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Enantiospecific total synthesis of 8- and 12-hydroxyeicosatetraenoic acid
Tetrahedron Letters,Vo1.27,No.50,pp Printed in Great Britain
ENANTIOSPECIFICTOTAL SYNTHESIS Pendri
OF 8-
Yadagiri,
Jorge Departments
Sun
12-HYOROXYEICOShTETRAENOIC
Lumin,
of Molecular
Paul
Health
Texas
Mosset,
and
Biochemistry
Science
75235
Center
USA
The R- and S-isomers of 8- and 12-hydroxyeicosatetraenoic Summary: --synthesized from dimethyl malate derived precursors. Recently,
enantiomeric including
two 1
monooxygenases
,
form human
and
other
the
six 8-
The
have
while
availability strategies
of
of
and
enantiomers
8-HETE
make
and
R-isomer
In
As
we
an
contrast,
human
little
primarily
is
as
of
our
consequence program'
of arachidonic
herein
the
psoriatic
systems Both
inflammation
the
distribution the
develop
readily
total
by
either
of
of
to
acid
convergent
in
scale3.
mediators about
were
generated
of biological
known
a
lP-HETE)
naturally
by a variety in
and
(HETEs)
occur
as putative
extensfon
(8-
acids
to
predominates attention6
metabolites
describe
found
is produced
enantiomers,
monooxygenase
study,
been
IP-HETE
widespread
material.
biological
of 8-
have
conditions7.
the
would
the
engendered
authentic
which
chemical
of
acid
hydroxyeicosatetraenoic
12-HETE,
S-antipode
pathophysiological
pharmacology8
regioisomeric
and
platelets'
12..HETE enantiomers or
of
i.e., 2-5
ACID
Falck*
Genetics
of Texas Dallas.
and
and J.R.
Capdevila,
University
oo40-4039/86 $3.00 + .OO Perqamon Journals Ltd.
6039-6040,1986
limited synthetfc
available
syntheses
of
for both
12-HETE.
OH
0 OMe
a:
R=Et
b: R=CO,Me
Epoxy-aldehyde &ram-enal
2al"'I
E.
70-230
Merck,
MeOHKH2C12,
la,
fabricated'
(90-92%) mesh)
by
for
Rf-0.50).
methyl
extractive 12(S)-HETE
20-30
with
min,
(-78
isolation, (2)
from
stirring
in
to
and
65-68%
dimethyl
of
-15OC,
[a]';
and 2a
3h)
chromatography
yield,
L-malate,
an ethereal
filtration
Condensation
l-ylidenetriphenylphosphorane NH40Ac,
4
in
was
suspension
chromatographic with THF/HMPA
6039
(c 1.64,
silica
isomerized gel
(100
purification
to
mg I/g, (SiO2:5%
7-carbomethoxyhepta-3-(Z)-en(4:1),
(Si02:Et20/hexane +lZ.V'
smoothly of
quenching l:l,
acetone);
with
Rf-0.55) lit.6b
25%
aq
afforded [o]':
+13O
594c
cc
lh
ILikewice,
acst,nne).
i-5,
furnished
3--(i)-norirnylidpnrttript,enyl~hospl~nrane ~ci:~oma!.og~~al>l~y (RF-0.35), Sta;,Linq iitil
with
ciimethyl
T lhr t i C T E
w ‘-. t i II .1y
investjgations 1~~ reported
1.69,
optically
methyl
which
in
plus
turr? W~F
P,(S)-iilTF (4)
C:HC13); repc,rtetl
in
;$;
71%
cci~plpd
-4.75'
with
f~l lowing
virld
(c 0.4,
S(g)-- arc1 12(R)-IIF;F
mcthy!
in due
George
Just
CHC13).
W~?P
realized
(I-782)
University)
and
extra*-tiv? and
origin.
f: .’
j .s:‘ds. wl+ h i
from
in
rurrelit
pharmap:: 1rxl'g?f IlFTf rnantinmers
will
by grants
and
for
NATO
fror,
(RG
it?;> IlSPIiS PiILl(GM
-71278
I 110 a~i;.!~ar~.
85t’C375).
a cop\: pi hi? mant:s-l,ipt.prinr
providing
and
-33541),
I ndpbted
a :‘e
to
the
Prof.
to publication.
Notes
*I. Capdevila, Boobis,
4,
enzymatic
financially
Foundation
and
pH
course.
(McGill
References
to
occ!Irrence,
Supported
,A. Welch
t_t;F c.cil I pc!i;~iifi/r,y
~,'r'e roriverteti tn
Vster'c
lnl.0 the
Robert
G.
J.
Snyder,
and
Caldwell,
Philadelphia,
1985,
Biochemistry M.
-4 7'," (c
&malat2,
acidifica'ion
Acknpwledgment:
2.
give
anal~~i~ous procedures.
i7fncl
MpiXl/ti2fi ( 3. 1) .
1.
[a]';
2!) (R,,-0.44)
to
F. PP.
J,
"Micrnsomes
in and
DeMatteis,
94-94.
19: 40-141,
Hamberp.
,l.R. Falck
M.
C.R.
John5or;.
and
Drug
Elcombe;
r.
Cxidations"; and
Taylor
rarey,
and
Fds.,
Francis,
MrKi Ilan.
R M.
A.R. Ltd.:
Essays
in
1983.
Svensson,
A :1a :j
ant-1 rl. iamllcl;znr!, I'ror. Nat.1
.5i:i
ti? A
71
3825-.X28.
1974.
3.
P.M.
4.
i;.I_.Bundy,
Wo,lllard,
Biychem.
Bilp'lys. Re;.
E.G.
Nidy.
D.F:
Z.Y.
Wang,
pr;vate
COrnil!.;.',!S: !ro-l/h,
1986.
LIpp;, i; A. Missal., dtl:ii; ,i Wnuk,
J.
Bioi.
Chem.
261:
743-751,
1986. 5.
G. &st
6.
Recent
and
chiral
I.e>_ter~s27:
Perez,
J.
and
A.R.
Brastt,
Woollard. 8.
E.J.
Tauber, and 9.
<].A. Oates,
R.W.
Bryant,
P. Mosset,
and
Satisfactory
Develop.
11.
Spectral
nmr?
1.80.-2.17 J-16,8,2Hz, (s,
J-16,8liz, (m, (dd,
iOH),
for
(m.
ZH),
IH),
3H),
2.37
in
6.77
(dd,
(t,
The 11
22-33,
spectral
:H),
and
Fitzsimmnns.
(c)
G.
Cunninqham.
39:
JuTt
,!.R. Falck, .I. Adams,
and
L.Y.
F.
Wang,
M W.
GroavPs.
and
P.M.
ZH),
i979.
F ,l
491-5ni,
Ci,et.il, A.R.
i780.
IL. Meijer.
Brash,
A.I.
J. Maclouf,
1986. and J.R.
data
90
MHz)
iH),
5.2i-5.67
were
lFa!rk, iyrecedinq
obtained
6 0.88
9.611 (d,
3.62
(s,
3H),
of 4 was
1986)
(t,
(t,
(m,
(In, 2H),
3: il.88
1Hj.
spectrum
August
Yadagiri.
fur. all
report.
ne:q compounds
using
samples
Ja16,BH.r.
J-8Hz,
J&Hz,
iH).
P. R J
1986.
406-411,
Immurology
J,-692, _7H), 4.29-4.57
(m,
(d.
F M.
>J. Capdevila,
(CDCl3,
(t,
4.27-4.57
USA
114:
mass
NMR
2.38
:h'), 9.60
J-lS,llHz,
(Received
23:
189-?93,
fled. 150:
Hubbard,
homogeneous
data
Viala.
LeRlartc,
11X1:, 1486.
Biol.
and
51.
Y
1%5.
S. Lumin,
ir,
chromatographically
Chem.
~~ Exp. J.
W.C.
Mann,?, %J (b)
7rj?-7i171 1985.
87:
Sun,
P. Yadagiri,
10.
3.62
72:
J.. Phsrm.
arid F.F.
Org.
9.
1986
2993-2996,
Circulation
Brit.
Goetrl
J.
26:
(a)
?67q-$h87,
Rokach.
Letters
rommunication.
syntheses:
Tetrahedrons
Tetrahedron 7.
12-HETF
IHj,
J+Hz. 6.24
5.14-5.71 1H)
(ddd,
.I--6Hi, 3H),
4.0(1-4.25
virtually
(m,
LH),
,?h. 1.54-2.60 LJ-1E,8.ZHz.
1.06-1.44 IH),
identica;
l.U8-1.48 (m,
(m.
5.i4-6.00
to that
IH).
(m, 6.23
7H), (ddd,
(m,
8H),
6.77
(dd,
bti), 1.51-2.37 (m,
of 3.
7t1), 6.48
ENANTIOSPECIFICTOTAL SYNTHESIS Pendri
OF 8-
Yadagiri,
Jorge Departments
Sun
12-HYOROXYEICOShTETRAENOIC
Lumin,
of Molecular
Paul
Health
Texas
Mosset,
and
Biochemistry
Science
75235
Center
USA
The R- and S-isomers of 8- and 12-hydroxyeicosatetraenoic Summary: --synthesized from dimethyl malate derived precursors. Recently,
enantiomeric including
two 1
monooxygenases
,
form human
and
other
the
six 8-
The
have
while
availability strategies
of
of
and
enantiomers
8-HETE
make
and
R-isomer
In
As
we
an
contrast,
human
little
primarily
is
as
of
our
consequence program'
of arachidonic
herein
the
psoriatic
systems Both
inflammation
the
distribution the
develop
readily
total
by
either
of
of
to
acid
convergent
in
scale3.
mediators about
were
generated
of biological
known
a
lP-HETE)
naturally
by a variety in
and
(HETEs)
occur
as putative
extensfon
(8-
acids
to
predominates attention6
metabolites
describe
found
is produced
enantiomers,
monooxygenase
study,
been
IP-HETE
widespread
material.
biological
of 8-
have
conditions7.
the
would
the
engendered
authentic
which
chemical
of
acid
hydroxyeicosatetraenoic
12-HETE,
S-antipode
pathophysiological
pharmacology8
regioisomeric
and
platelets'
12..HETE enantiomers or
of
i.e., 2-5
ACID
Falck*
Genetics
of Texas Dallas.
and
and J.R.
Capdevila,
University
oo40-4039/86 $3.00 + .OO Perqamon Journals Ltd.
6039-6040,1986
limited synthetfc
available
syntheses
of
for both
12-HETE.
OH
0 OMe
a:
R=Et
b: R=CO,Me
Epoxy-aldehyde &ram-enal
2al"'I
E.
70-230
Merck,
MeOHKH2C12,
la,
fabricated'
(90-92%) mesh)
by
for
Rf-0.50).
methyl
extractive 12(S)-HETE
20-30
with
min,
(-78
isolation, (2)
from
stirring
in
to
and
65-68%
dimethyl
of
-15OC,
[a]';
and 2a
3h)
chromatography
yield,
L-malate,
an ethereal
filtration
Condensation
l-ylidenetriphenylphosphorane NH40Ac,
4
in
was
suspension
chromatographic with THF/HMPA
6039
(c 1.64,
silica
isomerized gel
(100
purification
to
mg I/g, (SiO2:5%
7-carbomethoxyhepta-3-(Z)-en(4:1),
(Si02:Et20/hexane +lZ.V'
smoothly of
quenching l:l,
acetone);
with
Rf-0.55) lit.6b
25%
aq
afforded [o]':
+13O
594c
cc
lh
ILikewice,
acst,nne).
i-5,
furnished
3--(i)-norirnylidpnrttript,enyl~hospl~nrane ~ci:~oma!.og~~al>l~y (RF-0.35), Sta;,Linq iitil
with
ciimethyl
T lhr t i C T E
w ‘-. t i II .1y
investjgations 1~~ reported
1.69,
optically
methyl
which
in
plus
turr? W~F
P,(S)-iilTF (4)
C:HC13); repc,rtetl
in
;$;
71%
cci~plpd
-4.75'
with
f~l lowing
virld
(c 0.4,
S(g)-- arc1 12(R)-IIF;F
mcthy!
in due
George
Just
CHC13).
W~?P
realized
(I-782)
University)
and
extra*-tiv? and
origin.
f: .’
j .s:‘ds. wl+ h i
from
in
rurrelit
pharmap:: 1rxl'g?f IlFTf rnantinmers
will
by grants
and
for
NATO
fror,
(RG
it?;> IlSPIiS PiILl(GM
-71278
I 110 a~i;.!~ar~.
85t’C375).
a cop\: pi hi? mant:s-l,ipt.prinr
providing
and
-33541),
I ndpbted
a :‘e
to
the
Prof.
to publication.
Notes
*I. Capdevila, Boobis,
4,
enzymatic
financially
Foundation
and
pH
course.
(McGill
References
to
occ!Irrence,
Supported
,A. Welch
t_t;F c.cil I pc!i;~iifi/r,y
~,'r'e roriverteti tn
Vster'c
lnl.0 the
Robert
G.
J.
Snyder,
and
Caldwell,
Philadelphia,
1985,
Biochemistry M.
-4 7'," (c
&malat2,
acidifica'ion
Acknpwledgment:
2.
give
anal~~i~ous procedures.
i7fncl
MpiXl/ti2fi ( 3. 1) .
1.
[a]';
2!) (R,,-0.44)
to
F. PP.
J,
"Micrnsomes
in and
DeMatteis,
94-94.
19: 40-141,
Hamberp.
,l.R. Falck
M.
C.R.
John5or;.
and
Drug
Elcombe;
r.
Cxidations"; and
Taylor
rarey,
and
Fds.,
Francis,
MrKi Ilan.
R M.
A.R. Ltd.:
Essays
in
1983.
Svensson,
A :1a :j
ant-1 rl. iamllcl;znr!, I'ror. Nat.1
.5i:i
ti? A
71
3825-.X28.
1974.
3.
P.M.
4.
i;.I_.Bundy,
Wo,lllard,
Biychem.
Bilp'lys. Re;.
E.G.
Nidy.
D.F:
Z.Y.
Wang,
pr;vate
COrnil!.;.',!S: !ro-l/h,
1986.
LIpp;, i; A. Missal., dtl:ii; ,i Wnuk,
J.
Bioi.
Chem.
261:
743-751,
1986. 5.
G. &st
6.
Recent
and
chiral
I.e>_ter~s27:
Perez,
J.
and
A.R.
Brastt,
Woollard. 8.
E.J.
Tauber, and 9.
<].A. Oates,
R.W.
Bryant,
P. Mosset,
and
Satisfactory
Develop.
11.
Spectral
nmr?
1.80.-2.17 J-16,8,2Hz, (s,
J-16,8liz, (m, (dd,
iOH),
for
(m.
ZH),
IH),
3H),
2.37
in
6.77
(dd,
(t,
The 11
22-33,
spectral
:H),
and
Fitzsimmnns.
(c)
G.
Cunninqham.
39:
JuTt
,!.R. Falck, .I. Adams,
and
L.Y.
F.
Wang,
M W.
GroavPs.
and
P.M.
ZH),
i979.
F ,l
491-5ni,
Ci,et.il, A.R.
i780.
IL. Meijer.
Brash,
A.I.
J. Maclouf,
1986. and J.R.
data
90
MHz)
iH),
5.2i-5.67
were
lFa!rk, iyrecedinq
obtained
6 0.88
9.611 (d,
3.62
(s,
3H),
of 4 was
1986)
(t,
(t,
(m,
(In, 2H),
3: il.88
1Hj.
spectrum
August
Yadagiri.
fur. all
report.
ne:q compounds
using
samples
Ja16,BH.r.
J-8Hz,
J&Hz,
iH).
P. R J
1986.
406-411,
Immurology
J,-692, _7H), 4.29-4.57
(m,
(d.
F M.
>J. Capdevila,
(CDCl3,
(t,
4.27-4.57
USA
114:
mass
NMR
2.38
:h'), 9.60
J-lS,llHz,
(Received
23:
189-?93,
fled. 150:
Hubbard,
homogeneous
data
Viala.
LeRlartc,
11X1:, 1486.
Biol.
and
51.
Y
1%5.
S. Lumin,
ir,
chromatographically
Chem.
~~ Exp. J.
W.C.
Mann,?, %J (b)
7rj?-7i171 1985.
87:
Sun,
P. Yadagiri,
10.
3.62
72:
J.. Phsrm.
arid F.F.
Org.
9.
1986
2993-2996,
Circulation
Brit.
Goetrl
J.
26:
(a)
?67q-$h87,
Rokach.
Letters
rommunication.
syntheses:
Tetrahedrons
Tetrahedron 7.
12-HETF
IHj,
J+Hz. 6.24
5.14-5.71 1H)
(ddd,
.I--6Hi, 3H),
4.0(1-4.25
virtually
(m,
LH),
,?h. 1.54-2.60 LJ-1E,8.ZHz.
1.06-1.44 IH),
identica;
l.U8-1.48 (m,
(m.
5.i4-6.00
to that
IH).
(m, 6.23
7H), (ddd,
(m,
8H),
6.77
(dd,
bti), 1.51-2.37 (m,
of 3.
7t1), 6.48