THE CHEMISTRY OF UNSATURATED STEROIDS. V

[CONTRIBUTION FROM

THE

STERLING CHEMISTRY LABORATORY, YALE

UNIVERsITY]

THE CHEMISTRY O F UNSATURATED STEROIDS. V. REARRANGEMENTS AND STRUCTURE OF STEROID PEROXIDES* WERNER BERGMANN, FRIEDA HIRSCHMANN, AND EVALD L. SKAU

Received January 9, 1939 REARRANGEMENTS OF 2,5-PEROXIDOCHOLESTENE-3

In the last paper of this series' it was pointed out that the photooxidation of 2,Ccholestadiene leads to one of two products depending upon the light source. When a 200-watt Mazda bulb was used, a peroxide of m.p. 113-114' and [aID+48' was obtained, which was shown to be 2,Bperoxidocholestene-3 (I). When, on the other hand, sunlight was used, an ~ which did not seem to be a isomeric substance of m.p. 169' and [ a ]+141', peroxide, was formed. It was shown that this substance could also be obtained by sunlight irradiation of 2,5-peroxidocholestene-3. One can therefore assume that the mechanism of the photooxidation of 2,4cholestadiene in sunlight involves the formation of 2, Bperoxidocholestene-3 followed by its rearrangement into the substance of m.p. 169' (172' corr.). The assumption that this rearrangement product was not a peroxide has now been substantiated. One of its two oxygen atoms is present in the form of a keto group. It reacts with hydroxylamine to give a crystalline monooxime. This ketone, which will be referred to as ketone A, C27H140~, does not show the presence of a double bond on titration with perbenzoic acid. Its absorption spectrum shows only general absorption, below 250 mp. On treatment with acetic anhydride or by distillation a t 1 mm. pressure, ketone A is isomerized into ketone B, m.p. 174' and [& $36". Ketone B resembles ketone A in its absorption spectrum and in its behavior toward perbenzoic acid. On treatment with a solution of potassium hydroxide in methyl alcohol both ketones give a product of the formula C~gI4,0,. This substance, which is also a ketone, ketone C, contains one methoxyl group, and is therefore probably formed by some sort of addition of methyl alcohol to the molecule. Ketone C can also be obtained directly from 2,5-peroxido-

* Aided by grants from The Jane Coffin Childs Memorial Fund for Medical Research and the International Cancer Research Foundation. 1 SKAU AND BERGMANN, J. ORG.CHEM., 3,166 (1938). 29

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W. BERGMA",

F. HIRSCHMANN AND E. L. SKAU

cholestene-3 by similar treatment. Ketone C differs from the other two ketones in that it does not absorb ultraviolet light in the region measured. It does not react with perbenzoic acid nor with acetic anhydride. On distillation at 1 mm. pressure ketone C loses one mole of methyl alcohol to form ketone B. On catalytic hydrogenation with platinum oxide catalyst all three ketones take up one mole of hydrogen to form hydroxy compounds which will be discussed in a later communication. The isomerization of 2 ,5peroxidocholestene-3 into ketonic substances resembles the rearrangement undergone by ergosterol peroxide on distillation in vacuum2. Here too a ketone is obtained which, apart from the double bond in the side-chain, does not contain a recognizable double bond, and which contains only one hydroxyl group, namely the one a t C3. An oxygen bridge was postulated to account for the nonreactive oxygen of the rearrangement product of ergosterol peroxide. The rearrangement of the steroid peroxides finds an interesting parallel in the isomerization which ascaridol undergoes on heating to 150°a. Ascaridol (VI) is a naturally occurring transannular peroxide of the terpene series. It has been demonstrated that heating causes one of the oxygen atoms to split out of the peroxide bridge and to add to the double bond forming an ethylene oxide (VII), the presence of which has been proved by its conversion into the corresponding glycol (VIII).

CH3 CH3

CHs CH3

CH3 CH3

6) (+ (5 \/

\/

lao.-

I

CHa CH3 V. a-Terpinene VI. Ascaridol

CHI CHa

\/

$-OH -OH

(3% VI1

CHa VI11

It seems probable that a similar reaction takes place during the rearrangement of the steroid peroxides. In the case of 2,5-peroxidocholestene-3 one of the oxygen atoms of the peroxide bridge probably splits out and adds to the double bond between C3 and Cd. The ethylene oxide may then rearrange into a Cs or Cr-ketone (11). Such rearrangements of ethylene oxides are well known in the aliphatic series. Ketones A and B seem to be stereoisomers of the cis-trans-decalii type. 2 3

WINDAUS, BERGMANN, AND L~~TTRINGHAUS, Ann., 471, 195 (1929). RICHTER AND PRESTING, Ber., 64,878 (1931).

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W. BERGMANN, F. HIRSCHMA" AND E. L. SKAU

In the less stable ketone A the transannular oxide ring is probably in the trans position with respect to the methyl group a t Clo. In the rearrangement of ketone A to the more stable ketone B the transannular oxygen bridge is probably shifted into a position cis with respect to the methyl group a t C I ~(111). The nature of the ultraviolet absorption of ketones A and B can perhaps be explained by the fact that the keto group is adjacent to one of the carbon atoms carrying the oxygen bridge. Since ketone C does not show absorption in the ultraviolet it is very likely that it contains no oxygen bridge between C2 and Cg. Treatment of ketone B with a solution of potassium hydroxide in methyl alcohol to form ketone C seems therefore to involve the opening of the transannular oxygen bridge and the addition of the elements of methyl alcohol. Thus ketone C would be a monomethoxy monohydroxy ketone. Since it remains unchanged on treatment with acetic anhydride it does not contain a secondary hydroxyl group. The methoxyl group may therefore be placed a t C2 and the hydroxyl group at Cs. Heating of ketone C in vacuum causes the loss of one mole of methyl alcohol and the reestablishment of the transannular oxygen bridge to form ketone B. The transformation of the peroxide (I) and of ketone A into ketone C probably involves the intermediate formation of ketone B. DISCUSSION OF THE STRUCTURE OF STEROID PEROXIDES

Attention should be called to the fact that all stable steroid peroxides so far known have been derived from compounds which contain conjugation in a cyclohexane ring. The same can be said of a representative of the terpene series, ascaridol (VI), which is a peroxide formed from aterpinene (V). Attempts have been made in this laboratory to prepare peroxides by the photooxidation of mono-unsaturated steroids as well as of dienes containing a system of conjugation extending over two rings, but these have always led to negative results. Therefore it seems justifiable to draw the conclusion that in the steroid series the ability to form stable peroxides presupposes the presence of conjugation in a cyclohexane ring. Since 1,4 addition is one of the characteristic properties of such a system of conjugation it seems quite logical to assume that oxygen is always added in such a manner as to give transannular peroxides. In two of the better known steroid peroxides, uiz., those derived from 2,4cholestadiene' (I) and dehydroerg~sterol~(X), the presence of a 4

MULLER,2.physiol. Chem., 331, 75 (1931).

CHEMISTRY OF UNSATURATED STEROIDS

33

IX. Dehydroergosterol

X. Dehydroergosterol peroxide transannular peroxide bridge has been definitely established. For ergosterol peroxide6 however, two fundamentally different structural formulas have been proposed. On the basis of their experimental work, the group of Gottingen investigators4*6as well as Heilbron’, have come to the conclusion that the peroxide bridge in ergosterol peroxide is not transannular but attached to CS and CC,(XI). Fiesel.8, on the other hand, has concluded that the available experimental evidence can be better interpreted in favor of a transannular formula for ergosterol peroxide (XVI). The establishment of formula X I for ergosterol peroxide has been based principally on the study of ergostadiene triol, triol I, which is obtained by the reduction of the peroxide with zinc in alkalie. On heating with maleic anhydride, triol I isomerizes into 3,5,6-trihydroxyergostadiene, WINDAUSAND BRUNKEN, Ann., 460,225 (1928). ACHTERMANN, 2. physiol. Chem., 217,281 (1933). DUNN,HEILBRON, PHIPERS, SAMANT, AND SPRING, J . Chem. SOC.,1934, 1576. S FIESER, “The Chemistry of Natural Products Related t o Phenanthrene.” Reinhold Publishing Corporation, New York, 1936, p. 174. 9 WINDAUS AND LINSERT, Ann., 466, 156 (1928). 6 0

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W. BERGMANN, F. HIRSCHMANN AND E. L. SKAU

triol6 I1 (XIV). This triol, whose constitution has been well established, is the product of hydrolysis of ergosterol monoxide6J0(XIII). The ease of rearrangement of triol I into triol I1 seemed to prove that the twocomlo

WINDAUSAND L~TTRINGHAUS, ibid., 481, 119 (1930).


35

pounds were not mere position isomers but stereoisomers of the cis- and trans-decalin type. They were assigned the structural formulas XI1 and XIV respectively. Heilbron7 gave as additional evidence in favor of such formulations the fact that both triols render the same diketo compound (XV) on oxidation. He reasoned that during the oxidation of triol I (XII) the hydroxyl group at c6 had undergone inversion from the trans into the cis position with respect to the methyl group at Clo. It seems more logical, however, to interpret the fact that both triols give the same diketo compounds as proof for the identical position of the hydroxyl group at c6. Since the reactions mentioned above were thought to prove that triols I and I1 were stereoisomers, the conclusion was drawn that triol I had the formula XI1 and that ergosterol peroxide carried a peroxide bridge at CSand C6 (XI). The formulation of triol I as a 3,5,6-trihydroxy compound can not, however, be readily reconciled with several of its properties. On acetylation it gives a monoacetate only6,and on distillation in vacuum (IX). In it loses two molecules of water to give dehydroergoster~l~ contrast, triol I1 forms a diacetate, and can be distilled without decompositionlo. As has already been pointed out by Fiesera, these observations strongly indicate the presence of two tertiary hydroxyl groups in triol I and favor its formulation as a 3,5,8-triol (XVII), which obviously must have been derived from a trans-annular peroxide (XVI). The transformation of triol I (XVII) into triol I1 (XVIII) is explained by Fieser as due to an allylic shift. Fieser’s formulas for ergosterol peroxide (XVI) and triol I (XVII) seem to be the most logical expressions for all the known properties of these compounds. The fact that triols I and I1 form the same oxidation product does not contradict Fieser’s formula for triol I. It is quite conceivable that as the first step of oxidation of triol I (XVII) a 3-keto tetrahydroxy compound (XIX) is formed; which then loses, first one molecule of water to give a diketo diol (XX), and then a second molecule of water to give Heilbron’s diketone (XXI). On the basis of Fieser’s formula for ergosterol peroxide one may also postulate that the photoijxidation products of 22-dihydroergosterol11and 7-dehydrocholesterol’2 are transannular peroxides with a peroxide bridge between C, and Cs. Ergosterol peroxide differs from 2,5-peroxidocholestene-3 in its reluctance to undergo rearrangements and its stability toward alcoholic solutions of alkali. This stability is probably due to the fact that in ergosterol peroxide the peroxide bridge is attached to two tertiary carbon atoms. If 11

12

WINDAUS AND LANGER, ibid., 608, 110 (1934). SCHENK, BUCHHOLZ, AND WIESE, Ber., 69,2699 (1936).

XVI. Ergosterol peroxide

OH v

OH

36


37

ergosterol peroxide, however, is heated and then distilled in high vacuum2 it also rearranges into a ketone which may best be formulated as XXII.

EXPERIMENTAL^ Ketone A Preparation.-One part of 2,5-peroxidocholestene-3 was dissolved in 50 parts of absolute alcohol, and the solution was exposed t o sunlight in a stoppered Pyrex flask. One week later the dense crystals which had formed were filtered off, washed with small amounts of alcohol, and recrystallized from boiling absolute alcohol (yield 88%). The pure ketone melted a t 172"; [a]: +141" (30.0 mg. in 3.06 cc. CHCls). Anal. Calc'd for C2~H1101: C, 80.93; H, 11.08. Found: C, 81.13;H, 11.05. Determination of active oxygen.-A 36.9-mg. sample of substance was introduced into a glass-stoppered bottle, and 20 cc. of a saturated solution of potassium iodide in glacial acetic acid was added. After standing 24 hours a t room temperature in the dark, the mixture containing the sample required 3.81 cc., and the blank 3.71 cc. of 0.0990N thiosulfate solution. The difference corresponded t o 0.07 atoms of active oxygen. Titration with perbenzoic acid.-Upon titration with perbenzoic acid in the usual manner the ketone was found t o take up no oxygen. Oxime.-An alcoholic solution containing ketone A and an excess of hydroxylamine hydrochloride and potassium acetate was refluxed for three hours. Sufficient water was then added so that the oxime separated on cooling. After several recrystallizations from small amountEi of absolute alcohol the oxime melted a t 225-229". Anal. Calc'd for C2,HtsNO2: C, 78.01; H, 10.92. Found: C, 77.89; H, 10.98. Ketone B Preparation. (a) By vacuum distillation of ketone C.-Ketone C was distilled a t 220-230" and 1 mm. pressure. The crystalline distillate was then recrystallized several times from small amounts of ether. Ketone B crystallizes in fine long needles; m.p. 173"; [a]:+36.0" (39mg. in 3.06 cc. ether).

t All melting points given below are corrected.

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W. BERGMANN, F. HIRSCHMANN AND E. L. SKAU

Anal.

Calc'd for C27H4402: C, 80.93; H, 11.08. Found: C, 81.04; H, 11.32. ( b ) By vacuum distillation of ketone A.-Ketone A was distilled from a small retort at 210-230" and 1 mm. pressure. The solid distillate was then recrystallized several times from alcohol. The yield was 80%. After drying at 100" in an Abderhalden dryer the substance melted a t 173.5-174"; [a]: $36" (20.4 mg. in 3.06 cc. ether). A mixture of the substance with a sample of ketone B obtained by distillation of ketone C gave no depreosion of the melting point. Anal. Calc'd for C27H44Oz: C, 80.93; H, 11.08. Found: C, 80.72; H, 11.28. (c) By treatment of ketone A with acetic anhydride.-Ketone A (210 mg.) was refluxed for two and one-half hours with acetic anhydride (0.6 cc.). The crystalline material which separated on cooling was filtered and recrystallized several times from absolute alcohol. The purified ketone melted a t 171.5". A mixture of this ketone with an authentic sample of ketone B of m.p. 173.5' melted a t 172.5". On the other hand, a mixture with a sample of ketone A melted over a range 145-156". The yield was unsatisfactory due to the formation of resinous impurities. Titration with perbenzoic acid.-By titration with perbensoic acid in the usual manner 48 mg. of ketone B took up 0.19 mg. of oxygen in 18 hours, an amount corresponding to 0.10 double bonds. 8emicarbazone.-An alcoholic solution containing ketone B and an excess of semicarbazide hydrochloride and fused potassium acetate was refluxed for one hour. The semicarbazone which separated on cooling was recrystallized from alcohol. It melted a t 234" with decomposition. Anal. Calc'd for C ~ ~ H ~ ~ N SC,O73.46; S : H, 10.36. Found: C, 73.39; H, 9.55. Ketone C Preparation. (a) From 8,6-peroxidocholestene-d.-Three grams of the peroxide was refluxed for one and a half hours with 350 cc. of a 5% solution of potassium hydroxide in 95% methyl alcohol. Upon concentration t o one-half of the original volume and addition of 4 cc. of water, crystals began to separate. After several recrystallizations from methyl alcohol the ketone melted a t 153.5-154"; [CY]: $35.4" (51.8 mg. in 3.06 cc. CHCla). The yield was 65%. Anal. Calc'd for C ~ S H ~ S O C,S77.72; : H, 11.18; -OCHa, 7.17. Found: C, 77.87; H, 10.98; -OCHs, 6.88. ( b ) From ketone A.-A 240-mg. portion of ketone A was refluxed for one and a half hours with 25 cc. of a 5% solution of potassium hydroxide in 95% methyl alcohol. The solution was then concentrated to half its volume, and sufficient water added so that the reaction product began to separate on cooling. After several recrystallisations from small amounts of alcohol the substance melted a t 152.5-153'; [a];+35.5' (36 mg. in 3.06 cc. ether). A mixture of this substance with a sample of ketone C prepared by method (a) gave no depression of the melting point. Anal. Calc'd for C28H,sO~:C, 77.72;H, 11.18. Found: C, 77.76; H, 11.44. (c) From ketone B.-When ketone B was treated with a solution of potassium hydroxide in methyl alcohol in an analogous manner, an 80% yield of a product of m.p. 152.5" wa8 obtained. Mixed with an authentic sample of ketone C i t gave no depression of the melting point. Titration with perbenzoic acid.-Upon titration with perbenzoic acid in the usual


39

manner 66 mg. of ketone C took up 0.05 mg. of oxygen in 24 hours, an amount corresponding t o 0.02 double bonds. Semicarbazone.-An alcoholic solution containing ketone C and an excess of semicarbazide hydrochloride and fused potassium acetate was refluxed for one hour. The semicarbazone crystallized upon cooling. It was recrystallized several times from absolute alcohol; m.p. 251-254'' with decomposition. Anal. Calc'd for CzoHslN~Oa:c, 71.12;H,10.50. Found: C, 71.37; H, 10.43. Treatment with acetic anhydride.-Ketone C (99 mg.) was refluxed for 3 hours with acetic anhydride (0.8 cc.). The crystals which formed on cooling were recrystallized once from methyl alcohol. The product melted at 153" and gave no depression of the melting point when mixed with ketone C. SUMMARY

(1) 2,5-Peroxidocholestene-3 rearranges quantitatively under the influence of sunlight to give a saturated ketone, ketone A, of m.p. 172" and [I.D +141°. (2) On vacuum distillation ketone A rearranges into ketone B, m.p. 174", and [a]D +36", which is probably a stereoisomer of ketone A. (3) On treatment with a solution of potassium hydroxide in methyl alcohol, 2 ?5-peroxidocholestene-3? ketone A and B give a monomethoxy monohydroxy ketone, c;m.p. 153.5'; [a]D +35". (4) On distillation in vacuum, ketone C is transformed into ketone B. ( 5 ) The structure of steroid peroxides and their rearrangement products has been discussed.

THE CHEMISTRY OF UNSATURATED STEROIDS. V

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