- Email: [email protected]
boron trifluoride and dimethyl sulfoxide
307
SOLVOLYSES OF SCME POTASSIU?dSTEHYL SULFATES BY EE?S?ANOL/BOBON'lBIFIdJOl?IDEANDDI?dETBTL SULFOXIDE
S.I. Beyynk and A.M. Jureydini
Department of Chemistry, Ameriaan University of Beirut, Beirut, Lebanon
Received May 20, 1967
In this work the Bfi-catalyaedmethanolysis of some potassium ateryl sulfates and their 8olvolytio cleavage by dimethyl sulfoxide were investigated. Whereas the salts were solvolyzedby MeOH/B& at a faster rate than by dimethyl aulfoxide/rater,the latter reagent seems to be milder. Unlike MeOH/B&, it does not effect dehydration of A'-Cholesten-3ti-ol.
In recent years, considerable interest has been shown in the solvolysis of sterol sulfates. In a procedure designed to prevent structural alterations resulting from drastic treatment, Lieberman and ooworkers (l-3) liberated the free sterols from pure steryl sulfate conjugates by protracted hydrolysis at room temperaturewith aqueous HCl end continuous extractionwith ether. In 1950 Grant and Beall (4) observed that sodium estrone sulfate underwent rapid and complete hydrolysis in dioxane at room temperature. Later, in en investigationof the hydrolysis of the pyridinium and potassium sulfates of cholesterol, p -cholestanoland estrone by a number of ethers and other solvents,YcKenna and Norymberski (5) found that the rate
10:3
STEROIDS
308
was fastestin dioxane,and decreasedin other ethers as the basic characterof the solventdiminished. Other solventsgenerally exhibitedlow reactivity. In this work, we reportresultsof the chemiaaleolvolyeieof certainpotaseiumsteryl&fates in M&H/H&
and D~O~O,
in the
hope that they mey have useful applicationto biologicalextracts.
Resultsand Discussion
Since the ethanol&s of salts of eterylsulfatesis known to proceedby nucleophilicattaokat the S atom (3). it was assumed,in this investigation, that sny factorwhich increasesthe susoeptibility of the S atom to nucleophiles will acceleratethe reaction. Ihe potassiumsulfatesOX threedifferentjl-hydro~sterols(cholesterol, g -cholestenol, epiandrosterone) and a 17-hydroxyaterol (testosterone) were synthesizedfrom theirparent alcohols(6), and were then methanolysed in the presenceand absenceof BF3 at about 65’ and at room temperature. TADLE I Time( PotassiumSulfateof Cholesterol k -Cholestanol Epiandrosterone Testosterone
requiredfor completesolvolysisbyt xeoHfh8R at refluXb 3p
~0~~0 at 100 2
16 2
Prom the resultsobtainedby methanolysisat 65’ (TablesI and II), it is obviousthat the presenceof Bfi has markedlyincreasedthe rate of the reaction. The maximum time limitsrequiredto achieveaomplete
STEROIDS
Sept. 1967
309
TABLEII &tent of eolrolysia($) by*
PotassiumSulfateof
15
Cholesterol (34lholestanol Bpiandrosterone Testosterone Each remitt is b” Approxim@tely65
“rb
0
About 20 .
IdeOH reflux 11 hr.)
i.5 0.6
MeOH MeoH/BP3 ~Ollltempo room temp (10 hr.) IlO hr.) 42 0 20 14
DMSO/fIaO room temp 110 hr.)
80 2: 56
0 0 0 0
everageof at least two determinations. .
aethanolysieof the differentsalts rangedbetween 3/4 - 2 hours, and were shorterthan those requiredby many of the previouslyreported solventsystems. The catalyticeffeotof B& oould also be observed when methsnolysiswas effectedat room temperature(TableII). In all cases the parent sterolswere isolatedwith completeretentionof oonfigurationas evidenoedfrom optic&Lrotationand mixturemelting point determinations.Evidently,clemege occurredat the S-O bond. The catalyst,most Wkely, aoted by attaokingone of the exposed0 atoms of the sulfategroup,thus increasingthe formalpositivecharge on the S atom end facilitatingatteokby MeOH. Due to its aprotiooharaoter,anhydrousdimethylsulfoxidecould not exert any detectablesolvolytica&ion on cholesterylpotassium of the sulfate. In the presenoeof He0 however(5 x molar oonsentration salt),
to MeOH/B&, the steryl sulfateswere solvolyxedat 100°. Simailar
solvolysisby DMSO/HeOaffordedthe parent sterolswithoutany detectableahange in atruotureor oonfiguration.This oould be t&en
10:3
STEROIDS
310
as evidence of cleavage at the S-O bond of the salt by a mechanism similar to that postulated for solvolysisby ethers (5).
Unlike
MeOH/B&, this solvent system did not exhibit any detectable activity at room temperature. In conclusion, MeOH/BF3 is more effective than DMSO/HzO since it solvolyzed the salts faster at a lower temperature. Ihe latter solvent system, however, has the advantage of being a milder reagent toward sterols with allylic-OH groups. Unlike MeOH/BFJ, it did not dehydrate A'-Cholesten-3o(-01 even after two hours of heating at loo', and it may prove useful in the solvolysis of steryl sulfates oontaining functional groups susceptible to Lewis acids.
Experimental All melting points are uncorrected. Ultraviolet spectra were measured in EtOH end rotations in CHC13 at about 20 . Infrared spectra were determined on a Model 13’7 Perkin-Elmer Infracord. Solvents. All were chemically pure end anhydrous unless otherise specified. Petroleum ether had a boiling point range 35 - 70 . $-Cholestanol. gholesterolwas repeatedly hydrogenated in glacial acetic acid at 75 and 50 p.s.i. using freply prepared platinic oxide The product hed[#] D + 23.4 and m.p. 140 - 142 . catalyst (7). A4-Cholesten-3o(-01. A'-Cholesten-j-onewas prepared from cholesterol (8) end then reduced with sodium borohydride (9.10). A'-Cholesten-3d -01 was separated from its epimer and purified by two gonsecutive digiThe alcohol melted at 130 - 131 and had
Preparation of the Potassium Steryl Sulfates (6). !Thesterols were treated with pyridine sulfur trioxide (11). The resultant pyridinium sulfates were then converted to the correspondingpotassium salts by treatment with lC$ aqueous KCl. After recrystallizationfrom MeOH, cholesteryl potassium sulfate melted with decomposition at 236’ [reported values (5,6)t 226 - 227’, 210' and 239'3; the p-cholestanyl salt at 236' with deoompositionc[lit.(5,12): 234 - 235' end 236’1 ; the epiendrosteryl sa&t at 225 with decomposition; and the testosteryl salt at 235 - 236 with decomposition. The identities of the selts were further ascertained by examination of the indrared spectra.
Sept. 1967
STEROIDS
311
Solvol~sier by Me~H~~ In a typicalrun, an accuratelyweighed specimenof about 220 & of the potassiumsterylsulfatewas dissolved in 22.1,ml of MeOH, and 0.3 ml of boron trif;luoride etheratewas added. After heating the solutionat reflu~, (~65 ) the methanolcontentwas rapidlyremovedunder reducedpressureat room temperature. !Fheresidue was extractedwith about 100 ml of petroleumether, and the extractwas washed with water, dried, and finallyevaporated. We weight of the final dry orystallineproductwas used to calculatethe extentof methanolysis @). The identitiesof the sterolswere establishedby melting point,mixturemeltingpoint and specificrotationdeterminations, and by comparisonsof UV and IB spectra. Bdethanolysis of the salts under the other oonditionswas effeutedin a similarmanner. !!!reatment of wtassium cholesterolsulfatewith anhvdrousdimethyl
sulfoxide. A solutionof 230 mg of oholeetergfpotassiumsulfatein 50 ml of azihydrous DMSO was heated at 100 under a nitrogenatmosphere for 10 hr. The reactionmixturewas then extraotedwith two 125 ml portionsof petroleumether,and the extractwas worked up as previously describedin the preoeedingsection. Therewas no detectablesolvolysis. Solvolysisby DMSO/H20. Accuratelywei&ed samples(about105 mg) of the saltswere dissolvedin a mixtureof 10.5 ml of DES0 and 1.5 ml of H20. Heatingof the solutionsat 100' precipitatedthe free sterolsin crystallineform. The productswere isolatedby extractingeach reaction mixturewith 100 ml of petroleumether. When the reactions were conduoted at room temperature,no detectable solvolysis could be observed even after 10 hours.
Effectof ldeOH/BF3 on is!-oholesten-34-01. Since certainsterols containingallylic-OH groupsare readilydehydratedby acids, it was essentielto ascertainwhether the B&-catalyzedmethanolysisof sulfate salts of such sterolsis accompanied by such a side reaction. Several attemptsto prepare the pyridiniumsulfateof A4-cholesten-3c(-01 were made using differentsolventsystemsand differentconditions. All were unsuccessful,and resultedin the dehydrationof the a.&oohol to ,A3r5cholestadiene which was identifiedby its m,p, 79 - 80 ; h 235 m)li andlF:l- 121°. This couldbe attributedto the ready dehy%%tion of the alooho T!by the pyridinesulfurtrioxidersagmnt. In view of this fact, it was deoidedto treat A-cholesten-40(-01 directlywith MeOH/B& under the same conditionsused for the methanolysisof the salts. To this effect,0.3 ml of boron trifluorideetheratewas added to a solution of 200 mg of &-cholesten-34-01 in 25 ml of MeOH, and the reaotion mixturewas heated at reflux (~65') for 1 hr. After coolingto room temperature, the crystalline product was collected, washed with 8 smaLlill portion of iae-cold MeOH, snd finally identified as b3"cholestadieneby melting point determination, speoific rotation, and ultraviolet absorption. Similarly, solutions containing 30 mg of the eterol in 24 ml of DMSO and 1 ml of H20 were heated at 100 for 1 end
2 hours. After coolingto room temperature,the solutionswere extract-
312
STEROIDS
lo:3
ed with petroleumether. The c stalls productobtainedcro;sisted of A'-o-hole&en-3o(-01.It hadfP + 1siQ , laeltsdst 130 - 131 , and its meltingpoint was not depressedon admixtam With snthentic A’oholasten-3a(-01. A&nowledment This ~0x4~wae supportedby Arts and SciencesRockefellerReseamh Grant. References 1. Lieberman,S., Hariton,L.B., and ZUcushima,D.K., J. AH. CHm. SOC. 70, 1427 (1948). 2. Liebemmn, S., and Dobriner,K., REC. PROG. HORMONERES. 1, 71 (194Q. 3. Liebeman, S., Mmd, B., and Saylea,E., REX. PRO% HONOR RES. 2, 113 (1954). 4. Grant,G.A., and Beall, D., m. PROG. HOmONE as. 1, 307 (1950). 5. bfdbi?m89 J., antiHozaberaki,JJ., J. CHEX SOC., 3889 (1957). 6. Sobel,A.E., 8nd Spoerri,P.E., J. AM. CHEX. SOC. 3, 1259 (1941). 7. Bruce,W-P., 8nd Rails, J.O., ORGANICSYNmSIS, CollectiveVol. 2, Editor A.H. Blatt,John Wiley and Sons, InO,, Hew York, 1948, p. 191, 8. Fieser,L.F. ORGANICSYEaEESLS,Vol. 35, EditorT.L. Cairns,John Wiley and Sons, Ino., New York, 1955, pq 43. 9. Dauben,W.G., Micheli,R.A., and Es&ham, J.P., J. AM. CHIK Sot. j'& 3s52 (1952). 10, Haddadin,H.J., and Issidorides,C.H., J, ORG. C5M. 3, 403 (1960). 115, 11, Sobel, A.E., Drekter,I.J., and Natelson,S., J. BIOL. CIEQII. 381 (193% 12. Sob&, A.E., and Rosen,M.J., J. AM. CHEX. SOC. &, 3536 (1941).
SOLVOLYSES OF SCME POTASSIU?dSTEHYL SULFATES BY EE?S?ANOL/BOBON'lBIFIdJOl?IDEANDDI?dETBTL SULFOXIDE
S.I. Beyynk and A.M. Jureydini
Department of Chemistry, Ameriaan University of Beirut, Beirut, Lebanon
Received May 20, 1967
In this work the Bfi-catalyaedmethanolysis of some potassium ateryl sulfates and their 8olvolytio cleavage by dimethyl sulfoxide were investigated. Whereas the salts were solvolyzedby MeOH/B& at a faster rate than by dimethyl aulfoxide/rater,the latter reagent seems to be milder. Unlike MeOH/B&, it does not effect dehydration of A'-Cholesten-3ti-ol.
In recent years, considerable interest has been shown in the solvolysis of sterol sulfates. In a procedure designed to prevent structural alterations resulting from drastic treatment, Lieberman and ooworkers (l-3) liberated the free sterols from pure steryl sulfate conjugates by protracted hydrolysis at room temperaturewith aqueous HCl end continuous extractionwith ether. In 1950 Grant and Beall (4) observed that sodium estrone sulfate underwent rapid and complete hydrolysis in dioxane at room temperature. Later, in en investigationof the hydrolysis of the pyridinium and potassium sulfates of cholesterol, p -cholestanoland estrone by a number of ethers and other solvents,YcKenna and Norymberski (5) found that the rate
10:3
STEROIDS
308
was fastestin dioxane,and decreasedin other ethers as the basic characterof the solventdiminished. Other solventsgenerally exhibitedlow reactivity. In this work, we reportresultsof the chemiaaleolvolyeieof certainpotaseiumsteryl&fates in M&H/H&
and D~O~O,
in the
hope that they mey have useful applicationto biologicalextracts.
Resultsand Discussion
Since the ethanol&s of salts of eterylsulfatesis known to proceedby nucleophilicattaokat the S atom (3). it was assumed,in this investigation, that sny factorwhich increasesthe susoeptibility of the S atom to nucleophiles will acceleratethe reaction. Ihe potassiumsulfatesOX threedifferentjl-hydro~sterols(cholesterol, g -cholestenol, epiandrosterone) and a 17-hydroxyaterol (testosterone) were synthesizedfrom theirparent alcohols(6), and were then methanolysed in the presenceand absenceof BF3 at about 65’ and at room temperature. TADLE I Time( PotassiumSulfateof Cholesterol k -Cholestanol Epiandrosterone Testosterone
requiredfor completesolvolysisbyt xeoHfh8R at refluXb 3p
~0~~0 at 100 2
16 2
Prom the resultsobtainedby methanolysisat 65’ (TablesI and II), it is obviousthat the presenceof Bfi has markedlyincreasedthe rate of the reaction. The maximum time limitsrequiredto achieveaomplete
STEROIDS
Sept. 1967
309
TABLEII &tent of eolrolysia($) by*
PotassiumSulfateof
15
Cholesterol (34lholestanol Bpiandrosterone Testosterone Each remitt is b” Approxim@tely65
“rb
0
About 20 .
IdeOH reflux 11 hr.)
i.5 0.6
MeOH MeoH/BP3 ~Ollltempo room temp (10 hr.) IlO hr.) 42 0 20 14
DMSO/fIaO room temp 110 hr.)
80 2: 56
0 0 0 0
everageof at least two determinations. .
aethanolysieof the differentsalts rangedbetween 3/4 - 2 hours, and were shorterthan those requiredby many of the previouslyreported solventsystems. The catalyticeffeotof B& oould also be observed when methsnolysiswas effectedat room temperature(TableII). In all cases the parent sterolswere isolatedwith completeretentionof oonfigurationas evidenoedfrom optic&Lrotationand mixturemelting point determinations.Evidently,clemege occurredat the S-O bond. The catalyst,most Wkely, aoted by attaokingone of the exposed0 atoms of the sulfategroup,thus increasingthe formalpositivecharge on the S atom end facilitatingatteokby MeOH. Due to its aprotiooharaoter,anhydrousdimethylsulfoxidecould not exert any detectablesolvolytica&ion on cholesterylpotassium of the sulfate. In the presenoeof He0 however(5 x molar oonsentration salt),
to MeOH/B&, the steryl sulfateswere solvolyxedat 100°. Simailar
solvolysisby DMSO/HeOaffordedthe parent sterolswithoutany detectableahange in atruotureor oonfiguration.This oould be t&en
10:3
STEROIDS
310
as evidence of cleavage at the S-O bond of the salt by a mechanism similar to that postulated for solvolysisby ethers (5).
Unlike
MeOH/B&, this solvent system did not exhibit any detectable activity at room temperature. In conclusion, MeOH/BF3 is more effective than DMSO/HzO since it solvolyzed the salts faster at a lower temperature. Ihe latter solvent system, however, has the advantage of being a milder reagent toward sterols with allylic-OH groups. Unlike MeOH/BFJ, it did not dehydrate A'-Cholesten-3o(-01 even after two hours of heating at loo', and it may prove useful in the solvolysis of steryl sulfates oontaining functional groups susceptible to Lewis acids.
Experimental All melting points are uncorrected. Ultraviolet spectra were measured in EtOH end rotations in CHC13 at about 20 . Infrared spectra were determined on a Model 13’7 Perkin-Elmer Infracord. Solvents. All were chemically pure end anhydrous unless otherise specified. Petroleum ether had a boiling point range 35 - 70 . $-Cholestanol. gholesterolwas repeatedly hydrogenated in glacial acetic acid at 75 and 50 p.s.i. using freply prepared platinic oxide The product hed[#] D + 23.4 and m.p. 140 - 142 . catalyst (7). A4-Cholesten-3o(-01. A'-Cholesten-j-onewas prepared from cholesterol (8) end then reduced with sodium borohydride (9.10). A'-Cholesten-3d -01 was separated from its epimer and purified by two gonsecutive digiThe alcohol melted at 130 - 131 and had
Preparation of the Potassium Steryl Sulfates (6). !Thesterols were treated with pyridine sulfur trioxide (11). The resultant pyridinium sulfates were then converted to the correspondingpotassium salts by treatment with lC$ aqueous KCl. After recrystallizationfrom MeOH, cholesteryl potassium sulfate melted with decomposition at 236’ [reported values (5,6)t 226 - 227’, 210' and 239'3; the p-cholestanyl salt at 236' with deoompositionc[lit.(5,12): 234 - 235' end 236’1 ; the epiendrosteryl sa&t at 225 with decomposition; and the testosteryl salt at 235 - 236 with decomposition. The identities of the selts were further ascertained by examination of the indrared spectra.
Sept. 1967
STEROIDS
311
Solvol~sier by Me~H~~ In a typicalrun, an accuratelyweighed specimenof about 220 & of the potassiumsterylsulfatewas dissolved in 22.1,ml of MeOH, and 0.3 ml of boron trif;luoride etheratewas added. After heating the solutionat reflu~, (~65 ) the methanolcontentwas rapidlyremovedunder reducedpressureat room temperature. !Fheresidue was extractedwith about 100 ml of petroleumether, and the extractwas washed with water, dried, and finallyevaporated. We weight of the final dry orystallineproductwas used to calculatethe extentof methanolysis @). The identitiesof the sterolswere establishedby melting point,mixturemeltingpoint and specificrotationdeterminations, and by comparisonsof UV and IB spectra. Bdethanolysis of the salts under the other oonditionswas effeutedin a similarmanner. !!!reatment of wtassium cholesterolsulfatewith anhvdrousdimethyl
sulfoxide. A solutionof 230 mg of oholeetergfpotassiumsulfatein 50 ml of azihydrous DMSO was heated at 100 under a nitrogenatmosphere for 10 hr. The reactionmixturewas then extraotedwith two 125 ml portionsof petroleumether,and the extractwas worked up as previously describedin the preoeedingsection. Therewas no detectablesolvolysis. Solvolysisby DMSO/H20. Accuratelywei&ed samples(about105 mg) of the saltswere dissolvedin a mixtureof 10.5 ml of DES0 and 1.5 ml of H20. Heatingof the solutionsat 100' precipitatedthe free sterolsin crystallineform. The productswere isolatedby extractingeach reaction mixturewith 100 ml of petroleumether. When the reactions were conduoted at room temperature,no detectable solvolysis could be observed even after 10 hours.
Effectof ldeOH/BF3 on is!-oholesten-34-01. Since certainsterols containingallylic-OH groupsare readilydehydratedby acids, it was essentielto ascertainwhether the B&-catalyzedmethanolysisof sulfate salts of such sterolsis accompanied by such a side reaction. Several attemptsto prepare the pyridiniumsulfateof A4-cholesten-3c(-01 were made using differentsolventsystemsand differentconditions. All were unsuccessful,and resultedin the dehydrationof the a.&oohol to ,A3r5cholestadiene which was identifiedby its m,p, 79 - 80 ; h 235 m)li andlF:l- 121°. This couldbe attributedto the ready dehy%%tion of the alooho T!by the pyridinesulfurtrioxidersagmnt. In view of this fact, it was deoidedto treat A-cholesten-40(-01 directlywith MeOH/B& under the same conditionsused for the methanolysisof the salts. To this effect,0.3 ml of boron trifluorideetheratewas added to a solution of 200 mg of &-cholesten-34-01 in 25 ml of MeOH, and the reaotion mixturewas heated at reflux (~65') for 1 hr. After coolingto room temperature, the crystalline product was collected, washed with 8 smaLlill portion of iae-cold MeOH, snd finally identified as b3"cholestadieneby melting point determination, speoific rotation, and ultraviolet absorption. Similarly, solutions containing 30 mg of the eterol in 24 ml of DMSO and 1 ml of H20 were heated at 100 for 1 end
2 hours. After coolingto room temperature,the solutionswere extract-
312
STEROIDS
lo:3
ed with petroleumether. The c stalls productobtainedcro;sisted of A'-o-hole&en-3o(-01.It hadfP + 1siQ , laeltsdst 130 - 131 , and its meltingpoint was not depressedon admixtam With snthentic A’oholasten-3a(-01. A&nowledment This ~0x4~wae supportedby Arts and SciencesRockefellerReseamh Grant. References 1. Lieberman,S., Hariton,L.B., and ZUcushima,D.K., J. AH. CHm. SOC. 70, 1427 (1948). 2. Liebemmn, S., and Dobriner,K., REC. PROG. HORMONERES. 1, 71 (194Q. 3. Liebeman, S., Mmd, B., and Saylea,E., REX. PRO% HONOR RES. 2, 113 (1954). 4. Grant,G.A., and Beall, D., m. PROG. HOmONE as. 1, 307 (1950). 5. bfdbi?m89 J., antiHozaberaki,JJ., J. CHEX SOC., 3889 (1957). 6. Sobel,A.E., 8nd Spoerri,P.E., J. AM. CHEX. SOC. 3, 1259 (1941). 7. Bruce,W-P., 8nd Rails, J.O., ORGANICSYNmSIS, CollectiveVol. 2, Editor A.H. Blatt,John Wiley and Sons, InO,, Hew York, 1948, p. 191, 8. Fieser,L.F. ORGANICSYEaEESLS,Vol. 35, EditorT.L. Cairns,John Wiley and Sons, Ino., New York, 1955, pq 43. 9. Dauben,W.G., Micheli,R.A., and Es&ham, J.P., J. AM. CHIK Sot. j'& 3s52 (1952). 10, Haddadin,H.J., and Issidorides,C.H., J, ORG. C5M. 3, 403 (1960). 115, 11, Sobel, A.E., Drekter,I.J., and Natelson,S., J. BIOL. CIEQII. 381 (193% 12. Sob&, A.E., and Rosen,M.J., J. AM. CHEX. SOC. &, 3536 (1941).