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Synthesis of 16-16-dimethyl-trans-Δ2-PGE1 methyl ester (ONO-802)
PROSTAGLANDINS
LETTER TO THE EDITOR SYNTHESIS OF 16,16-DIMETHYL-TRANS-A2-PGEI
METHYL ESTER
(0NO-802) Dear Sir: A novel PG analog, 16,16-dimethyl-trans-A2-PGE1 methyl ester
(i) is 25-100 times more potent on a dosage
basis in inducing uterine contraction than PGE2 and PGF2~, and has less side effects~ ) such as vomiting, diarrhea, and change in blood pressure.
From these results this
analog may be used as an effective abortifacient first and second trimester of pregnancy.
in the
We now report
the synthesis of this significant analog i. A first route to 1 was developed starting with the readily available lactol 22) using our procedure reported previously 3) for the preparation of trans-A2-PGs.
The
Wittig reaction of the lactol 2 with 2-carboxyethylidenetriphenylphosphorane
(2.4 equiv) in DMSO at room tempera-
ture for 2 h afforded the ~,y-unsaturated acid 3. Selective hydrogenation of the B,y-double bond of 3 using 5% palladium on carbon catalyst followed by esterification with diazomethane gave the ester 4. ester 4 with diisobutylaluminum hydride
Reduction of the (2.4 equiv) in
toluene at -78°C for 15 min produced the aldehyde S, which was immediately converted to the ~,B-unsaturated ester 6 by treatment with methyl diethyl phosphonoacetate (2.4 equiv) in THF at room temperature for 2 h.
anion ~) The ester
6 was transformed to 7 with Jones reagent, and subsequently hydrolyzed with 65% aqueous acetic acid to yield the desired analog i~ ) A second route was started with 16,16-dimethyl-PGF~, ll,15-bis THP (8)2b)which was prepared by the Wittig reac-
MAY 1978 VOL. 15 NO. 5
907
PROSTAGLANDINS
tion of the lactol 2 with 4-carboxybutylidenetriphenylphosphorane.
The compound 8 was converted to the ester
with diazomethane and hydrogenated selectively to the ester 9 over 5% palladium on carbon catalyst. of 9 with lithium diisopropylamide
Treatment
(2.2 equiv) in THF at
-78°C for 15 min followed by addition of diphenyldiselenide 6) (1.5 equiv) resulted in the formation of the selenide i_O0, which yielded ~,B-unsaturated ester 6 on exposure to 30% hydrogen peroxide
(i0 equiv) in THF-AcOEt
(i:I) at 35°C for 5 min. A third route was as follows: starting with the lactone i_~i,7) the A2-~-chain of PG was introduced prior to the u-chain. hydride
Reduction of Ii with diisobutylaluminum
(2.4 equiv) in toluene at -78°C for 15 min led to
the lactol i_2_2,which was condensed with 4-carboxybutylidenetriphenylphosphorane
(4 equiv) in DMSO at 25°C for 2 h
to afford the acid 13.
Esterification of 13 with diazo-
methane followed by hydrogenation over 5% palladium on carbon catalyst produced the ester i__44,which was transformed to the ~,B-unsaturated ester 16 via the selenide i_55 by the same procedure as 9 ÷6. acetic anhydride
Acetylation of i__66with
(15 equiv) in pyridine at room tempera-
ture for 15 h gave the diacetate i__77,which was converted to the m o n o a l c o h o 1 1 8
by selective deacetylation with
anhydrous potassium carbonate methanol at 0°C for 2h.
(i equiv)
in absolute
The Collins oxidation of 18
afforded the aldehyde i_99, which was treated with the anion of dimethyl 2-oxo-3,3-dimethylheptylphosphonate 2b)
(i.i
equiv) in THF at room temperature to give the ~,fi-unsaturated ketone 20.
Reduction of 20 with sodium borohydride
(5 equiv) in methanol at -22°C gave the allyl alcohol 21~ ) The compound 21 was converted to the tetrahydropyranyl ether 2__22with dihydropyran in the presence of E-toluenesulfonic acid in methylene chloride and then treated with
908
MAY 1978 VOL. 15 NO. 5
PROSTAGLANDINS
anhydrous potassium carbonate
(1.2 equiv) in absolute
methanol at 45°C for 1 h to afford the alcohol 23. The intermediate 19 in route 3 is a stable and useful compound which can be transformed through the short steps to the A2-PG analogs containing various kinds of w-chains by the Wittig reaction with a variety of phosphonates or phosphoranes.
Route 1 OH
o
ot
OH
6THP
6THP
1 01-! ',
2
OH
OTttP
" OTHP
OTHP
3
OTttP
4
R=COOMe R=CHO
QH
'
0
( / ~ ' ~ C O
.-
OTHP
6THP
6
MAY 1978 VOL. 15 NO. 5
0THP
OMe
OTHP 7
909
PROSTAGLANDINS
Route 2
OH
~
QH
I
~
bTHP
6THP
OH
'
OTHP
OMe
8
Route 3 0
bTHP 9 R=H ID- R=~)Se
OH
,~OH
~j~,/OH
" OTHP
O'THP
ii
.•'•.__•-/•C H
O'THP
12
Oil
OOH
13
OR: ,,,~"-~OOMe 2
0THP
OTHP 16 I--7 1-~ i--9
14
R=H 1---~ R--¢~Se
OOMe
OMe
O 2O
910
R2=CH20H R2=CH2OAc R2=CH20H R2=CH0
OR l
0Ac
OTHP
RI=H, R:=Ac, RI=Ac, RI=Ac,
21
RI=Ac, R2=H RI=Ac, R2=THP RX=H, R2=THP MAY 1978 VOL. 15 NO. 5
PROSTAGLANDINS Table Compound
yield %
ir (liquid {ilm)
I. nmr
(CDC13)
C~1
72 from 7
3400, 1750, 1730, 1660.
3
48 from 2
1710
5.50(4H,m), 4.68(2H,m).
4
81 from 3
1710
5.30(2H,m), 4.60(2H,m), 3.60 (3H,s).
6 --
73 from 4 i00 from T0
1650
5.69(iH,d, J=16.0Hz), 3.66(3H, s).
7
85 from 6
9
90 from 8
I0
85 from 9
3460, 1738, 1580.
7.44(5H,m), 5.43(2H,m), 4.68 (2H,m), 3.61(3H,s).
14
82 from ii
3455, 1742.
4.70(iH,m), 3.65(3H,s).
15
65 from 14
1735, 1580.
7.45(5H,m), 4.75(iH,m),3.64 (3H,s).
16
i00 from 15
1725, 1655.
6.98(iH,dt), 5.77(iH,d), 3.68(3H,s).
18
60 from 16
1730, 1658.
6.98(iH,dt), 5.78(IH,d), 3.68 (3H,s), 2.02(3H,s).
19
95 from 18
2220, 1725 1655.
9.82(iH,m), 6.96(iH,dt), 5.78 (iH,d), 3.68(3H,s), 2.05(3H,s).
20
98 from 19
1740, 1690, 1660, 1625
6.94(3H,m), 5.78(iH,d), 5.12 (iH,m), 3.68(3H,s), 2.05(3H,s), 1.10(6H,s), 0.87(3H,t).
22
95 from 20
1735, 1660.
6.94(iH,dt), 5.70(3H,m), 5.10 (iH,m), 4.60(2H,m), 3.70(3H,s), 2.03(3H,s), 0.89(9H,m).
23
72 from 22
3480, 1735, 1660
6.95(iH,dt), 5.10(3H,m), 4.68 (2H,m), 3.70(3H,s).
1745, 1728, 1656. 1745
MAY 1978 VOL. 15 NO. 5
6.92(iH,dt, J=15.5Hz and 7Hz), 5.79(iH,d, J=15.5Hz), 5.85 and 5.37(2H,m), 3.71(3H,s).
6.85(iH,dt), 5.69(iH,d, J=16.0 Hz), 3.66(3H,s). 5.45(2H,m), 4.68(2H,m), 3.66 (3H,s).
911
PROSTAGLANDINS
R e f e r e n c e s and Notes i)
a) Oshima, K., K. Matsumoto, T. Tsuda, K. Shibata, and M. Hayashi, Prostaglandins, in press; b) Ninagawa, T., M. 0hta, T. Hiroshima, Y. Tomida, K. Itoh, N. Imoto, and R. Matsukawa, Proceedings of the First Inter-Congress on Obstetric and Gynaecological Uses of Prostaglandins at Singapore on April 27-30, 1975, vol. i, S. M. M. Karim, Ed., Eurasia Press, Singapore, pp55-66; c) Takagi, S., H. Sakata, T. Yoshiba, S. Nakazawa, K.T. Fujii, Y. Tominaga, Y. lwasa, T. Ninagawa, T. Hiroshima, Y. Tomida, K. Itoh, and R. Matsukawa, Prostaglandins, 14, 791 (1977).
2)
a) Corey, E.J., T.K. Schaaf, W. Huber, and N.M. Weinshenker, J. Am. Chem. Soc., 92, 397 (1970); b) Magerlein, B.J., D.W. DuCharme, W.E. Magee, W.L. Miller, A. Robert, and J.R. Weeks, Prostaglandins, 4, 143 (1973). Wakatsuka, tt., S. Kori, and M. H a y a s h i , P r o s t a g l a n dins, 8, 341 (1974). House, H.O., V.K. Jones, and G.A. Frank, J. Org. Chem., 29, 3327 (1964). Specific rotation (EtOH, c 0.985) [a]~5 _41.8o; homogeneous by tlc (two developments ~ith cyclohexane:AcOEt:THF 3:6:1, Rf 0.35). Sharpless, K.B., R.F. Lauer, and A.Y. Teranishi, J. Am. Chem. Soc., 95, 1637 (1973). Corey, E.J., H. Shirahama, H. Yamamoto, S. Terashima, A. Venkateswarlu, and T.K. Schaaf, J. Am. Chem. Soc., 93, 1491 (1971). C-15 epimer and a small amount o f 1 3 , 1 4 - d i h y d r o compound which was produced by over-reduction with sodium borohydride could be easily separated from _i at the final step by column chromatography on silica gel. Both of them are less polar than 2.
3) 4) 5)
6) 7)
8)
II. Wakatsuka, H. Miyake, S. Kori, and M. Hayashi ~ H. Suga, Y. Konishi,
Ono Pharmaceutical Co., Ltd., Research Institute, 3-1-i, Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618, Japan
912
MAY 1978 VOL. 15 NO. 5
LETTER TO THE EDITOR SYNTHESIS OF 16,16-DIMETHYL-TRANS-A2-PGEI
METHYL ESTER
(0NO-802) Dear Sir: A novel PG analog, 16,16-dimethyl-trans-A2-PGE1 methyl ester
(i) is 25-100 times more potent on a dosage
basis in inducing uterine contraction than PGE2 and PGF2~, and has less side effects~ ) such as vomiting, diarrhea, and change in blood pressure.
From these results this
analog may be used as an effective abortifacient first and second trimester of pregnancy.
in the
We now report
the synthesis of this significant analog i. A first route to 1 was developed starting with the readily available lactol 22) using our procedure reported previously 3) for the preparation of trans-A2-PGs.
The
Wittig reaction of the lactol 2 with 2-carboxyethylidenetriphenylphosphorane
(2.4 equiv) in DMSO at room tempera-
ture for 2 h afforded the ~,y-unsaturated acid 3. Selective hydrogenation of the B,y-double bond of 3 using 5% palladium on carbon catalyst followed by esterification with diazomethane gave the ester 4. ester 4 with diisobutylaluminum hydride
Reduction of the (2.4 equiv) in
toluene at -78°C for 15 min produced the aldehyde S, which was immediately converted to the ~,B-unsaturated ester 6 by treatment with methyl diethyl phosphonoacetate (2.4 equiv) in THF at room temperature for 2 h.
anion ~) The ester
6 was transformed to 7 with Jones reagent, and subsequently hydrolyzed with 65% aqueous acetic acid to yield the desired analog i~ ) A second route was started with 16,16-dimethyl-PGF~, ll,15-bis THP (8)2b)which was prepared by the Wittig reac-
MAY 1978 VOL. 15 NO. 5
907
PROSTAGLANDINS
tion of the lactol 2 with 4-carboxybutylidenetriphenylphosphorane.
The compound 8 was converted to the ester
with diazomethane and hydrogenated selectively to the ester 9 over 5% palladium on carbon catalyst. of 9 with lithium diisopropylamide
Treatment
(2.2 equiv) in THF at
-78°C for 15 min followed by addition of diphenyldiselenide 6) (1.5 equiv) resulted in the formation of the selenide i_O0, which yielded ~,B-unsaturated ester 6 on exposure to 30% hydrogen peroxide
(i0 equiv) in THF-AcOEt
(i:I) at 35°C for 5 min. A third route was as follows: starting with the lactone i_~i,7) the A2-~-chain of PG was introduced prior to the u-chain. hydride
Reduction of Ii with diisobutylaluminum
(2.4 equiv) in toluene at -78°C for 15 min led to
the lactol i_2_2,which was condensed with 4-carboxybutylidenetriphenylphosphorane
(4 equiv) in DMSO at 25°C for 2 h
to afford the acid 13.
Esterification of 13 with diazo-
methane followed by hydrogenation over 5% palladium on carbon catalyst produced the ester i__44,which was transformed to the ~,B-unsaturated ester 16 via the selenide i_55 by the same procedure as 9 ÷6. acetic anhydride
Acetylation of i__66with
(15 equiv) in pyridine at room tempera-
ture for 15 h gave the diacetate i__77,which was converted to the m o n o a l c o h o 1 1 8
by selective deacetylation with
anhydrous potassium carbonate methanol at 0°C for 2h.
(i equiv)
in absolute
The Collins oxidation of 18
afforded the aldehyde i_99, which was treated with the anion of dimethyl 2-oxo-3,3-dimethylheptylphosphonate 2b)
(i.i
equiv) in THF at room temperature to give the ~,fi-unsaturated ketone 20.
Reduction of 20 with sodium borohydride
(5 equiv) in methanol at -22°C gave the allyl alcohol 21~ ) The compound 21 was converted to the tetrahydropyranyl ether 2__22with dihydropyran in the presence of E-toluenesulfonic acid in methylene chloride and then treated with
908
MAY 1978 VOL. 15 NO. 5
PROSTAGLANDINS
anhydrous potassium carbonate
(1.2 equiv) in absolute
methanol at 45°C for 1 h to afford the alcohol 23. The intermediate 19 in route 3 is a stable and useful compound which can be transformed through the short steps to the A2-PG analogs containing various kinds of w-chains by the Wittig reaction with a variety of phosphonates or phosphoranes.
Route 1 OH
o
ot
OH
6THP
6THP
1 01-! ',
2
OH
OTttP
" OTHP
OTHP
3
OTttP
4
R=COOMe R=CHO
QH
'
0
( / ~ ' ~ C O
.-
OTHP
6THP
6
MAY 1978 VOL. 15 NO. 5
0THP
OMe
OTHP 7
909
PROSTAGLANDINS
Route 2
OH
~
QH
I
~
bTHP
6THP
OH
'
OTHP
OMe
8
Route 3 0
bTHP 9 R=H ID- R=~)Se
OH
,~OH
~j~,/OH
" OTHP
O'THP
ii
.•'•.__•-/•C H
O'THP
12
Oil
OOH
13
OR: ,,,~"-~OOMe 2
0THP
OTHP 16 I--7 1-~ i--9
14
R=H 1---~ R--¢~Se
OOMe
OMe
O 2O
910
R2=CH20H R2=CH2OAc R2=CH20H R2=CH0
OR l
0Ac
OTHP
RI=H, R:=Ac, RI=Ac, RI=Ac,
21
RI=Ac, R2=H RI=Ac, R2=THP RX=H, R2=THP MAY 1978 VOL. 15 NO. 5
PROSTAGLANDINS Table Compound
yield %
ir (liquid {ilm)
I. nmr
(CDC13)
C~1
72 from 7
3400, 1750, 1730, 1660.
3
48 from 2
1710
5.50(4H,m), 4.68(2H,m).
4
81 from 3
1710
5.30(2H,m), 4.60(2H,m), 3.60 (3H,s).
6 --
73 from 4 i00 from T0
1650
5.69(iH,d, J=16.0Hz), 3.66(3H, s).
7
85 from 6
9
90 from 8
I0
85 from 9
3460, 1738, 1580.
7.44(5H,m), 5.43(2H,m), 4.68 (2H,m), 3.61(3H,s).
14
82 from ii
3455, 1742.
4.70(iH,m), 3.65(3H,s).
15
65 from 14
1735, 1580.
7.45(5H,m), 4.75(iH,m),3.64 (3H,s).
16
i00 from 15
1725, 1655.
6.98(iH,dt), 5.77(iH,d), 3.68(3H,s).
18
60 from 16
1730, 1658.
6.98(iH,dt), 5.78(IH,d), 3.68 (3H,s), 2.02(3H,s).
19
95 from 18
2220, 1725 1655.
9.82(iH,m), 6.96(iH,dt), 5.78 (iH,d), 3.68(3H,s), 2.05(3H,s).
20
98 from 19
1740, 1690, 1660, 1625
6.94(3H,m), 5.78(iH,d), 5.12 (iH,m), 3.68(3H,s), 2.05(3H,s), 1.10(6H,s), 0.87(3H,t).
22
95 from 20
1735, 1660.
6.94(iH,dt), 5.70(3H,m), 5.10 (iH,m), 4.60(2H,m), 3.70(3H,s), 2.03(3H,s), 0.89(9H,m).
23
72 from 22
3480, 1735, 1660
6.95(iH,dt), 5.10(3H,m), 4.68 (2H,m), 3.70(3H,s).
1745, 1728, 1656. 1745
MAY 1978 VOL. 15 NO. 5
6.92(iH,dt, J=15.5Hz and 7Hz), 5.79(iH,d, J=15.5Hz), 5.85 and 5.37(2H,m), 3.71(3H,s).
6.85(iH,dt), 5.69(iH,d, J=16.0 Hz), 3.66(3H,s). 5.45(2H,m), 4.68(2H,m), 3.66 (3H,s).
911
PROSTAGLANDINS
R e f e r e n c e s and Notes i)
a) Oshima, K., K. Matsumoto, T. Tsuda, K. Shibata, and M. Hayashi, Prostaglandins, in press; b) Ninagawa, T., M. 0hta, T. Hiroshima, Y. Tomida, K. Itoh, N. Imoto, and R. Matsukawa, Proceedings of the First Inter-Congress on Obstetric and Gynaecological Uses of Prostaglandins at Singapore on April 27-30, 1975, vol. i, S. M. M. Karim, Ed., Eurasia Press, Singapore, pp55-66; c) Takagi, S., H. Sakata, T. Yoshiba, S. Nakazawa, K.T. Fujii, Y. Tominaga, Y. lwasa, T. Ninagawa, T. Hiroshima, Y. Tomida, K. Itoh, and R. Matsukawa, Prostaglandins, 14, 791 (1977).
2)
a) Corey, E.J., T.K. Schaaf, W. Huber, and N.M. Weinshenker, J. Am. Chem. Soc., 92, 397 (1970); b) Magerlein, B.J., D.W. DuCharme, W.E. Magee, W.L. Miller, A. Robert, and J.R. Weeks, Prostaglandins, 4, 143 (1973). Wakatsuka, tt., S. Kori, and M. H a y a s h i , P r o s t a g l a n dins, 8, 341 (1974). House, H.O., V.K. Jones, and G.A. Frank, J. Org. Chem., 29, 3327 (1964). Specific rotation (EtOH, c 0.985) [a]~5 _41.8o; homogeneous by tlc (two developments ~ith cyclohexane:AcOEt:THF 3:6:1, Rf 0.35). Sharpless, K.B., R.F. Lauer, and A.Y. Teranishi, J. Am. Chem. Soc., 95, 1637 (1973). Corey, E.J., H. Shirahama, H. Yamamoto, S. Terashima, A. Venkateswarlu, and T.K. Schaaf, J. Am. Chem. Soc., 93, 1491 (1971). C-15 epimer and a small amount o f 1 3 , 1 4 - d i h y d r o compound which was produced by over-reduction with sodium borohydride could be easily separated from _i at the final step by column chromatography on silica gel. Both of them are less polar than 2.
3) 4) 5)
6) 7)
8)
II. Wakatsuka, H. Miyake, S. Kori, and M. Hayashi ~ H. Suga, Y. Konishi,
Ono Pharmaceutical Co., Ltd., Research Institute, 3-1-i, Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618, Japan
912
MAY 1978 VOL. 15 NO. 5