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Prostaglandin analogs modified at the 10 and 11 positions
Tetrahedron Letters No. 41, pp 3933 - 3936. @Pergamon Press Ltd. 1979. Printed in Great Britain.
PROSTAGLANDIN ANALOGS MODIFIED AT THE 10 AND 11 POSITIONS Andre G. Pernet* Abbott Laboratories, 5400 CSte de Liesse, Montreal, Que., Canada Hiromasa Nakamoto, Naoyasu Ishizuka, Masakazu Aburatani, Kazuaki Nakahashi, Keiji Sakamoto and Tadashi Takeuchi Fuji Chemical Industries Ltd., 530 Chokeiji, Takaoka-Shi, Toyama 933, Japan
Summary: A simplified methodology for the building of prostaglandins substituted at the 10 and 11 positions is presented.
During our search for a general chemical approach which would yield PG analogs modified in the ring, we realized that modifications at the 10 position would drastically simplify the synthetic process. The general scheme adopted is shown in figure I.
When X is a heteroatom or
a substituted carbon, the respective starting lactone (2 a-b) or cyclopentenone (AC-f) can be alkylated directly in two steps with the complete side-chains.' Therefore, each new analog can be prepared in four steps starting from a simple cyclopentenoneand the readily available side-chains. Illustrative examples of analogues made are shown in Table I.
In a typical experiment a 0.2 M solution of ring moiety precursor&in a 0.2 M solution of the cuprate sin
ether was added to
ether at -78OC (prepared as described by Sih et al' with
s-Bu3P as a ligand for CuI), the mixture was stirred at -78'C for 30 min, then warmed slowly to -15'C; HCl (1 N) was added and the mixture rapidly extracted and washed twice with water. The residual syrup was freed from E-Bu~P and vinyl by-products by column chromatography (wakogel C-200, ethyl acetate-hexane 7:l) to afford pure>
(step 1). The ketone&was
added
to a 0.2 M solution of lithium diisopropylamidein THF at -78'C, stirred for one hour, then the iodide 42 was added and stirred for one additional hour at -30°C, -15'C. Work up with 0.5 N HCl a;
ether afforded the protected PG 5_(step 2). Deblocking of the hydroxy group was
effected in methanol containing a trace of l-toluenesulfonic acid at m3OC for 6 hours, followed by the action of pancreatic lipase in McIlvaine buffer to afford the acid 6.3 N
3933
3934
No. 41
FIGURE
I
12 2 u
1 (a-f) W
:THP 3 (a-f) &
@
COOCH3
I_ 4 c 1
X is a heteroatom Y is a substituted
Most of the analogs the preparation
prepared
of optically
used, the two diastereomeric 7734, chloroform-methanol then continued [U]",= +29'
-19.8'
could be separated
99:l) when the hydroxy
A small amount
was isolated
The same rotation
the method
function
during
assuming
(less than 3%) of the c& the chromatographic
calculated
12-e&
%
after equilibration that the
from the rotation
also allows
values
2,
are cis/trans --
was
isomer d&&
&,
to equilibrate
of [a]25D=+37.80.
6c.
The configu-
more stable.
= 38.6161.4.
[aJ*g=
[o]"5D'+51.8
When allowed
is thermodynamically
(Merck
PGEz, nat 6~,~ PGE*, d&
to a final value
of the
for was
The synthesis
isomer 12-eq
separation.
epimerized
isomer
w-2'
by column chromatography
at 15 was free.
to afford nat-11-deoxy-lO,lO-dimethyl
(1:4) for 19 hours,
was obtained
were assigned
concentrations
However,
When 3-(g)-tm-1-iodo-1-octen-3-01
(C 1.84 in CHCls) and 8,12-diepi-11-deoxy-lO,lO-dimethyl
in 1 N NaOH/methanol
rations
forms of 2
carbon
carbon
were racemic mixtures.
pure analogs.
with the pure isomers
(C 2 in CHCls).
(C 1 in CHCls),
or substituted
Relative
No.
41
3935
TABLE
Starting
I
ketone
Yield
step 2
step 1
3
Yield
%
I
0
75
57
3
O
I
54
22
84
Ifa rC
56
CHs
presented
ties of approximately readily
Although
Ra=SiPhaBu(tJ
Ra'Ac;
offers
optimal
equal weight
44
63
62
in 1, 3_, 5 and RI=Rz=R~=H M I
efficiency
are linked
for modifying
the ring, since three moie-
Changes
in two steps.
in 6.
in the side-chains
can be
introduced.
lO,lO-dimethyl
smooth muscle,
84
RsOCHa
Rl'THP;
equally
a
CH3
CHs
The approach
77
CHaORz
CHZORI
1c7 4
step 2
ORn
C&
lb6
step 1 0
0
la rr/
%
have been reported
PGs9"'
we found analogs 2
(a,c,d,e,f)
to be inactive
to be highly potent
in stimulating
as gastric
uterus
secretion
inhibi-
in rats and dogs.ll
tors in dogs and as antihypertensives
Acknowledgment
We thank professor utility
S. Hanessian
of t-butyldiphenylsilyl
of the reagent.
for useful
chloride
We are also indebted
discussions
and for letting us know of the
prior to publication,
to Dr. D.L. Garmaise
as well as for generous
for his constant
support.
supplies
No. 41
39%
References
1)
For previous examples of conjugate addition see: K.F. Bernady, J.F. Paletto and M.J. Weiss, Tetrahedron Lett., g,
765 (1975).
C.J. Sih, R.G. Salomon, P. Price, R. Sood and G. Peruzzoti, J. Am. Chem. Sot., z, 857 (1975). J.W. Patterson Jr. and J.H. Fried, J. Org. Chem., 2,
2506 (1974).
T. Tanaka, S. Kurozoni, T. Toru, M. Kobayashi, S. Miura and S. Ishimoto, Tetrahedron Lett., 1535 (1975).
2)
E.J. Corey and H.S. Sachdev, J. Am. Chem. Sot., 2,
3)
The silyl protective groups were deblocked with z-Bu+NF in THF as described by E.J. Corey
8484 (1973).
and A. Wenkateswarly, J. Am. Chem. Sot., 92, 6190 (1972).
4)
A.F. Kluge, K.G. Untch and J.H. Fried, J. Am. Chem. Sot., 2,
7827 (1972).
5)
The structures were tentatively assigned on the difference of biological activity as Nat 6c was found to be at least 10 times as potent as diepi precedented in reference 2. -r* 6c in reducing blood pressure in SHR rats when given I.V. in a single dose. N
6)
J. Font, Anales de Fisica y Chemica, 477 (1966).
7)
W.C. Agosta, A.B. Smith III, J. Am. Chem. Sot., 2,
8)
T. Matsumoto, H. Shirhama, A. Ichihara, H. Shin, S. Kagawa, F. Sakan, S. Nishida, S. Matsumoto, K.
9)
5513 (1971).
Saito and H. Hashimoto, Bull. Sot. Chim. Japan, 45, 1140 (1972).
O.G. Plantema, H. De Koning and H.O. Huisman, Tetrahedron Lett., 4595 (1975).
10) A. Hamon, E. Lacoume, G. Pasquet and W.R. Pilgram Tetrahedron Lett., 211 (1976). 11) To be published in full elsewhere. (Received in USA 9 April 1979)
PROSTAGLANDIN ANALOGS MODIFIED AT THE 10 AND 11 POSITIONS Andre G. Pernet* Abbott Laboratories, 5400 CSte de Liesse, Montreal, Que., Canada Hiromasa Nakamoto, Naoyasu Ishizuka, Masakazu Aburatani, Kazuaki Nakahashi, Keiji Sakamoto and Tadashi Takeuchi Fuji Chemical Industries Ltd., 530 Chokeiji, Takaoka-Shi, Toyama 933, Japan
Summary: A simplified methodology for the building of prostaglandins substituted at the 10 and 11 positions is presented.
During our search for a general chemical approach which would yield PG analogs modified in the ring, we realized that modifications at the 10 position would drastically simplify the synthetic process. The general scheme adopted is shown in figure I.
When X is a heteroatom or
a substituted carbon, the respective starting lactone (2 a-b) or cyclopentenone (AC-f) can be alkylated directly in two steps with the complete side-chains.' Therefore, each new analog can be prepared in four steps starting from a simple cyclopentenoneand the readily available side-chains. Illustrative examples of analogues made are shown in Table I.
In a typical experiment a 0.2 M solution of ring moiety precursor&in a 0.2 M solution of the cuprate sin
ether was added to
ether at -78OC (prepared as described by Sih et al' with
s-Bu3P as a ligand for CuI), the mixture was stirred at -78'C for 30 min, then warmed slowly to -15'C; HCl (1 N) was added and the mixture rapidly extracted and washed twice with water. The residual syrup was freed from E-Bu~P and vinyl by-products by column chromatography (wakogel C-200, ethyl acetate-hexane 7:l) to afford pure>
(step 1). The ketone&was
added
to a 0.2 M solution of lithium diisopropylamidein THF at -78'C, stirred for one hour, then the iodide 42 was added and stirred for one additional hour at -30°C, -15'C. Work up with 0.5 N HCl a;
ether afforded the protected PG 5_(step 2). Deblocking of the hydroxy group was
effected in methanol containing a trace of l-toluenesulfonic acid at m3OC for 6 hours, followed by the action of pancreatic lipase in McIlvaine buffer to afford the acid 6.3 N
3933
3934
No. 41
FIGURE
I
12 2 u
1 (a-f) W
:THP 3 (a-f) &
@
COOCH3
I_ 4 c 1
X is a heteroatom Y is a substituted
Most of the analogs the preparation
prepared
of optically
used, the two diastereomeric 7734, chloroform-methanol then continued [U]",= +29'
-19.8'
could be separated
99:l) when the hydroxy
A small amount
was isolated
The same rotation
the method
function
during
assuming
(less than 3%) of the c& the chromatographic
calculated
12-e&
%
after equilibration that the
from the rotation
also allows
values
2,
are cis/trans --
was
isomer d&&
&,
to equilibrate
of [a]25D=+37.80.
6c.
The configu-
more stable.
= 38.6161.4.
[aJ*g=
[o]"5D'+51.8
When allowed
is thermodynamically
(Merck
PGEz, nat 6~,~ PGE*, d&
to a final value
of the
for was
The synthesis
isomer 12-eq
separation.
epimerized
isomer
w-2'
by column chromatography
at 15 was free.
to afford nat-11-deoxy-lO,lO-dimethyl
(1:4) for 19 hours,
was obtained
were assigned
concentrations
However,
When 3-(g)-tm-1-iodo-1-octen-3-01
(C 1.84 in CHCls) and 8,12-diepi-11-deoxy-lO,lO-dimethyl
in 1 N NaOH/methanol
rations
forms of 2
carbon
carbon
were racemic mixtures.
pure analogs.
with the pure isomers
(C 2 in CHCls).
(C 1 in CHCls),
or substituted
Relative
No.
41
3935
TABLE
Starting
I
ketone
Yield
step 2
step 1
3
Yield
%
I
0
75
57
3
O
I
54
22
84
Ifa rC
56
CHs
presented
ties of approximately readily
Although
Ra=SiPhaBu(tJ
Ra'Ac;
offers
optimal
equal weight
44
63
62
in 1, 3_, 5 and RI=Rz=R~=H M I
efficiency
are linked
for modifying
the ring, since three moie-
Changes
in two steps.
in 6.
in the side-chains
can be
introduced.
lO,lO-dimethyl
smooth muscle,
84
RsOCHa
Rl'THP;
equally
a
CH3
CHs
The approach
77
CHaORz
CHZORI
1c7 4
step 2
ORn
C&
lb6
step 1 0
0
la rr/
%
have been reported
PGs9"'
we found analogs 2
(a,c,d,e,f)
to be inactive
to be highly potent
in stimulating
as gastric
uterus
secretion
inhibi-
in rats and dogs.ll
tors in dogs and as antihypertensives
Acknowledgment
We thank professor utility
S. Hanessian
of t-butyldiphenylsilyl
of the reagent.
for useful
chloride
We are also indebted
discussions
and for letting us know of the
prior to publication,
to Dr. D.L. Garmaise
as well as for generous
for his constant
support.
supplies
No. 41
39%
References
1)
For previous examples of conjugate addition see: K.F. Bernady, J.F. Paletto and M.J. Weiss, Tetrahedron Lett., g,
765 (1975).
C.J. Sih, R.G. Salomon, P. Price, R. Sood and G. Peruzzoti, J. Am. Chem. Sot., z, 857 (1975). J.W. Patterson Jr. and J.H. Fried, J. Org. Chem., 2,
2506 (1974).
T. Tanaka, S. Kurozoni, T. Toru, M. Kobayashi, S. Miura and S. Ishimoto, Tetrahedron Lett., 1535 (1975).
2)
E.J. Corey and H.S. Sachdev, J. Am. Chem. Sot., 2,
3)
The silyl protective groups were deblocked with z-Bu+NF in THF as described by E.J. Corey
8484 (1973).
and A. Wenkateswarly, J. Am. Chem. Sot., 92, 6190 (1972).
4)
A.F. Kluge, K.G. Untch and J.H. Fried, J. Am. Chem. Sot., 2,
7827 (1972).
5)
The structures were tentatively assigned on the difference of biological activity as Nat 6c was found to be at least 10 times as potent as diepi precedented in reference 2. -r* 6c in reducing blood pressure in SHR rats when given I.V. in a single dose. N
6)
J. Font, Anales de Fisica y Chemica, 477 (1966).
7)
W.C. Agosta, A.B. Smith III, J. Am. Chem. Sot., 2,
8)
T. Matsumoto, H. Shirhama, A. Ichihara, H. Shin, S. Kagawa, F. Sakan, S. Nishida, S. Matsumoto, K.
9)
5513 (1971).
Saito and H. Hashimoto, Bull. Sot. Chim. Japan, 45, 1140 (1972).
O.G. Plantema, H. De Koning and H.O. Huisman, Tetrahedron Lett., 4595 (1975).
10) A. Hamon, E. Lacoume, G. Pasquet and W.R. Pilgram Tetrahedron Lett., 211 (1976). 11) To be published in full elsewhere. (Received in USA 9 April 1979)