THECONSTITUTION OF ~-CHOLESTECROL
Feb., 1938
Summary Attempts to prepare hexa-8-styrylethane and di-P-styryltetraphenylethane have yielded isomeric stable hydrocarbons. In the second of these cases the hydrocarbon has been definitely
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identified as 1,1,3,4,6,6-hexaphenylhexadiene - 1,5, showing that a 1)3-rearrangement had Preceded the coupling reaction involved in the synthesis. URBANA, ILLINOIS
RECEIVED DECEMBER 24, 1937
FRICKCHEMICAL LABORATORY, PRINCETON UNIVERSITY ]
Molecular Rearrangements in the Sterols. 111. The Constitution of i-Cholesterol and of the Isomeric Ethers of Cholesterol B Y E. GILMORE FORD,' PURNENDUK'ATH CHa4KRAVORTY2AND EVERETTs. WALLIS
In a paper recently published3from this Labora- crystalline chloro ketone, 111, which is easily puritory certain experimental results were reported fied as such and which forms a characteristic on the action of anhydrous potassium acetate on oxime. This chloro ketone was found by detercholesteryl p-toluenesulfonate in acetic anhydride minations of the melting point and mixed melting solution. The preparation of a new isomer of point to be identical with the a-3-chlorocholescholesterol, designated as i-cholesterol, was de- tanone-6 prepared by Windaus and Dalmer6 from scribed. Some important chemical properties of cholesteryl chloride. Removal of hydrogen chlothis new compound and of its acetate were also ride by means of alkali produces the same "hetrecorded. From the chemical behavior of these erocholestenone," IV (m. p. 95-96'). Hydrotwo new compounds the authors were led to the genation of samples of this unsaturated ketone conclusion that in this reaction a molecular rear- obtained from both sources with palladium black rangement occurred. Accordingly, they sug- gives the same cholestanone (m. p. 98-99') identigested a tentative formula, I, for i-cholesterol. cal with the compound prepared from cholestene They also pointed out that a close relationship by the method of W i n d a ~ s . ~ * ~ exists between this new alcohol and the isomeric From these facts i t can be seen that in i-cholesethers of cholesterol discovered by S t ~ l l . In ~ terol the hydroxyl group is in position 6 of the Part 115 of this series this relationship was clari- sterol molecule and that during its formation from fied, and evidence was submitted which shows con- cholesteryl 9-toluenesulfonate a molecular rearclusively that the abnormal ethers of cholesterol rangement occurs. We think, therefore, that the recently referred to in the literature as "cis-choles- structural formulas for i-cholesterol and the isoteryl ethers" are in reality ethers of i-cholesterol. meric ethers of cholesterol first discovered by We are now able to substantiate the validity of Stol14 are now established and that the recent the formula suggested for i-cholesterol, I, by the arguments and contentions of Heilbron, et 0 1 . , ~ series of reactions shown in the chart. are untenable. As shown in Part Ia of this series i-cholesterol In conclusion we also would like to point out on oxidation in glacial acetic acid solution with that in this new isomer of cholesterol there are chromic acid (CrO$ gives a ketone which was interesting possibilities. The method of breaking isolated in the form of its oxime (m.p. 143-144'). the cyclopropane ring gives a new route to the From this oxime we have been able to prepare i- preparation of many highly interesting compounds cholestanone, 11, whose crystals melt a t 110-111', and further investigations in this direction are in progress. and have the specific rotation [ c Y ] ~ ~ $64.9'. D Treatment of this compound with dry hydrogen Experimental Part chloride dissolved in glacial acetic acid yields a Preparation of a-3-chlorocholestanone-6 (III) from z(1) tion. (2) tion. (3) (4)
Research Assistant on special funds from the Chemical FoundaResearch Fellow on special funds from the Rockefeller Founda-
Wallis, Fernholz and Gephart, THIS JOURNAL, 59, 137 (1937). Stoll, 2. 9hrsiol. Chcm., 801, 147 (1932). ( 5 ) Ford and Wallis, THIS JOURNAL, 59, 1415 (1937).
Cholestanone 0xime.i-Cholestanone oxime (m. p. 143-144') prepared by the method of Wallis, Fernholz and (6) Windaus and Dalmer, Ber., 58, 168 (1919); see also Mauthner and Suida, Monatsh., 84, 656 (1903). (7) Windaus, Ber., 53, 492 (1920). (8) Heilbron, et al., J . Chcm. Soc., 406,1459 (1937).
414
E. GILMORE FORD, PURNENDUNATH CHAKRAVORTY AND EVERETT S.WALLIS
0 I1
1
Vol. 60
a
1
I11 -HCl
J.
Heterocholestenone
I? HNOa in ____f
CHsCOOH
cl/ NO2
VI
VI1
Gepharta was hydrolyzed with dilute sulfuric acid in al- ride. When samples of the oxime from each source were cohol solution. The solution was boiled for one-half hour, mixed no depression of the melting point was observed. It also should be noted that in subsequent experiments it diluted with water, and extracted several times with ether. The ether solution was then freed from acid and dried over was found that a-3-chlorocholestanone-6could be obtained anhydrous sodium sulfate. Evaporation of the ether gave easily in a pure form from a n impure specimen of i-cholesa gummy material. Recrystallization from dilute al- tanone. It is a compound which crystallizes with great cohol, dilute acetone and dilute methyl alcohol gave a readiness and is very easy to purify. sample of crystalline ketone which melted at 110-11lo; [ a I z 6 ~ Preparation of Cholestanone-6 (V).-A +64.9’ (11.1 mg. in 2 cc. of chloroform solution gave a p 6 ~a-3-chlorocholestanone-6 (0.25 g.) prepared from icholesterol by the method described above was dissolved +0.36’). To a solution of 6 cc. of glacial acetic acid containing 3% in a 5% alcoholic potassium hydroxide solution and boiled hydrogen chloride there was added 120 mg. of the above for one-half hour. The solution was then diluted and described ketone (i-cholestanone). The solution so ob- worked up in the usual manner. Recrystallization from tained was allowed to stand overnight a t room tempera- methyl alcohol gave a product which melted a t 95-96’, the ture. It was then diluted with 3 volumes of water and ex- melting point recorded for “heterocholestenone” prepared tracted several times with ether. The ether solution was from cholesteryl chloride by Windaus and Dalmer. When freed from acid and worked up in the usual manner. Crys- mixed with an authentic specimen of “heterocholestenone” tals were readily obtained from alcohol which melted at prepared by Windaus and Dalmer’s method no depression 129-130”. Subsequent recrystallizations’ gave a product of the melting point was observed. One-tenth of a gram of this unsaturated ketone was diswhich melted a t 129.5-130.5; yield 120 mg. Twenty milligrams of this material dissolved in 2 cc. of chloroform solved in 20 cc. of glacial acetic acid, and was hydrogenated solution showed no appreciable rotation. When mixed in the presence of palladium black. On working up the with an authentic specimen of the chloro ketone prepared solution in the usual manner crystals were obtained from from cholesteryl chloride by the method of Windaus and alcohol which melted a t 88-90’. An oxime was prepared Dalmere no depression of the melting point was observed. in the usual manner from a portion of this material. ReAs a further check on the identity of the two compounds crystallization from alcohol gave a crystalline product samples of each were converted in the usual manner into which melted a t 195”, the melting point recorded for the their oximes. In both cases crystals were obtained from oxime of cholestanone-6 prepared by the method of Winalcohol which melted af 175’, identical with the melting daus and Dalmer from cholesteryl chloride. Further point recorded by Windaus and Dalmer for the oxime of purification of the ketone itself gave crystals which melted a-3-chlorocholestanone-6prepared from cholesteryl chlo- a t 98-99’, the melting point recorded by Windaus and
SOME REACTIONS OF PENTAERYTHRITOL
Feb., 1938
Dalmer for cholestanone-6 prepared from cholesteryl chloride and for the same ketone prepared from nitrocholestene by Windaus? When mixed with an authentic specimen of this ketone no depression of the melting point was observed.
We wish to express our thanks to the Rockefeller Foundation and to the Chemical Foundation for the grants-in-aid which made this work possible.
Summary Evidence is submitted which leads to the con-
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clusion that the hydroxyl group in &cholesterol is in position six of the sterol molecule and that during its formation from cholesteryl p-toluenesulfonate a molecular rearrangement occurs. The results obtained and described in this paper substantiate the validity of the structural formula proposed by investigators in this Laboratory for i-cholesterolaj6 and for the isomeric ethers of cholesterol. PRINCETON, N. J.
RECEIVED DECEMBER 18, 1937
KENTAND GEORGE HERBERT JONES CHEMICAL LABORATORIES, UNIVERSITY OF CHICAGO ]
The C,-Saccharinic Acids. VIII. Some Reactions of Pentaerythritol. Preparation of 2,2’-Diiodoisobutyric Acid and its Hydrolysis to 2,2’-Dihydroxyisobutyric Acid’ BY J. W. E. GLATTFELDAND
Previous attempts to prepare 2,2’-dihydroxyisobutyric acid in these Laboratories2s3indicated pentaerythritol to be the most promising starting material for the synthesis of this acid (hereafter referred to as the 2,Y-acid) so far untried. Oxidation of two hydroxymethyl groups to carboxyl groups and subsequent elimination of carbon dioxide according to the following scheme would give the desired 2,2’-acid CHZ05Cc
c
c
