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Prostaglandins II : 8,12-diiso-PGE2 (ent-11, 15-epi-PGE2)
Press. TetrahedronLetters ITO.42, pP 4505 - 4506, 19-P. Pergamon
Printed in Great Britain.
PROSTAGLANDINSII : 8,12-DIISO-PGE2 (ent-ll,lS-WI-PGE2)
Carmelo Candolfi,GisnfedericoDoria and Pietro Gaio IstitutoRicercheltCarloFMa"
Via Inbonati,24
201.59Milan
(Receivedin DK 6 September1972; accepted for publication15 September1972) The inversionof configurationat C-4 (C-11 in prostaglandinnumbering)performedeither on -acetic acid (I), by-productof Co_ the resolved (-)1( hydroxy-.%a-methoxvmethvl-cvclonent-2-en-1 B ?1 rey synthesisof natural prostnclandins or on its relatedDerivativesmakes them suitableinteE mediatesfor the total synthesisof opticallyactive ent-ll,lS-epi-prostaglandins. 0
“”
OH 1
i
OH
OH
ent-ll,l5-epi-PG!? 1
!!
293 that pure ent-11,15_ Gur interestin these unnaturalcompoundsarose from the observations appears to be at least as potent as nat-PGE, on rat uterus and epi-PGEl, A, 4[ent-PG(Efp)I]5 far more potent on other tissue preparationsand
its
de.gradation rste should be only 1% of the
rate of nat-PGE,.In this way, two aims can be achieved : 5) resistenceto effect of dehydrogenase, a) modificationof biolodcal properties. 6 A recent Darer , regardingto inversionof configurationat G4 in dl-S~bensyloxymethyl-2c(,&-dihydroxy-cvclopentan*lU-acetic acid-(1'42) -1actone , ,B, to obtain ll-epi-prostaglz$ Y dins, prompts us to report our experimentalresults on the synthesisof opticallypure 8,12-d.iiso -PGE2 ~-PG(E~~)$ An aqueous solutionof the &-ephedrine7salt1 of the (-)Sa-methoxym&hyl -4/l-hydroxy-cyclg pent-2-en-1 (2')aceticacid (I) was treated for 12 hr at r.t. with 2 equiv of aqueouspotassium B 8 triiodidesolutionto form the iodolactoneIIa in 96% field, as a colorlessoil,/a/D=+45.S" . 74.5-760/M/D =+18.5°(r~.97) was then convertedwith tributyltin Its ncct-tc, TIb , 111.17.
4304
No. 42
hydride9at 55O for 3 hr into the lactone acetate,IIc,acolorlessoil, /U/D= +74.3°1c=1.51)
in
90% yield after chromatographic purification.Selectivecleavageof the acetate IIc by perchloric acid in methanol,for ~a.3 hr, gave the hydroxylactoneIId , oil ,/m/D=+22.5O(c=l.35). The same compoundIId was directlyobtained from IIa by reductioneither with tributyl tin 10,ll hydride or with chromousacetate in dimethylsulfoxide in the presenceof ethanethiol Treatmentof the (+)hydroxylactone, III , in pyridineat 2S" with p-toluensulfonylchloride (1.25 equiv) for 20 hr affordedthe tosylateIIe,m.p. 102-103°,/o(/D=+56.10. The reaction of this compoundwith potassiumacetate and acetic acid (8 equiv) in dimethylformamideat reflux temperatureyielded a mixture of the invertedaceta.te,IIIb,m.a. 8688c(from =1B"(c==C.82)and of cyclopent-3-ene derivative,IVa,m.p.47-4A"(from hexane),/a/Da-12.90,/a/3650 hexane),/U/I,= -256*,/01/~6~c= -811.4°(~=0.5),N.M.R. : 5.996(2H,m, Cs and C1 vinylic protons),5.15 6(1H,m,C2 proton near to oxygen),resulting from eliminationreactionin a ratio of 84 : 16. Several attemptsto convertthe 5c(-methoxymethylether IIIb into the 5d-hydroxymethyl-4a-acetoxy-lactoneIIId failed: in fact,BRr cleavageof IIIb gave a dial derivativein poor yield,and 3
the treatmentof the same IIIb with iodine and sodium borohydridein carbon tetrachloride l2 af-28,3O,fromwhich the followinsreac forded the iodomethyl derivativeIIIc, m.p. 102-1030,/~/D= tion with notassiumacetatein dimethylformamide led to hexocyclicmethylenecompound,IIIe,oil, 13 as the only product . On the contrary,in methylenechlorideat O",BRr3-cleavageof the .5c+methoxymethvletherdk14 -p-toluenesulfonate,IIe,easilv affordedthe 5a-hvdrcuvmethyl-4~-p-toluenesulfonate,IIf,m.p.77 -7B0,/diD=
+54.8o,/d365,,=
+177O,
from which,by inversionat C-4 with potassiumacetate in dime-
thylformamide,a mixture of the 5a-hydroxymethylcyclopent-.l-ene derivative,IVb ,oil,/U/Da217°, /o/365% -76j0,TR : 1765 cm-'( carhonylTactone),Th0Ccm-'(doublebond), and of the exoocted Tc+ hydroxymethyl-4ti-acetoxylactone,IIId,m.p. 165-T66,5°,/~/D=+46.50,/a/3h50=+1660, was obtained. Unfortunately,it was impossibleto ohtain an aldehydiccompoundfrom IIId either with a mo16 15 dified Collinsprocedure or with Moffatt'sreagent . However,the use of the o-nhenplhenznate esters allowed 115to overcomeall these difficulti*?. Selectivecleavageof the acetate IJIb with HCTO in nethnnolat ?.5Ofcr 4 hr nave the irver 4 ted (-)4a-hydroxy-5c+methoxymethyl ether-TnctoneTTTa,differingfirst of all,fromthe (+)-!a-hydrop epimer IId for being a solid,m.n.lC5-lD6°,/Q/D=-:~.60,/~/365,,=+120(c~.92). Esterificationof IIIa with n-phenylben;ovlchloricii: (1.5 ecuiv) in ryridine for 2 dnvs at IIIf,m.p.81-82~,/~/'D~ -76.50,fromwhich,by BBr.-clenvapein r.t. affordedthe r-phenylbenzoate 3 methylenachloridefor 15 min at Oo,the 5u-hydroxvmethyl-lactone-4a-p-phenvlheoate,TTIe, m.r. 145-1460,/U/D= -30.S0 was obtained. 15 By oxidationof the alcohol TIIg with the Collinsrencent the p-nhenylbrnzoate aldehyde , = -16.7O was obtnined,which was treatedwith the sodium derivative IIIi,m.n. 148-1490(dec.),/o(/ D
No. 42
4305
0
0 0
X--
I
*
c9
d
‘- R
“CH2DR
:P
OP
TT P b c d
e f
X T 1 H HH H H
? H AC
R & Ele
AC
ble
III P b c a e f
Me 'rosy1 Ile Tosvl H
s i 1
P H
R CH2lMe
E AC AC PR PB PB PB
Yk CH2OH XH CH20 M2 e CH OH CH6 'cH2
PR = p-nhenylbenzoate
P
b_COOH
h!
X TI
H 'OH =c
XII
,>fdinc+hl,l-l-ore-hppt~rlnhosohonate in benzene to form the a-enone-lactone Line product, m.n.. lk-113°(from
ether),/o(/D=-196°,/01/365d
The followin,e sten,Ln(BH4)2 reduction in ethc~imetho~ethRllr(~:l),
’ 51;.:?A ’ W evi-rra,showin.; -1vvt
tFn P.-:-Pchrc-qtovr,??hi
V , as a crystal-
-928O,with 60% yield from NC.
c r:obil i ty.
afforded a mixture of
4306
k.
42
After several fractionatedcrystallizations from isopropylether,theless polar 15Ijeoimer, -152o;thereafter from the mother VIb,couIdbe obtainedas a pure compound,m.p. l4l-142o,/o1/D= Liquors,by chromatography on Si02 (ethyl ether-isopropyl ether 1:l as eluent),the 1% epimer, Via , m.p. 9C-910,/U/D=-154e was recovered. Using a well known procedure17: i) saponificationto the dial-lactoneaVIIa (m.p. 79-810,
/a/,,= -36")and VIIb (m.p. 78-79O,/U/ = -57“);ii) conversionto the related THP-ethersVIIIa (oil,/d/=-86O)and VIIIb (oil&D=
f3.5“) ; iii) diisobutylaluminum hydride reductionto the
lactols IXa (oil,/U/D=-75O) and IXb (oil,/ti/D-=+15.5") were performed. Condensationof IXa with the Wittig reagent derived from triphenylphosphoniopentanoic acid and NaH in DWO affordedthe 5-cis-13-tr.ans-8,12_diiso-9 lla,l5S_trihydroxy_prostadienoic acid _Py ll,&bis-THP-ether, Xa ,(oil,/a/D=-lOlO).Oxidationof Xa to XIa,followadby acetone-O.11oxalic acid treatmentprovidedpure 8,12-diiso-PGE2 ent-PC(Epp)2,XIIa,nil,/o(/D= +33.20,/U/ =+323O 36S" [ (c= 1% ethanol).In similarway from IXb we preparedthe d,12-diiso-l%PGE2, XIIb , oil,/ti/ = D +270° (~0.3% in ethanol.). +22oa/u/365o Ezperimental:UnIess othezwisestated, specificrotationswere measuredin CHCl solution (c=l%) at 200, with a P-141 Perkin-Rlmerpolarimeter.N.M.R.spectrawere recordedon a Varian HA-100 (100 l#iz)spectrometerin CDC13 with TMS as internalreference(s = 0.0). Acknowladgmentslhe authors are gratefulto Dr. E.Dradi for N.M.R. analysis,and wish to express their thanks to Mr. A. Andreoniand Mr. W. Moretti for their valuableassistance.
Referencesand footnotes
and N.M.Weinshenker,J.A.Chem.Soc.&,397 (1970) 1) E.J.Corey,T.K.Schaaf,W.Huber,U.Koelliker and F.J.Corey,Exoerientia,26,355 (1970) 2) H.Shio,P.W.Ramwell,N.H.Andersen and NJLAndersen,Nature,221,1251 (1969) 3) P.W.Ramwell,J.E.Shaw,E.J.Corey and M.Casey,J.Amer.Chem.Soc.,&3643(1972) 4) J.Sih,P.Price,R.Sood~R.G.Salomon,G.Peruzzotti Res.,lO,316(1969) 5) N.H.Andersen,J.Liuid Letters,111(1972) 6) E.J.Coreyand Shiro Terashima,Tetrahedron 71 Knoll A.C. Ludwigshafenam Rhein. 8) Satisfactoryanalytical,IRand NMR data have been obtainedfor this and followingcompounds, and V.K.Jones,J.Org&hem.,~2519 (196.5) 9) H.O.House,S.G.Boots and M..N.Pechet,J.Amer.Cbem.Soc.,88,3016 (1966) 10)D.H.R.Barton,N,K.Basu,R.H.Hesse,F.S.Morehouse and H.J.K.Loewenthal,J.Org.Chem.,&l26 (1969) 11) H.D.Bachi,Y.W.@stein,Y.Herzberg-Minzly 12)G.Odham and B.Samuelsen,ActaChem>cand.,2&468 (1970) : m-p. 16+l?1°,/~/=-1340. 13) This compoundwas characterizedas 4-p-phenylbenzoate 14)For use of boron trichlorideto effect demethylationof a methyletherwitRout cleavageof P tosyl ester group, see S.D.Qro,TetrahedronLetters,591(i%6) (1970) 15)R.RactIiffeand R.Rodehorst,J.Ors.Chem.,&&4COO (1965) 16)K.E.Pfnitznerand J.G.Moffatt,J.Amer.Chem.Soc.,~5670 and W.Huber,J.Amer.Chem.Soc.,gl,5675 (1969) 17) E.J.Corey,N.M.Weinshenker,T.K.Schaaf
Printed in Great Britain.
PROSTAGLANDINSII : 8,12-DIISO-PGE2 (ent-ll,lS-WI-PGE2)
Carmelo Candolfi,GisnfedericoDoria and Pietro Gaio IstitutoRicercheltCarloFMa"
Via Inbonati,24
201.59Milan
(Receivedin DK 6 September1972; accepted for publication15 September1972) The inversionof configurationat C-4 (C-11 in prostaglandinnumbering)performedeither on -acetic acid (I), by-productof Co_ the resolved (-)1( hydroxy-.%a-methoxvmethvl-cvclonent-2-en-1 B ?1 rey synthesisof natural prostnclandins or on its relatedDerivativesmakes them suitableinteE mediatesfor the total synthesisof opticallyactive ent-ll,lS-epi-prostaglandins. 0
“”
OH 1
i
OH
OH
ent-ll,l5-epi-PG!? 1
!!
293 that pure ent-11,15_ Gur interestin these unnaturalcompoundsarose from the observations appears to be at least as potent as nat-PGE, on rat uterus and epi-PGEl, A, 4[ent-PG(Efp)I]5 far more potent on other tissue preparationsand
its
de.gradation rste should be only 1% of the
rate of nat-PGE,.In this way, two aims can be achieved : 5) resistenceto effect of dehydrogenase, a) modificationof biolodcal properties. 6 A recent Darer , regardingto inversionof configurationat G4 in dl-S~bensyloxymethyl-2c(,&-dihydroxy-cvclopentan*lU-acetic acid-(1'42) -1actone , ,B, to obtain ll-epi-prostaglz$ Y dins, prompts us to report our experimentalresults on the synthesisof opticallypure 8,12-d.iiso -PGE2 ~-PG(E~~)$ An aqueous solutionof the &-ephedrine7salt1 of the (-)Sa-methoxym&hyl -4/l-hydroxy-cyclg pent-2-en-1 (2')aceticacid (I) was treated for 12 hr at r.t. with 2 equiv of aqueouspotassium B 8 triiodidesolutionto form the iodolactoneIIa in 96% field, as a colorlessoil,/a/D=+45.S" . 74.5-760/M/D =+18.5°(r~.97) was then convertedwith tributyltin Its ncct-tc, TIb , 111.17.
4304
No. 42
hydride9at 55O for 3 hr into the lactone acetate,IIc,acolorlessoil, /U/D= +74.3°1c=1.51)
in
90% yield after chromatographic purification.Selectivecleavageof the acetate IIc by perchloric acid in methanol,for ~a.3 hr, gave the hydroxylactoneIId , oil ,/m/D=+22.5O(c=l.35). The same compoundIId was directlyobtained from IIa by reductioneither with tributyl tin 10,ll hydride or with chromousacetate in dimethylsulfoxide in the presenceof ethanethiol Treatmentof the (+)hydroxylactone, III , in pyridineat 2S" with p-toluensulfonylchloride (1.25 equiv) for 20 hr affordedthe tosylateIIe,m.p. 102-103°,/o(/D=+56.10. The reaction of this compoundwith potassiumacetate and acetic acid (8 equiv) in dimethylformamideat reflux temperatureyielded a mixture of the invertedaceta.te,IIIb,m.a. 8688c(from =1B"(c==C.82)and of cyclopent-3-ene derivative,IVa,m.p.47-4A"(from hexane),/a/Da-12.90,/a/3650 hexane),/U/I,= -256*,/01/~6~c= -811.4°(~=0.5),N.M.R. : 5.996(2H,m, Cs and C1 vinylic protons),5.15 6(1H,m,C2 proton near to oxygen),resulting from eliminationreactionin a ratio of 84 : 16. Several attemptsto convertthe 5c(-methoxymethylether IIIb into the 5d-hydroxymethyl-4a-acetoxy-lactoneIIId failed: in fact,BRr cleavageof IIIb gave a dial derivativein poor yield,and 3
the treatmentof the same IIIb with iodine and sodium borohydridein carbon tetrachloride l2 af-28,3O,fromwhich the followinsreac forded the iodomethyl derivativeIIIc, m.p. 102-1030,/~/D= tion with notassiumacetatein dimethylformamide led to hexocyclicmethylenecompound,IIIe,oil, 13 as the only product . On the contrary,in methylenechlorideat O",BRr3-cleavageof the .5c+methoxymethvletherdk14 -p-toluenesulfonate,IIe,easilv affordedthe 5a-hvdrcuvmethyl-4~-p-toluenesulfonate,IIf,m.p.77 -7B0,/diD=
+54.8o,/d365,,=
+177O,
from which,by inversionat C-4 with potassiumacetate in dime-
thylformamide,a mixture of the 5a-hydroxymethylcyclopent-.l-ene derivative,IVb ,oil,/U/Da217°, /o/365% -76j0,TR : 1765 cm-'( carhonylTactone),Th0Ccm-'(doublebond), and of the exoocted Tc+ hydroxymethyl-4ti-acetoxylactone,IIId,m.p. 165-T66,5°,/~/D=+46.50,/a/3h50=+1660, was obtained. Unfortunately,it was impossibleto ohtain an aldehydiccompoundfrom IIId either with a mo16 15 dified Collinsprocedure or with Moffatt'sreagent . However,the use of the o-nhenplhenznate esters allowed 115to overcomeall these difficulti*?. Selectivecleavageof the acetate IJIb with HCTO in nethnnolat ?.5Ofcr 4 hr nave the irver 4 ted (-)4a-hydroxy-5c+methoxymethyl ether-TnctoneTTTa,differingfirst of all,fromthe (+)-!a-hydrop epimer IId for being a solid,m.n.lC5-lD6°,/Q/D=-:~.60,/~/365,,=+120(c~.92). Esterificationof IIIa with n-phenylben;ovlchloricii: (1.5 ecuiv) in ryridine for 2 dnvs at IIIf,m.p.81-82~,/~/'D~ -76.50,fromwhich,by BBr.-clenvapein r.t. affordedthe r-phenylbenzoate 3 methylenachloridefor 15 min at Oo,the 5u-hydroxvmethyl-lactone-4a-p-phenvlheoate,TTIe, m.r. 145-1460,/U/D= -30.S0 was obtained. 15 By oxidationof the alcohol TIIg with the Collinsrencent the p-nhenylbrnzoate aldehyde , = -16.7O was obtnined,which was treatedwith the sodium derivative IIIi,m.n. 148-1490(dec.),/o(/ D
No. 42
4305
0
0 0
X--
I
*
c9
d
‘- R
“CH2DR
:P
OP
TT P b c d
e f
X T 1 H HH H H
? H AC
R & Ele
AC
ble
III P b c a e f
Me 'rosy1 Ile Tosvl H
s i 1
P H
R CH2lMe
E AC AC PR PB PB PB
Yk CH2OH XH CH20 M2 e CH OH CH6 'cH2
PR = p-nhenylbenzoate
P
b_COOH
h!
X TI
H 'OH =c
XII
,>fdinc+hl,l-l-ore-hppt~rlnhosohonate in benzene to form the a-enone-lactone Line product, m.n.. lk-113°(from
ether),/o(/D=-196°,/01/365d
The followin,e sten,Ln(BH4)2 reduction in ethc~imetho~ethRllr(~:l),
’ 51;.:?A ’ W evi-rra,showin.; -1vvt
tFn P.-:-Pchrc-qtovr,??hi
V , as a crystal-
-928O,with 60% yield from NC.
c r:obil i ty.
afforded a mixture of
4306
k.
42
After several fractionatedcrystallizations from isopropylether,theless polar 15Ijeoimer, -152o;thereafter from the mother VIb,couIdbe obtainedas a pure compound,m.p. l4l-142o,/o1/D= Liquors,by chromatography on Si02 (ethyl ether-isopropyl ether 1:l as eluent),the 1% epimer, Via , m.p. 9C-910,/U/D=-154e was recovered. Using a well known procedure17: i) saponificationto the dial-lactoneaVIIa (m.p. 79-810,
/a/,,= -36")and VIIb (m.p. 78-79O,/U/ = -57“);ii) conversionto the related THP-ethersVIIIa (oil,/d/=-86O)and VIIIb (oil&D=
f3.5“) ; iii) diisobutylaluminum hydride reductionto the
lactols IXa (oil,/U/D=-75O) and IXb (oil,/ti/D-=+15.5") were performed. Condensationof IXa with the Wittig reagent derived from triphenylphosphoniopentanoic acid and NaH in DWO affordedthe 5-cis-13-tr.ans-8,12_diiso-9 lla,l5S_trihydroxy_prostadienoic acid _Py ll,&bis-THP-ether, Xa ,(oil,/a/D=-lOlO).Oxidationof Xa to XIa,followadby acetone-O.11oxalic acid treatmentprovidedpure 8,12-diiso-PGE2 ent-PC(Epp)2,XIIa,nil,/o(/D= +33.20,/U/ =+323O 36S" [ (c= 1% ethanol).In similarway from IXb we preparedthe d,12-diiso-l%PGE2, XIIb , oil,/ti/ = D +270° (~0.3% in ethanol.). +22oa/u/365o Ezperimental:UnIess othezwisestated, specificrotationswere measuredin CHCl solution (c=l%) at 200, with a P-141 Perkin-Rlmerpolarimeter.N.M.R.spectrawere recordedon a Varian HA-100 (100 l#iz)spectrometerin CDC13 with TMS as internalreference(s = 0.0). Acknowladgmentslhe authors are gratefulto Dr. E.Dradi for N.M.R. analysis,and wish to express their thanks to Mr. A. Andreoniand Mr. W. Moretti for their valuableassistance.
Referencesand footnotes
and N.M.Weinshenker,J.A.Chem.Soc.&,397 (1970) 1) E.J.Corey,T.K.Schaaf,W.Huber,U.Koelliker and F.J.Corey,Exoerientia,26,355 (1970) 2) H.Shio,P.W.Ramwell,N.H.Andersen and NJLAndersen,Nature,221,1251 (1969) 3) P.W.Ramwell,J.E.Shaw,E.J.Corey and M.Casey,J.Amer.Chem.Soc.,&3643(1972) 4) J.Sih,P.Price,R.Sood~R.G.Salomon,G.Peruzzotti Res.,lO,316(1969) 5) N.H.Andersen,J.Liuid Letters,111(1972) 6) E.J.Coreyand Shiro Terashima,Tetrahedron 71 Knoll A.C. Ludwigshafenam Rhein. 8) Satisfactoryanalytical,IRand NMR data have been obtainedfor this and followingcompounds, and V.K.Jones,J.Org&hem.,~2519 (196.5) 9) H.O.House,S.G.Boots and M..N.Pechet,J.Amer.Cbem.Soc.,88,3016 (1966) 10)D.H.R.Barton,N,K.Basu,R.H.Hesse,F.S.Morehouse and H.J.K.Loewenthal,J.Org.Chem.,&l26 (1969) 11) H.D.Bachi,Y.W.@stein,Y.Herzberg-Minzly 12)G.Odham and B.Samuelsen,ActaChem>cand.,2&468 (1970) : m-p. 16+l?1°,/~/=-1340. 13) This compoundwas characterizedas 4-p-phenylbenzoate 14)For use of boron trichlorideto effect demethylationof a methyletherwitRout cleavageof P tosyl ester group, see S.D.Qro,TetrahedronLetters,591(i%6) (1970) 15)R.RactIiffeand R.Rodehorst,J.Ors.Chem.,&&4COO (1965) 16)K.E.Pfnitznerand J.G.Moffatt,J.Amer.Chem.Soc.,~5670 and W.Huber,J.Amer.Chem.Soc.,gl,5675 (1969) 17) E.J.Corey,N.M.Weinshenker,T.K.Schaaf