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The total syntheses of several 8, 15 dihydroxy arachidonic acid derivatives (8,15, LTB's)
Tetrahedron Letters,Vol.25,No.29,Qp Printed in Great Britain
THE TOTAL
SYNTHESES
OF SEVERAL
3043-3046,1984
8, 15 DIHYDROXY (8.15. LTB’s)
OO4O-4039/84 $3.00 + 01984 Pergamon Press
ARACHIDONIC
ACID
-00
Ltd.
DERIVATIVES
Brian J. Fitzsimmons* and Joshua Rokach Merck Frosst Canada Inc. P.O. Box 1005, Pointe Claire/Dorval, Ouebec, Canada H9R 4P8 The synthesis of the 8S, 15s and 8R, 15s diastereomers of 8,15 dihydroxy Abstract: 5Z,9E,llE,13Z eicosatetraenoic acid (8,15-LTB4) and of 8,15 dihydroxy 5Z,9E,llZ,13E eicosatetraenoic acid (8,15-LTB,) from arabinose are described. The initial enzymatic derivative.
at carbon
These initial Of the various
further. pathway
step of the lipoxygenase
oxidation
hydroperoxy
arachidonic
from hydrolysis
L-diHETE,
If the pathways
of formation
from the 5-lipoxygenase
metabolites,
hydrolysis
5,12-diHETEs,
of the LTA4 epoxide
The second type of 5,12-diHETE is non-enzymatic
The third type of 5,12-diHETE
dihydroxy
further to the corresponding
are general
compounds.
is derived
8,15-diHETEs,
3043
in nature,
For example
also arises giving
This gives the 52,122-6,lO E-8,13L-diHETE
of the 5,12-diHETEs
HPETEs should give rise to analogous metabolized
LTB4.
from enzymtic
in this case the hydrolysis
on 5-HETE.
is its hydroperoxy
HPETEs, are then metabolised those derived
three types of dihydroxy
5S_, 8i and 52, 82-6,8,10 E-13 L-diHETEs. action of 12-1 ipoxygenase
acid metabolism
studied.
The first type is derived
of LTA4, however,
termed
products,
Of the 5-HPETE derived metabolites
to give the 52,125 6,8 -lo,13
of arachidonic
acid metabolites,
have been the most thoroughly
have been isolated.
pathway
5, 8, 9, 11, 12 or 15 to yield the corresponding
1.
5,12-LTB,.
then the other
15-HPETE
as shown in Figure
the
from the
should be
3045
-
3046
with excess triphenylphosphine
gave the phosphonium
salt -15 required
for the preparation
of
the 8,15 LTBx's in an 87% yield over the two steps. Condensation treatment disilyl
8S,15S-LTB4
anticipated, Removal methyl
of the ylide generated
with one equivalent
and 8R,15S-LTB4
approximately
82,15?-LTB4Q diHETEs
in yields
were converted
Condensation -15 (Scheme
carbonate
diHETEs.
Removal
tetrabutylammonium then hydrolysis yields
afforded
lla orb
2), by
respectively
plus, as
8, 15s L-9,11,13 -E-diHETEs. fluoride
and hydrolysis
the free acids of 82,152 Similarly
disilyl
with the ylide
with one equivalent
of the desired
respectively,
(Scheme
the protected
of the
LTB43and
9,11,13
E-
to the acid diols 2 and -6.
products.
of HMPA at -lOO°C in THF, condensed
39% yields
in 47% and 36% yields
of the protected
of 86% and 82% respectively.
2), by treatment
added the desired
esters
amounts
salt 12 a orb
at -78'C, with the aldehyde -13 gave the
groups with tetrabutylammonium
potassium
of the aldehyde
only a 12% yield
methyl
equivalent
of the silyl protecting ester with aqueous
from the phosphonium
of LiHMDS in THF/HMPA
However,
82,15S-LTB, -
and 8E,152-LTB, by equivalent
of the silyl protecting
groups
fluoride with two equivalents
of the ester with aqueous
from the phosphonium at -78'C in THF/HMPA
if the ylide was generated
with the aldehyde
accompanied
generated
of n-butyllithium,
and then 5 equivalents methyl
amounts
in the absence
of HMPA were
esters were obtained
of the 8,15S_ 9,11,13
from these compounds
salt gave
in 43% and
trans
utilizing
of acetic acid to prevent
decomposition
and
base gave the 82,152-LTB, 1 and 8L,15S-LTB, 2
in
of 72% and 69% respectively
In summary, 9,11,13E
diHETE
properties.
and the 8,15S 5 and 2. - 52 -' 9,11,13E-diHETEs the 82,152 and 82,152 diastereomers of 8,15 LTB4, B,15 LTB, and 8,15,5Z
have been prepared
It is worthwhile
to facilitate
the determination
noting that all the asymmetric
described
here come from synthon -7a and 7b.
currently
being investigated
The biological
of their physiological
centers
in the Six-8,15-diHETEs
properties
and the results will be reported
of these diHETEs
are
at a later date.
Acknowledgement NSERC of Canada References
1. 2. 3. 4. 5. 6. 7. 8. 9.
Post Doctoral
Fellowship
is gratefully
acknowledged
by Brian Fitzsimmons.
Samuelsson, B. Leukotrienes and Prostacylins 1983, Berti, F.; Folco, G. and Velo, G.P. editors. Plenum Press. London. D. 22. Shak, S;; Perez, H.D.-and Goldstein, I.M. J. Biol. Chem. 1983, 14948-14953. Turk, J.; Maas, R.L.; Brash, A.R. ; Roberts, L.J. II and Oates, J.A. J. Biol. Chem. 1982, 257, 7068-7076. Borgeat, P. and Samuelsson, B. ibid 1979,254, 7865-7869. Ford-Hutchinson, A.W.; Bray, M.A.;Doig, M.V.; Shipley, M.E. and Smith, M.J.H. Nature (London) 1980,286, 264-265. Zamboni, R. and Rokach, J. Tetrahedron Lett. 1982, 23, 4751-4754. Rokach, J.; Young,R.N.; Kakushima, M - Lau, C.-K.;Seguin, R.; Frenette, R. and Guindon, Y. Tetrahedron Lett. 1981, 22, 979-98;: Okyuama, S.; Myamoto, S.; STirmoji, K.; Konishi, Y.; Toda, M. and Hayaski, M. Chem. Pharm. Bull. 1982, 30, 2453-2462. Tii?liF, J.-L.x An. Chem. Sot. 1978,100, 2226-2227.
(Received in USA 23 April 1984)
THE TOTAL
SYNTHESES
OF SEVERAL
3043-3046,1984
8, 15 DIHYDROXY (8.15. LTB’s)
OO4O-4039/84 $3.00 + 01984 Pergamon Press
ARACHIDONIC
ACID
-00
Ltd.
DERIVATIVES
Brian J. Fitzsimmons* and Joshua Rokach Merck Frosst Canada Inc. P.O. Box 1005, Pointe Claire/Dorval, Ouebec, Canada H9R 4P8 The synthesis of the 8S, 15s and 8R, 15s diastereomers of 8,15 dihydroxy Abstract: 5Z,9E,llE,13Z eicosatetraenoic acid (8,15-LTB4) and of 8,15 dihydroxy 5Z,9E,llZ,13E eicosatetraenoic acid (8,15-LTB,) from arabinose are described. The initial enzymatic derivative.
at carbon
These initial Of the various
further. pathway
step of the lipoxygenase
oxidation
hydroperoxy
arachidonic
from hydrolysis
L-diHETE,
If the pathways
of formation
from the 5-lipoxygenase
metabolites,
hydrolysis
5,12-diHETEs,
of the LTA4 epoxide
The second type of 5,12-diHETE is non-enzymatic
The third type of 5,12-diHETE
dihydroxy
further to the corresponding
are general
compounds.
is derived
8,15-diHETEs,
3043
in nature,
For example
also arises giving
This gives the 52,122-6,lO E-8,13L-diHETE
of the 5,12-diHETEs
HPETEs should give rise to analogous metabolized
LTB4.
from enzymtic
in this case the hydrolysis
on 5-HETE.
is its hydroperoxy
HPETEs, are then metabolised those derived
three types of dihydroxy
5S_, 8i and 52, 82-6,8,10 E-13 L-diHETEs. action of 12-1 ipoxygenase
acid metabolism
studied.
The first type is derived
of LTA4, however,
termed
products,
Of the 5-HPETE derived metabolites
to give the 52,125 6,8 -lo,13
of arachidonic
acid metabolites,
have been the most thoroughly
have been isolated.
pathway
5, 8, 9, 11, 12 or 15 to yield the corresponding
1.
5,12-LTB,.
then the other
15-HPETE
as shown in Figure
the
from the
should be
3045
-
3046
with excess triphenylphosphine
gave the phosphonium
salt -15 required
for the preparation
of
the 8,15 LTBx's in an 87% yield over the two steps. Condensation treatment disilyl
8S,15S-LTB4
anticipated, Removal methyl
of the ylide generated
with one equivalent
and 8R,15S-LTB4
approximately
82,15?-LTB4Q diHETEs
in yields
were converted
Condensation -15 (Scheme
carbonate
diHETEs.
Removal
tetrabutylammonium then hydrolysis yields
afforded
lla orb
2), by
respectively
plus, as
8, 15s L-9,11,13 -E-diHETEs. fluoride
and hydrolysis
the free acids of 82,152 Similarly
disilyl
with the ylide
with one equivalent
of the desired
respectively,
(Scheme
the protected
of the
LTB43and
9,11,13
E-
to the acid diols 2 and -6.
products.
of HMPA at -lOO°C in THF, condensed
39% yields
in 47% and 36% yields
of the protected
of 86% and 82% respectively.
2), by treatment
added the desired
esters
amounts
salt 12 a orb
at -78'C, with the aldehyde -13 gave the
groups with tetrabutylammonium
potassium
of the aldehyde
only a 12% yield
methyl
equivalent
of the silyl protecting ester with aqueous
from the phosphonium
of LiHMDS in THF/HMPA
However,
82,15S-LTB, -
and 8E,152-LTB, by equivalent
of the silyl protecting
groups
fluoride with two equivalents
of the ester with aqueous
from the phosphonium at -78'C in THF/HMPA
if the ylide was generated
with the aldehyde
accompanied
generated
of n-butyllithium,
and then 5 equivalents methyl
amounts
in the absence
of HMPA were
esters were obtained
of the 8,15S_ 9,11,13
from these compounds
salt gave
in 43% and
trans
utilizing
of acetic acid to prevent
decomposition
and
base gave the 82,152-LTB, 1 and 8L,15S-LTB, 2
in
of 72% and 69% respectively
In summary, 9,11,13E
diHETE
properties.
and the 8,15S 5 and 2. - 52 -' 9,11,13E-diHETEs the 82,152 and 82,152 diastereomers of 8,15 LTB4, B,15 LTB, and 8,15,5Z
have been prepared
It is worthwhile
to facilitate
the determination
noting that all the asymmetric
described
here come from synthon -7a and 7b.
currently
being investigated
The biological
of their physiological
centers
in the Six-8,15-diHETEs
properties
and the results will be reported
of these diHETEs
are
at a later date.
Acknowledgement NSERC of Canada References
1. 2. 3. 4. 5. 6. 7. 8. 9.
Post Doctoral
Fellowship
is gratefully
acknowledged
by Brian Fitzsimmons.
Samuelsson, B. Leukotrienes and Prostacylins 1983, Berti, F.; Folco, G. and Velo, G.P. editors. Plenum Press. London. D. 22. Shak, S;; Perez, H.D.-and Goldstein, I.M. J. Biol. Chem. 1983, 14948-14953. Turk, J.; Maas, R.L.; Brash, A.R. ; Roberts, L.J. II and Oates, J.A. J. Biol. Chem. 1982, 257, 7068-7076. Borgeat, P. and Samuelsson, B. ibid 1979,254, 7865-7869. Ford-Hutchinson, A.W.; Bray, M.A.;Doig, M.V.; Shipley, M.E. and Smith, M.J.H. Nature (London) 1980,286, 264-265. Zamboni, R. and Rokach, J. Tetrahedron Lett. 1982, 23, 4751-4754. Rokach, J.; Young,R.N.; Kakushima, M - Lau, C.-K.;Seguin, R.; Frenette, R. and Guindon, Y. Tetrahedron Lett. 1981, 22, 979-98;: Okyuama, S.; Myamoto, S.; STirmoji, K.; Konishi, Y.; Toda, M. and Hayaski, M. Chem. Pharm. Bull. 1982, 30, 2453-2462. Tii?liF, J.-L.x An. Chem. Sot. 1978,100, 2226-2227.
(Received in USA 23 April 1984)