- Email: [email protected]
Synthesis of (±)-16-thioketal and 16-keto prostaglandins
PROSTAGLANDINS
Synthesis
of
(+_)-16-Thioketal
Wenling Wyeth Laboratories,
Rae
and 16-Veto
and Richard
Inc.,
Prostaglandins
W. Rees
Radnor,
Pennsylvania
19101
ABSTRACT
ester
The synthesis (11 and lJ)
of (+)-16-thioketal is herein described.
and 16-keto
PC%2 methyl
INTRODUCTION Studies have indicated that the first step in the metabolism of PCR and PCF prostaglandins is oxidation of the C-15 hydroxyl group by prostaglandin dehydr0genase.l This metabolism can be retarded by introduction of an alkyl substituent at the C-15 posltion as exemplified by 15-methyl prostaglandin.2 Moreover introduction of substituents at c-16 has also been shown to have a The most similar effect on the metabolism of prostaglandins. prominent compound in this series is 16,16-dimethyl prostaglandin E .3 Other substituents such as 16-methylene,4 16-ethano4 and 1z -methyl5 have also been employed effectively in this regard, but no report on the effect of 16-dithialkyl or 16-0~0 had appeared at the outset of this work. fter completion of this work a patent the synthesis and by Cno Pharmaceutical Co. % appeared describing biological activity of 16-thioketal prostaglandin E2 methyl ester This report and 16-keto dihydroprostaglandin El methyl ester. prompted us to publish our synthesis of (+)-16-thioketal and 16-keto prostaglandins. METHODSAND PREPARATIONS Treatment7 of the 1,3-dithiane (1) in tetrahydrofuran at -20’ with one equivalent of H-butyl lithium, followed by addition of 1-bromo-H-butane, g ave the H-butyldithianes (2) 180%; oil; b.p. 70-‘72°/o.05 axa; nmr (CDC13) 6 4.30 (lli, t, H- E-S), 2.94-2.77 .9 The 3,3-trlmethylenedithlo-heptan-2-01 (3) (4H, m, -(X2-S-)] was obtained by treating the lithio derivative of the 2-butyldithiane (2 with acetaldehyde [60$; oil, b.p. llO-ll2”/0.1 wm; ir 3400 Cm’ nmr (CDC13) 6 4.24 (lH, q, H-C-OH); s/e 220 (&)I, 1
SEPTEMBER
j
1978 VOL. 16 NO. 3
461
PROSTAGLANDINS
The alcohol (3) was oxidized at 250 with modified Collins reagent10 t; the methyl ketone (A) [57$; oil; b-p. 95-97“/0.1 m; . nmr (mc13) 6 2.35 (3H s Ca3-C-)I, which was :~y:~~~d~ with ethylformate to the ;-&to aldeh de (5) [92$* oil; ir 1730, 1690, 1625, 1580 cm’ 1; x/e 247 (~J)121. Rea&ion of the hydroxymethylene form of (5) with triphenylphosphine dibromidel3 at 250 led to the trans14-l-bromo-vinyl ketone (6) [58$;
oil;
ir
1690,
1585 cm-l;
UV e
244 w
(s 8,900);
a&
252,
254 (1:l ratio) (e-C4H8)]. Reduction of the enone (6) with sodium borohydride in methanol at 25” afforded the allylic alcohol (1) at 250 with trimethyl[65$; oil; ir 3470 cm-11, which was silylated chlorosilane and Fmidazol to the silyl derivative (& [52$j oil; ir 1250, 1090, 845 cm-l; nmr (CDCl ) 6 6.56 (dd, J-14, 7 Hz, -C=cH-C-O-), 6.30 (d, J=14 HZ, Br- SH=C-), 4.40 (d, 517, Hz, H-C-O); m/e 367 (* -CH3) 1.
The side chain (8 was added in a conjugate manner via lithium copper complex 15 to the cyclopentenone16 (a). In analogy to previous findings, l7 an all trans configuration at the cyclopentane ring was assumed for the addition product, which then resulted in a mixture of two C-15 epimeric racemates (u) [51$; oil; ir 1730 cm’li nmr (CDC13) 6 5.80 (2H, m, 13 h 14-H), 5.40 (2H, m, 5 & 6-H), 4.68 (lH, m, -O-CH-0-), 4.40 (lH, d, 435 ( 3.64 (3H, s, COoCH3)j x/e 537 (@-trimethylsilol), methylsilol-tetrahydropyranol)]. Removal of the hydroxyl protecting groups of (Is) with 6t$ aqueous acetic acid at 40” for three hours gave the (+_)-16-thioketal PCR2 methyl ester (11) and its C-15 epimer (l2) after chromatographic separation. It was not possible to determine the stereochemistry of (2) and (12) at C-15 by spectroscopy, and we had to resort to chromatographic mobilities. The less mobile (11) [32$; oil; ir 3500, 1755 cm’li nmr (CDC13) 8 5.88 (2H, m, 13 & 14-H), 5.40 (2H, m, 5 6r 6-H), 4.57 (lH, d, 15-H), 4.09 (lH, q, 11-H); rde 453 (e-2H2C), 435 was assigned the 15a-configuration (m-2H20), 175 (95g2)1 and the more mobile1 (12) was assigned the 15B-configuration in analogy to investigations by others.l7 The (+,) 16-keto pGE2 methyl esters (u) and (l4) were obtained from the epimeric mixture (x) by treatment with silver nitrat&chlorosuccinimidelg for one hour at 250 followed by aqueous acetic acid hydrolysis. The resulting C-15 epimers were separated into their 15a compound, l7 the more polar (u) [16$; ir 3450, 1750 cm-l; ~;~(rl ; ; 5.80 (2H, m, 13 & 14-H), 5.35 (2H, m, 5 6~ 6-H), z, 15-H), 4.l2 (lH, q, 11-H), . =6? ,“,;F3); n/e 381 (W)] and into their 15~ compound, %?;hL3Fes,’ (l.4) by column chrometography. The thioketals (11) and (l2) showed little, glandin effects on platelet aggregation, gastric bronchial smooth muscle, or blood pressure.
462
if any prostaacid secretion,
SEPTEMBER
1978 VOL. 16 NO. 3
(1) R,=R2=H
(&I x=0
(1) R,=H; R2=C,+Hs
(2)
(r, R,=CH3-S;l; R2=CkH9
(g) X=OSi(CH3)3
(4) R,=CH$;
X=OH
R2=CkHs -: R2=C4H9
(2) R,=OCH-CH26
HO"\ OH (E)
SEPTEMBER
1978 VOL. 16 NO. 3
463
PROSTAGLANDINS
The 16-keto prostaglandinmethyl ester (a) had a blood pressure depressor effect similar to prostaglandin E2, but had only about l$ of the activity of the parent E2 towards inhibiting acetylcholine-inducedbronchoconstrictionin the guinea pig testing. Whereas the ls-&-16-ketone (l4) showed little effect on bronchial smooth muscle and gastric acid secretion, it did have a blood pressure depressor effect (lC$ E2) and a platelet aggregation inhibiting effect (lU$ El).
ACKNOWLEDGEMENT The authors wish to thank Dr. D. P. Strike for encouragement during the study. We are grateful to Drs. T. Baum, R. Fenichel, M. Rosenthale and D. Shriver for providing us with the biological data.
REFERENCES AND NOTES 1.
B. Samuelsson, E. Granstrb;m,K. Green and M. Eamberg, a. N.Y. Acad. s., 180. 138 (1971).
2.
G. Bundy, F. Lincoln, N. Nelson, .I.Pike and W. Schneider, Ann. N.Y. Acad. S&., l&, 76 (1971). -
3.
B.J. Magerlein, D.W. DuCharme, W.E. Magee, W.L. Miller, A. Robert and J.R. Weeks, Prostaalandins,4, 143 (1973).
4.
H. Miyake, S. Iguchi, S. Kori and M. Hayashi, Chemistry
Letters, 211 (1976). 5.
M. Eayashi, H. Miyake, T. Tanouchi, S. Iguchi, Y. Iguchi and F. Tanouchi, J. a. m., & 1250 (1973).
6.
German Patent 26 05 584 (Oct. 1976), appearing after the completion of our studies, reports a different synthesis of 16-thioketal PGE2 methyl ester (2) and 16-keto dihydro PGBl methyl ester.
7.
E.J. Corey and D. Seebach, Annew. Chim., Internat. Edit, 4
1075 8.
464
(1965).
W.D. Woessner and R.A. Ellison, Tetrahedron Letters, 3735 (1972).
SEPTEMBER
1978 VOL. 16 NO. 3
PROSTAGLANDINS
9.
(a) All compounds reported have spectral and analytical data consistent with their assigned structures. (b) The yields of the products reported are for analytically pure compounds. (c) No effort was made to maximize the yields.
10.
R. Ratcliffe
11.
F.W. Swamer and C. R. Hauser,
12.
Mass spectral
13.
E. Piers
14.
W.R.
15.
E. J. Corey
16.
L. Gruber, I. Tdmb’skb’zi, Letters, 3729 (1974).
17.
and R. Rodehorst,
data
and I.
resulted
Nagakura,
2.
m.
&.
w., m.
m.,
from chemical Svnthetic
s,
4000 z,
(1970).
1352 (1950).
ionization.
Conraunications,
5 193
(1975). Benson and A.E. and D. J.
Pohland,
J.
Beames, 2.
a.
4.
m., m.
E. Major
29, &.,
385
54,
and G. Kovks,
(1964).
7210
(1972).
Tetrahedron
(a) P.W. Collins, E.Z. Dajani, M.S. Bruhn, C.H. Brown, J.R. Palmer and R. Pappo, Tetrahedron Letters 4217 (1975). (b) C. J. Sib, R.G. Salomon, P. Price, R. Sood and G. Peruzzotti, 857 (1975). (c) J.G. Miller, W. Kurz, 2. &. m. *. , z K.G. Untch and G. Stork, J. &. Qg~n. &. , s 6774 (1974). (d) C. J. Sib, J.B. Heather, G.P. Peruzzotti, P. Price, R. Sood and L. F.H. Lee, 2. &. &J& a., & 1676 ( 1973). spectral data of to and not noticeably epimer.
18. The
lg.
J.
E.J.
Corey
SEPTEMBER
the more mobile epimer are very similar different from those of the less mobile
and B.W. Erickson,
1978 VOL. 16 NO. 3
2.
&g.
m.,
36
3553 ( 1971) *
465
Synthesis
of
(+_)-16-Thioketal
Wenling Wyeth Laboratories,
Rae
and 16-Veto
and Richard
Inc.,
Prostaglandins
W. Rees
Radnor,
Pennsylvania
19101
ABSTRACT
ester
The synthesis (11 and lJ)
of (+)-16-thioketal is herein described.
and 16-keto
PC%2 methyl
INTRODUCTION Studies have indicated that the first step in the metabolism of PCR and PCF prostaglandins is oxidation of the C-15 hydroxyl group by prostaglandin dehydr0genase.l This metabolism can be retarded by introduction of an alkyl substituent at the C-15 posltion as exemplified by 15-methyl prostaglandin.2 Moreover introduction of substituents at c-16 has also been shown to have a The most similar effect on the metabolism of prostaglandins. prominent compound in this series is 16,16-dimethyl prostaglandin E .3 Other substituents such as 16-methylene,4 16-ethano4 and 1z -methyl5 have also been employed effectively in this regard, but no report on the effect of 16-dithialkyl or 16-0~0 had appeared at the outset of this work. fter completion of this work a patent the synthesis and by Cno Pharmaceutical Co. % appeared describing biological activity of 16-thioketal prostaglandin E2 methyl ester This report and 16-keto dihydroprostaglandin El methyl ester. prompted us to publish our synthesis of (+)-16-thioketal and 16-keto prostaglandins. METHODSAND PREPARATIONS Treatment7 of the 1,3-dithiane (1) in tetrahydrofuran at -20’ with one equivalent of H-butyl lithium, followed by addition of 1-bromo-H-butane, g ave the H-butyldithianes (2) 180%; oil; b.p. 70-‘72°/o.05 axa; nmr (CDC13) 6 4.30 (lli, t, H- E-S), 2.94-2.77 .9 The 3,3-trlmethylenedithlo-heptan-2-01 (3) (4H, m, -(X2-S-)] was obtained by treating the lithio derivative of the 2-butyldithiane (2 with acetaldehyde [60$; oil, b.p. llO-ll2”/0.1 wm; ir 3400 Cm’ nmr (CDC13) 6 4.24 (lH, q, H-C-OH); s/e 220 (&)I, 1
SEPTEMBER
j
1978 VOL. 16 NO. 3
461
PROSTAGLANDINS
The alcohol (3) was oxidized at 250 with modified Collins reagent10 t; the methyl ketone (A) [57$; oil; b-p. 95-97“/0.1 m; . nmr (mc13) 6 2.35 (3H s Ca3-C-)I, which was :~y:~~~d~ with ethylformate to the ;-&to aldeh de (5) [92$* oil; ir 1730, 1690, 1625, 1580 cm’ 1; x/e 247 (~J)121. Rea&ion of the hydroxymethylene form of (5) with triphenylphosphine dibromidel3 at 250 led to the trans14-l-bromo-vinyl ketone (6) [58$;
oil;
ir
1690,
1585 cm-l;
UV e
244 w
(s 8,900);
a&
252,
254 (1:l ratio) (e-C4H8)]. Reduction of the enone (6) with sodium borohydride in methanol at 25” afforded the allylic alcohol (1) at 250 with trimethyl[65$; oil; ir 3470 cm-11, which was silylated chlorosilane and Fmidazol to the silyl derivative (& [52$j oil; ir 1250, 1090, 845 cm-l; nmr (CDCl ) 6 6.56 (dd, J-14, 7 Hz, -C=cH-C-O-), 6.30 (d, J=14 HZ, Br- SH=C-), 4.40 (d, 517, Hz, H-C-O); m/e 367 (* -CH3) 1.
The side chain (8 was added in a conjugate manner via lithium copper complex 15 to the cyclopentenone16 (a). In analogy to previous findings, l7 an all trans configuration at the cyclopentane ring was assumed for the addition product, which then resulted in a mixture of two C-15 epimeric racemates (u) [51$; oil; ir 1730 cm’li nmr (CDC13) 6 5.80 (2H, m, 13 h 14-H), 5.40 (2H, m, 5 & 6-H), 4.68 (lH, m, -O-CH-0-), 4.40 (lH, d, 435 ( 3.64 (3H, s, COoCH3)j x/e 537 (@-trimethylsilol), methylsilol-tetrahydropyranol)]. Removal of the hydroxyl protecting groups of (Is) with 6t$ aqueous acetic acid at 40” for three hours gave the (+_)-16-thioketal PCR2 methyl ester (11) and its C-15 epimer (l2) after chromatographic separation. It was not possible to determine the stereochemistry of (2) and (12) at C-15 by spectroscopy, and we had to resort to chromatographic mobilities. The less mobile (11) [32$; oil; ir 3500, 1755 cm’li nmr (CDC13) 8 5.88 (2H, m, 13 & 14-H), 5.40 (2H, m, 5 6r 6-H), 4.57 (lH, d, 15-H), 4.09 (lH, q, 11-H); rde 453 (e-2H2C), 435 was assigned the 15a-configuration (m-2H20), 175 (95g2)1 and the more mobile1 (12) was assigned the 15B-configuration in analogy to investigations by others.l7 The (+,) 16-keto pGE2 methyl esters (u) and (l4) were obtained from the epimeric mixture (x) by treatment with silver nitrat&chlorosuccinimidelg for one hour at 250 followed by aqueous acetic acid hydrolysis. The resulting C-15 epimers were separated into their 15a compound, l7 the more polar (u) [16$; ir 3450, 1750 cm-l; ~;~(rl ; ; 5.80 (2H, m, 13 & 14-H), 5.35 (2H, m, 5 6~ 6-H), z, 15-H), 4.l2 (lH, q, 11-H), . =6? ,“,;F3); n/e 381 (W)] and into their 15~ compound, %?;hL3Fes,’ (l.4) by column chrometography. The thioketals (11) and (l2) showed little, glandin effects on platelet aggregation, gastric bronchial smooth muscle, or blood pressure.
462
if any prostaacid secretion,
SEPTEMBER
1978 VOL. 16 NO. 3
(1) R,=R2=H
(&I x=0
(1) R,=H; R2=C,+Hs
(2)
(r, R,=CH3-S;l; R2=CkH9
(g) X=OSi(CH3)3
(4) R,=CH$;
X=OH
R2=CkHs -: R2=C4H9
(2) R,=OCH-CH26
HO"\ OH (E)
SEPTEMBER
1978 VOL. 16 NO. 3
463
PROSTAGLANDINS
The 16-keto prostaglandinmethyl ester (a) had a blood pressure depressor effect similar to prostaglandin E2, but had only about l$ of the activity of the parent E2 towards inhibiting acetylcholine-inducedbronchoconstrictionin the guinea pig testing. Whereas the ls-&-16-ketone (l4) showed little effect on bronchial smooth muscle and gastric acid secretion, it did have a blood pressure depressor effect (lC$ E2) and a platelet aggregation inhibiting effect (lU$ El).
ACKNOWLEDGEMENT The authors wish to thank Dr. D. P. Strike for encouragement during the study. We are grateful to Drs. T. Baum, R. Fenichel, M. Rosenthale and D. Shriver for providing us with the biological data.
REFERENCES AND NOTES 1.
B. Samuelsson, E. Granstrb;m,K. Green and M. Eamberg, a. N.Y. Acad. s., 180. 138 (1971).
2.
G. Bundy, F. Lincoln, N. Nelson, .I.Pike and W. Schneider, Ann. N.Y. Acad. S&., l&, 76 (1971). -
3.
B.J. Magerlein, D.W. DuCharme, W.E. Magee, W.L. Miller, A. Robert and J.R. Weeks, Prostaalandins,4, 143 (1973).
4.
H. Miyake, S. Iguchi, S. Kori and M. Hayashi, Chemistry
Letters, 211 (1976). 5.
M. Eayashi, H. Miyake, T. Tanouchi, S. Iguchi, Y. Iguchi and F. Tanouchi, J. a. m., & 1250 (1973).
6.
German Patent 26 05 584 (Oct. 1976), appearing after the completion of our studies, reports a different synthesis of 16-thioketal PGE2 methyl ester (2) and 16-keto dihydro PGBl methyl ester.
7.
E.J. Corey and D. Seebach, Annew. Chim., Internat. Edit, 4
1075 8.
464
(1965).
W.D. Woessner and R.A. Ellison, Tetrahedron Letters, 3735 (1972).
SEPTEMBER
1978 VOL. 16 NO. 3
PROSTAGLANDINS
9.
(a) All compounds reported have spectral and analytical data consistent with their assigned structures. (b) The yields of the products reported are for analytically pure compounds. (c) No effort was made to maximize the yields.
10.
R. Ratcliffe
11.
F.W. Swamer and C. R. Hauser,
12.
Mass spectral
13.
E. Piers
14.
W.R.
15.
E. J. Corey
16.
L. Gruber, I. Tdmb’skb’zi, Letters, 3729 (1974).
17.
and R. Rodehorst,
data
and I.
resulted
Nagakura,
2.
m.
&.
w., m.
m.,
from chemical Svnthetic
s,
4000 z,
(1970).
1352 (1950).
ionization.
Conraunications,
5 193
(1975). Benson and A.E. and D. J.
Pohland,
J.
Beames, 2.
a.
4.
m., m.
E. Major
29, &.,
385
54,
and G. Kovks,
(1964).
7210
(1972).
Tetrahedron
(a) P.W. Collins, E.Z. Dajani, M.S. Bruhn, C.H. Brown, J.R. Palmer and R. Pappo, Tetrahedron Letters 4217 (1975). (b) C. J. Sib, R.G. Salomon, P. Price, R. Sood and G. Peruzzotti, 857 (1975). (c) J.G. Miller, W. Kurz, 2. &. m. *. , z K.G. Untch and G. Stork, J. &. Qg~n. &. , s 6774 (1974). (d) C. J. Sib, J.B. Heather, G.P. Peruzzotti, P. Price, R. Sood and L. F.H. Lee, 2. &. &J& a., & 1676 ( 1973). spectral data of to and not noticeably epimer.
18. The
lg.
J.
E.J.
Corey
SEPTEMBER
the more mobile epimer are very similar different from those of the less mobile
and B.W. Erickson,
1978 VOL. 16 NO. 3
2.
&g.
m.,
36
3553 ( 1971) *
465