerization
was observed.
would occur
in 11% yield.
We intend to use this strategy
acid and other alkaloids
The synthesis
Drs. R. A. Jacobson
starting
Scheme
for the synthesis
the pyrrolidine
and J. Benson
for a generous
of 1 from 2 proceeds
of dolomic acid,
cc-kainic
subunit.
- We thank the Alfred P. Sloan Foundation
Acknowledgement
1, Dr. Ohfune
containing
during ester to 1 did occur when the
Epimerization
acid was heated with an excess of base for lh at 155“C.
by the x-ray
for partial
for the x-ray structures,
sample of 1 and Marie Ahking
Professor
support Oppolzer
of this work, for spectra
and Jim Delano for preparation
of
materials.
1
1) tBuOK,tBuOH,CH31 >
2 2) HCl,EtOH
3
\
1) TMSOTf,
1) Bu3SnH
NaBH3CN
2) HCl, EtOH 3) tBuOC02C02tBu
il
2) tBuOC02C02tBu
.
3) DBu
67%
0
X
/ \ '
1) H2, Pd/C C02tBu
2) Jones 48% from 4
1) KOH/MeOH
1
2) CF3C02H
-
3) aq. NaOH
4 1) CH2N2 2) Ph3P=CH2 57%
5 R=H, X=0 __j 6, R=CH3.
X=CH2
of
3430
REFERENCES
1.
Murakami,
S.; Takemoto,
Morimoto,
H. Ibid.,
Takagi,
N.
T.; Shimizu, 37.
1955,2,
Ibid., 1955,2,
Z.
Murakami,
For a recent synthesis,
see Oppolzer,
3.
For a recent synthesis,
see Ohfune,
4.
Biscoe, J. J.; Evans, R. H.; Headly, McGeer,
166.
E. G.; McGeer,
5.
Oppolzer,
W.; Andres,
6.
Kraus, G. A.; Nagy, J. 0.
7.
The structure
needed
of the appropriate yield.
the assigned
45,
1
G.; Kober, W.
10. Gutierrez,
P. L.
Nature
Lett.
ylid
Helv. Chim. Acta.
M.; Watkins,
1976,263,
1979, 62, 1982,104,
J. C.
Nature
2282. 3511.
1975,
517.
1978, 3397.
Lett.
1981,22,
2727.
acid synthesis
was prepared
from the reaction
(see ref. 6) with 6-benzyloxy-3-hexen-2-one
by a Wittig reaction
in 65%
on 3-benzyloxy-propionaldehyde.
PMR, CMR, IR and high resolution
All
mass spec data in accord with
structures.
Brain, E. G.; Mcmillan,
Simchen,
1026.
T.; Tei, Z.; Daigo, K.;
J. Am. Chem. Sot.
P. M.; Martin,
Tetrahedron
thiazolim
H.
Y.; Tomita, M.
for the a-allokainic
exhibited
Sot. Perkin Trans. 9.
W.; Andres,
Tetrahedron
The enone was prepared
intermediates
8.
H.
S.; Takemoto,
1953,73,
1252.
2.
255,
J. Pharm. Sot. Japan
C. G.;
I.; Nayler, J.H.C.;
Southgate,
R.; To-liday,
P. J.
J. Chem.
1975, 562. Synthesis
Stringham,
1976, 259.
R. A.; Nitasaka,
T.; Glasscock,
K. G.
J. Org. Chem.
1980,
3393.
11. Pope, B. M.; Yamamoto, 12. Schnabel,
Y.; Tarbell,
E.; Klostermeyer,
(Received
D. S.
H.; Berndt, H.
in USA 25 April
1983)
Proc. Nat. Acad. Sci. USA Ann.
1971, 749,
90.
1972, 69, 730.