needles, m.p. 303-305' dec. (further recrystallization gave m.p. 301-302° dec., undepressed by admixture with X V I I a much darker product, m.p. 306-307" dec.). (e). 5,5 '-Methylene-bis-(7-chloro-8-quinolino1)(XVIII) .Anal. Calcd. for C19H12C12h'202:C, 61.47; H , 3.20. During an attempt t o apply the procedure of I11 t o the prepaFound: C, 61.47; H, 3.36. ration of the diethylamino analog of I X , from the reaction (B).-A solution of 9 g. (0.05 mole) of 5-chloro-8-quinolinol and 0.75 g. (0.025 mole) of paraformaldehyde in 100 mixture there separated 2.1 g. of light tan colored solid, m.p. 309-310" dec. Recrystallized from phenyl ether and ml. of acetic acid was heated under reflux for 90 minutes. then from xylene, it melted a t 310-311" dec. Then, 0.5 g. more of paraformaldehyde was added and Anal. Calcd. for ClgH&12N20: C, 61.47; H, 3.26. heating continued for about four hours. The solution was diluted with water and 6.5 g. (70% yield) of product was Found: C, 61.76; H , 3.62. collected by filtration, m.p. 304-305' dec. with no depresAn appreciable amount of what was apparently the hygrosion upon admixture with the analytical sample from A. scopic hydrochloride (dec. > 165') of the desired analog of (C) .-A mixture of 5.4 g. (0.03 mole) of 5-chloro-8-quinoI X was isolated, but it could not be purified readily. linol, 0.9 g. (0.03 mole) of paraformaldehyde, 3.1 g. (0.03 5,6,7-Trichloro-8-quinolinol(XIX) .-Solution of 4.6 g. mole) of triethylamine and 100 ml. of alcohol was heated a t (0.025 mole) of 6-chloro-8-quinolino1'6 in 250 ml. of absolute reflux. After 20 minutes of heating a precipitate was noted alcohol was effected by warming. Then, a t room temperaand the quantity increased as the heating continued. rlt ture, a stream of chlorine was bubbled into the solution for the end of two hours, less than a gram of XVII was obtained, 40 minutes. After 12 hours, 4.5 g. of yellow solid was colConcentration of the m.p. 285-290' dec. -4fter washing with alcohol, it melted lected on a filter, m.p. 215-218'. a t 297-302" and was not depressed by admixture with filtrate and neutralization with dilute ammonia gave 2.5 g. of white solid, m.p. 217-219'. The first crop was slightly S V I I (A). (D) .-About a gram of 5-chloro-7-diethylaminomethyl-8- acidic and it lost its yellow color when suspended in water. quinolinol (I) dihydrochloride4 was dissolved in 20 ml. of Recrystallization from alcohol-acetic acid gave 6 g. (96% Two rerryswater. After the mixture had been covered with an equal yield) of crystalline product, m.p. 219-220'. tallizations from acetic acid elevated the melting point only volume of ether, it was shaken with an excess of ammonia. The ether solution was decanted and t o it was added 10 ml. t o 220-220.5". of alcohol. The resulting solution mas evaporated until the A n d . Calcd. for CsH4Cl3XO: C, 43.FjO; H , 1.W. volume was only about 5 ml. Ten milliliters of alcohol was Found: C, 43.72; H , 2.01. added and the solution was heated a t reflux for 90 minutes. .4 few milligrams of tan solid was collected on a funnel, LAWRENCE, KASSAS
[CONTRIBUTION F R O M
THE
INSTITUTE
OF
PAPER CHEMISTRY]
The Constitution of Sapote Gum. 111. A Structural Evaluation BY E. V. WHITE' RECEIVED APRIL28, 1954 Previous communications have dealt n4th the monosaccharide components of sapote gum. The present study is concerned with that portion of the macromolecule which is extremely resistant to hydrolysis. This fraction is composed, for the most part, of aldobiouronic acid residues and can be separated from the methanolysis products of the methyl ether derivative as a mixture of alkylated aldobiosiduronates. Evidence is given to indicate the presence of two compounds of this type. The glycosidic linkage is evidently the same in each instance because complete methylation of the mixture, after reduction of the methoxycarbonyl group to the primary alcohol function, provides the anomeric forms of a single disaccharide. Hydrolysis and 3,4-di-O-methyl-~-xylose thus demonstrating of the latter furnishes equimolar parts of 2,3,4,6-tetra-0-methyl-~-glucose 3 I-2-glycosidic linkage in the original aldobiosiduronates. This new information, together with previous data, permits some description of the molecular architecture of the sapote gum polysaccharide.
The glycosiduronate fraction of the methanolysis The previous communications2a,bin this series have dealt with some of the products formed upon sirup has been more difficult to investigate because methanolysis of sapote gum methyl ether. The of the extreme resistance of the glycosidic linkage glycosidic components of the methanolysate proved in the uronic acids to hydrolysis. This fraction is, to be derived from 3-O-methyl-~-xylose,2,;?,4-tri-O- for the most part, of aldobiosiduronate character. Its further treatment with methanolic hydrogen 2,3,4-tri-O-methyl-~-arabinose methyl-D-xylose, and other compounds of glycosiduronate character. chloride eventually provided a sirup from which, The arabinose component evidently arises from a by the usual methods, methyl (methyl 8,4-di-0novel structure in the polysaccharides and reveals methyl-D-g1ucopyranosid)-uronate was isolated in for the first time the natural occurrence of the its anomeric forms as one of the components. The arabopyranose unit in these macromolecules. crystalline acid was obtained therefrom after This finding, so far as it concerns the polysaccha- removal of the ester and aglycone groups by hyrides, removes one objection to the hypothesis that drolysis. Certain of the uronic acid residues of D-galactose and L-arabinose are biosynthetically sapote gum are therefore resident in the internal interconvertible since the improbable shift in ring structure of the macromolecule and are joined structure accompanying the conversion from D- therein a t C-1 and C-2 to other carbohydrate units. galactopyranose to L-arabofuranose is not, of The latter type of glycosidic union has not been reported previously for uronic acid units occurring necessity, a requirement4 in the polysaccharides, although Lythgoe and ( 1 ) University of Toronto, Toronto 3 , Canada. Trippett? have recorded its occurrence in the carbo12) (a) R. V. m'hite, Tiirs J C J U K N A I . , 75, 2.ii fICLi3): ( I > ) 7 5 , 4G92 hydrate component of glycyrrhinic acid. Pro( 1 R53). ( 3 ) T h e isolation o f 3 - O - ( ~ - ~ - a r a b o p y r a n o s y I ) - ~ - a r a b i n ofrom se longed aqueous hydrolysis of the glycosiduronate larch e-galactan and from peach and cherry gum ha> nuw been refraction has furnished 8-0-methyl-D-xylose as the , 119531, and b y P. .4nported b y J . K. x. Jones, J . ( h a m . h ~l(i72 only sugar component. drews, D . H. Ball a n d J . K. N. Jones, i b t d , 4080 ( l M 3 ) , respectively. (4) E , L . Hirst, i b i d . , 70 ( 1 9 4 2 ) .
( 5 ) R 1.ythgor a n d S.T r i p p r t t , ibrd , 1983 (1950).
Oct. .5, 19.54
CONSTITITTION OF SAPOTE GUM: STRUCTURAL EVATJJATION
4907
A further study of this same fraction has assisted configuration of the disaccharide linkage was not materially in clarifying certain structural features determined. Curiously enough, the same comof the sapote gum system. In the present in- pletely methylated disaccharide, except for doubt vestigation, the aldobiosiduronate components as to the character of the glycosidic linkage, has were separated directly from the methanolysate of been preparedsa from an aldobiouronic acid isolated the methyl ether derivative by vacuum fractional from the hemicelluloses of aspen wood, Populus distillation. The product, as the methyl ester, tremuloides, and also from Hemicellulose-B of corn was reduced with lithium aluminum hydridee to cob.8b The present evidence, together with prior experiproduce the corresponding primary alcohol function and thus develop a glucosidic structure more mental data, now permits a tentative consideration susceptible to hydrolysis than was that of the of the molecular architecture of the sapote gum original aldobiosiduronates. When a portion of system. For this purpose, i t seems best to employ the reduced product was hydrolyzed and examined the concept of the repeating unit although it should on the paper chromatogram it became evident that be borne in mind that, as yet, there is no definite three components were present. These, evidently, evidence to support the hypothesis of discrete, were derived from the hydrolysis of two disac- uniformly reproduced, repeating systems as concharides and were identified as 3-O-methyl-~- stituting the structure of this or any other heteroxylose, 3,4-di-O-methyl-~-glucoseand 2,3,4-tri-0- glycan. In the present instance, the molar ratio methyl-D-glucose. Thus, relating back to the aldo- of the component saccharides, produced upon biosiduronates prior to reduction and hydrolysis, in hydrolysis of the methyl ether derivative, namely, one instance, 3,4-di-O-methyl-~-glucuronic acid is 3-O-methyl-~-xylose, 2,3,4-tri-0-methyl-~-xylose, 2,3,4-tri-O-inethylunited glycosidically with 3-O-methyl-~-xylose 2,3,4-tri-O-methyl-~-arabinose, while in the second case 2,3,4-tri-O-methyl-~- D-glucuronic acid and 3,4-di-O-methyl-~-glucuronic glucuronic acid is similarly joined, again, with 3-0- acid approximates within experimental error the methyl-D-xylose. The tri-0-alkylated glucuronic whole number ratio 3 : 1: 1 : 1: 1. The primary or acid has not been identified previously as a com- main chain structure is therefore based largely, if ponent of sapote gum methyl ether although its not entirely, upon units of D-xylose. In the presence as the corresponding glucose derivative aggregate, two of the three branch centers must was suspected in the chromatographic band con- engage in main chain linkage by 1-4 glycosidic These two union since the side chain substituents are evitaining 2,3,4-tri-O-methyl-~-arabinose. compounds move a t about the same rate chromato- dently attached a t C-2. Presumably the third graphically in the ethyl acetate-acetic acid-water D-xylose residue is engaged in a similar manner to system and no convenient method of separation provide a uniform main chain system. The side could be found. With the present information a t chain substituent in one of the three primary chain hand, through the isolation of ZI3,4-tri-0-methyl- units under consideration is a terminal residue of D-ghcosaccharolactone methyl ester as a charac- either D-xylopyranose or L-arabopyranose while the terizing derivative of 2,3,4-tri-0-methyl-~-glucose, second and third units are joined with D-glucuronic this chromatographic band can now be re-assessed.7 acid residues. One of the latter units is of terminal The molar ratio of the components of sapote gum character and one or other of these residues evimethyl ether is thus expressed as: 3-O-methyl-~- dently bears an 0-methyl s u b ~ t i t u e n t . ~The nonxylose, 2.80 parts; 3,4-di-O-methyl-~-glucuronic terminal uronic acid residue bears a t C-2 a glycoacid determined as 3,4-di-O-methyl-~-glucose,1.11 sidic union with the final pentose residue and repreparts; 2,3,4-tri-0-methyl-~-g~ucuronic acid deter- sents the only di-linked unit in the macromolecule. mined as 2,3,4-tri-0-methy~-~-gh1cose, by differ- These deductions are set forward as a tentative ence, 1.07 parts; 2,3,4-tri-O-methyl-~-arabinose, description of the sapote gum system but are with1.05 parts; and 2,3,4-tri-0-methy~-~-xylose, 0.97 out the implication that the side-chain substituents part. Again, the complexity of the evaluation and are necessarily repetitive throughout the macrothe possibility for error is emphasized. molecule on a repeating unit basis. The above-described disaccharides evidently There is, of course, no information a t hand conpossess the same type of glycosidic linkage and cerning the molecular weight of the polysaccharide. differ only in regard to the position of their 0- Indeed, as is always the case with amorphous methyl substituents. Upon complete methyla- compounds of natural origin, the homogeneity of tion a single product was obtained, namely, the the material under consideration may be open to anomeric forms of methyl 2-0-(2,3,4,6-tetra-O- question despite rigorous purification. The present methy~-~-glucopyranosyl) -3,4-di-o-methyl - D - xylo- evidence appears to favor ;4 basic constitution of pyranoside. The constitution of the disaccharide the type described. In this, i t is to be noted that became evident, after hydrolysis, through the the terminal unit of the primary chain should isolation of crystalline 2,3,4,6-tetra-O-methyl-~- produce 3,4-di-O-methyl-~-xylose upon hydrolysis glucose and 3,4-di-O-methyl-~-xylosein equimolar of the methyl ether derivative. No evidence has proportion. The latter compound, a sirup, was been found, as yet, in support of this concept alidentified as the corresponding crystalline lactone though the relatively small amount of the comof 3,4-di-O-methyl-~-xylonicacid. The a- or p- pound derivable from a macromolecule of high (6) M. A . Abdel-Akher and F . Smith, Nature, 166, 1037 (1950). (7) The ratio of 2,3,4-tri-O-methyl-~-arabinose to 2,3,4-tri-0methyl-D-xylose, determined upon a representative sample using the method previously employed for the separation of these components,Z* was found to be 1.05:0.97, respectively.
( 8 ) (a) J K . N. Jones and L. E Wise, J Chem S O L ,3389 (1952); (h) R . L, Whistler, H E. Conrad and L Hough, Txrs JOURNAL, 7 6 , 1668 (1954). (9) E. Anderson and H. D. Ledbetter, J Am. Pharm. Arsoc., 40, 623 (1961).
4908
E. V. WHITE
Vol. 76
molecular weight could easily escape detection. The further characterization of the sapote gum system may well be achieved through the preferential action of periodic acid followed by mild hydrolysis, The resulting product, on the basis of present evidence, should be a substantially linear polysaccharide molecule based largely upon units of D-xylose.
evolution of nitrogen oxides was complete (3 hours) 2,3,1tri-0-methyl-D-glucosaccharic acid was formed. The reaction mixture was diluted with water and distilled under reduced pressure with periodic addition of fresh water and finally with addition of anhydrous methanol to remove most of the nitric acid. The sirupy residue, in ether solution, was then treated with diazomethane to destroy residual nitric acid and esterify the reaction product. After removal of excess reagent and solvent the sirup, 0.15 g., was distilled, b.p. 110' a t 0.2 mm. It crystallized spontaneously and, recrystallized from ethyl ether, furnished the Experimental Part methyl ester of 2,3,~-tri-O-methyl-~-glucosaccharolactone with m.p. 107"ll alone or admixed with an authentic speciPreparation and Methanolysis of Sapote Gum Methyl men,12[ a l Z o D55" (c 2.0 in methanol). Ether.-Sapote gum was dissolved in water and treated with dnal. Calcd. for CloHls07: OMe, 50.0. Found: O M r , dimethyl sulfate and alkali as previously described2* to pre50.0. pare the ether derivative. The product was then dissolved in anhydrous methanol t o furnish a 10% solution t o which Methylation of the Reduction Product from Fraction 11.anhydrous hydrogen chloride was added t o 7% concentra- The reduction product from fraction I I , 4 . 5 g., was dissolved tion. The reaction mixture was heated under reflux for 8 in 20 ml. of methyl iodide and heated under reflux for 1 hours, cooled, neutralized with silver carbonate, filtered hours with 7 g. of freshly prepared silver oxide. The rcwand evaporated t o a sirup which was extracted with ethyl tion products were separated in the usual manner and, ether. After removal of excess solvent the resulting sirup after five separate treatments, the fully methylated derivawas distilled fractionally a t 0.2 mm. t o provide Fraction I, tive was eventually obtained in 4.0-g. yield. It distilled 10.6 g. (b.p. 60-180'); Fraction 11, 7.3 g. (b.p. 150-200'); under 0.2 mm. at b.p. 150-155'. and a still residue of 1.3 g. The components of Fraction I Anal. Calcd. for C18HJg010:OMe, 52.9. Found: OMe, have received previous consideration.28 The still residue, 51.0. comprising undistilled fraction I1 and a reaction tar, WAS When a sample of the sirup was hydrolyzed as previously discarded. Reduction of Fraction I1 with Lithium Aluminum Hy- described and the hydrolysate examined chromatographically under similar conditions as described above, evidence dride.-Fraction 11, 5.0 g., shown previously to consist for was obtained for the presence of two major components with the most part of methyl aldobiosiduronate esters, was disminor traces of other substances. solved in 100 ml. of anhydrous tetrahydrofuran and added Hydrolysis of the Methylated Reduction Product from slowly t o a well-stirred solution containing 1.0 g. of lithium aluminum hydride dissolved in 100 ml. of anhydrous tetra- Fraction II.-Three and one-half grams of the methylated hydrofuran. The temperature of the reaction mixture was reduction product from fraction I1 was dissolved in N sulmaintained a t 40" during addition of the reagents and for the furic acid, 15 ml., and heated under reflux for 6 hours. following 30 minutes. The excess hydride was then de- The reaction mixture was then cooled, neutralized with barium carbonate, filtered and evaporated t o a sirup, yield stroyed by the cautious addition of moist tetrahydrofuran 3.2 g. The hydrolysate, 1.7 g., dissolved in 50 ml. of followed by an excess of water t o decompose the addition chloroform, was added in 25-ml. portions t o two no. 3 complex and t o precipitate the hydroxides of lithium and aluminum. The latter were removed by filtration using columns packed with acid-washed Maghesol using 200 ml. of 25:l chloroform-ethanol (by vol.) as the developer in Celite and the filtrate was evaporated to a sirup which was each instance. The extruded columns were streaked, secextracted with acetone, filtered, and excess solvent removed by distillation. The product, 4.8 g., gave a negative tioned, and eluted with acetone in the usual manner t o naphthoresorcinol test and its saponification number was furnish, upon removal of solvent, fraction It, 0.09 g.; fraction I,, 0..562 g.; and fraction I b , 0.862 g. Fraction I t zero. moved at the same rate as the previously identified 3-0Hydrolysis of the Reduction Product from Fraction 11.-A portion, 1.0 g., of the reduction product from Fraction I1 methyl-D-xylose when developed on a paper Chromatogram was treated under reflux for 5 hours with N sulfuric acid. with a mixture of ethyl acetate, acetic acid and water, (9 :2 :2 ) . This component is believed t o be 3-O-methyl-~The hydrolyzate was isolated in the usual manner, yield 0.9 g. IVhen the latter was examined on the papcr chroma- xylose produced in the hydrolysis reaction from a small togram, developed with a mixture of ethyl acetate, acetic amount of incompletely methylated disaccharide or pocsiblv acid and water (9:2:2), against known reference standards by demethylation of the alkylated monose in the acidic medium. I t was not investigated further. there was evidence of three components. These, evidently, Identification of 3,4-di-O-methyl-n-xylose.-Fraction I,, were 3-O-methyl-~-xylose and 3,4-di-O-methyl-~-glucose a sirup which did not crystallize, was treated with 1 ml. of which have been isolated and identified previously2* in the bromine in 10 ml. of water and 36 hours a t room temperacourse of these investigations together with a third, as yet unidentified, component. The two known compounds, ture in t.he absence of light. Upon removal of the bromine by aeration, the non-reducing solution mas neutralized with eluted from the appropriate strips cut from several paper silver Carbonate and filtered. The filtrate was then treated chromatograms and crystallized from suitable solvents, had with hydrogen sulfide t o remove silver ion, filtered, evapomelting points and mixed melting points identical with rated to a sirup, and dried a t 50'. The yield was 0.53 g. those of the corresponding authentic compounds. Identification of 2,3,4-Tri-O-methyl-~-glucose.-The The sirup was extracted with ethyl ether and crystallized from the same solvent to furnish the lactone of 3,4-di-Ohydrolysate of the reduction product from fraction 11, 3.6 g., alone or admixed was dissolved in 75 ml. of chloroform and placed on a no. 5 methyl-D-xylonic acid with m.p. column of acid-washed Magnesol.lo The chromatogram was with an authentic specimen, [a]*'D -26' ( c 3.0 equilibrium in water). developed with 780 ml. of 2 5 : l chloroform-ethanol (by .4nal. Calcd. for C7111?05:OMe, 35.2. Found: OMe, vol.). The column was then extruded, streaked and sectioned. The individual sections were eluted with acetone 35.2. and, after removal of excess solvent, furnished fraction It, Identification of 2,3,4,6-Tetra-O-methyl-~-g~ucose.2.39 g., and fraction TI,, 1.01 g. Fraction It, comprising Fraction I h was distilled under 0.2 mm. to furnish 0.7 g. of a 3-O-methyl-~-xylose and 3,4-di-O-methyl-~-glucose, was colorless sirup. When the latter was dissolved in ethyl not examined further. Fraction I b wa: distilled a t 0.2 mm. ether 2,3,3,6-tetra-O-methyl-D-glucose crystallized in good t o provide a colorless sirup, b.p. 120 , with [ a l Z 0 D 65' (c yield. The compound melted a t 92'14 and had [ a l Z o ~ 3.7, equilibrium in water). 82' (c 2.9 equilibrium in water). Anal. Calcd. for CgHlsOG: OMe, 41.9. Found: OMe,
41.5. An attempt t o prepare the crystalline aniline derivative was not successful. However, when 0.2 g. of the sirup was oxidized with 5 ml. of nitric acid (d. 1.2) a t 90' until the (10) I. A. Pearl and E. E. Dickey,
THIS JOURNAL, 73,863 (1961).
(11) R . W. Humphries, J. Pryde and E. T. Waters, J . Chem. SOC., 1298 (1931). (12) The authentic specimen was prepared from 2,3,4-tri-O-methyllevoglucosan which was kindly supplied by Fred Smith. (13) Sybil P. James and F. Smith, J . Chem. SOC.,739 (1945). (14) T. Purdie and J. C. Irvine, {bid.. 83, 1021 (1903).
SYNTHESIS O F 17a-hf ETHYLDESOXYCORTICOSTERONE
Oct. 5 , 1954
Anal. Calcd. for ClOHHzoOe: OMe, 52.5. Found: OMe, 62.4. When 0.1 g. of the crystalline compound was treated with moles of aniline in the usual manner the aniline derivative of 2,3,4,6-tetra-O-methyl-~-glucose was obtained. It
[CONTRIBUTION FROM
THE
4909
crystallized from ether solution and melted a t 135OlSalone or admixed with an authentic specimen. (15) J. C.Irvine and Agnes M.Moodie, J . Chcm. Soc., 93, 95 (1908).
TORONTO 5, CANADA
COLLIPMEDICAL RESEARCH LABORATORY AND
FROM THE UNIVERSITY OF WESTERN ONTARIO, LONDON, CANADA]
DEPARTMENT OF
CHEMISTRY,
Steroids and Related Products. I. The Synthesis of 17a-Methyldesoxycorticosterone BY CH. R. ENGEL'AND G. JUST* RECEIVED MARCH29, 1954
A new hormone analog, 17~~-methyldesoxycorticosterone, has been synthetized from desoxycorticosterone. In the course of this investigation it has been shown that the alkali-sensitive a$-unsaturated 3-ketone, present in many natural steroid hormones, can be protected easily against strong alkaline treatment by the formation of the corresponding enol ethyl ether. 17a-Methyldesoxycorticosterone acetate was found to possess adrenal cortical activity.
Considering that 17a-methyltestosterone3 is a of such compoundss or by Oppenauer oxidation of highly potent, orally active androgen4 and that A6-3-hydroxysteroids.9 Desoxycorticosterone (I) 17a-rnethylproge~terone~~~~~~ possesses two to three was converted in good yield, according to Reichtimes the progestational activity of the natural stein's method,"J to a mixture of 21-tosyloxyprocorpus luteum hormone, progesterone,sb.c.6 i t gesterone (IIa)lO.ll and 21-chloroprogesterone (IIb) seemed of interest to prepare the corresponding 17 in which the latter predominated considerably. homologs of the adrenal cortical hormones and to We found that when the mixture was not eluted investigate their biological properties. The interest quickly from the chromatographic column (alumiin such experiments seemed the greater because the num oxide) no tosylate could be isolated. The chloimportant adrenal cortical hormones, cortisone roketone I I b underwent a rearrangement of the (Kendall's compound E), dihydrocortisone (Ken- Aston-Greenburg type12 when treated with potasdall's compound F) and 17a-hydroxydesoxycorti- sium methylate in methanol, according to the excosterone (Reichstein's compound S) also have a perimental conditions described by Plattner and substituent in the 17a-position in the form of a hy- co-workers,13and gave in 95% yield a mixture of the two epimeric methyl A4-3-keto-17-methyletienates droxyl group. I t was reported in 195Ojb and again more re- VI and VII. It was not necessary to employ centlysc that parts of such syntheses had been un- chloroprogesterone of very high purity to obtain dertaken in the desoxycorticosterone series. The high yields. When a crude mixture of chloroprosynthesis of 170-methyldesoxycorticosterone has gesterone and tosyloxyprogesterone containing apnow been accomplished by different methods by proximately 60% of chloroprogesterone (in this Heusser and co-workers a t the Swiss Federal Insti- mixture the ratio of tosyloxyprogesterone was detute of Technology in Zurich in collaboration with liberately made greater than in the original reacone of us (C.R.E.) and by our laboratory in paral- tion product obtained from desoxycorticosterone) lel experiments. It was agreed with the Swiss was subjected to an identical treatment, the same group to publish the results obtained in Zurich in mixture of VI and VI1 was isolated from the neuthe Helvetica Chimica Acta and to report the find- tral fraction of the reaction product in approxiings of our laboratory in THISJOURNAL. mately 53y0 yield; the relatively important acid Whereas in the earlier attempts5-' A5-3$-hydroxy- fraction, not obtained when chloroprogesterone steroids were used as starting materials, the experi- alone had been employed, gave upon methylation ments of this series proceeded from 3a-hydroxy- with diazomethane the same mixture of esters, steroids with saturated nuclei belonging to the bringing the total yield of these two esters to apnormal (bile acid) series, or from A*-3-ketosteroids, proximately 88%. The fact that the ester repretoday easily obtainable from the 3-keto derivatives senting approximately 63% of the mixture was (1) Holder of a Medical Fellowship of the Canadian Life Insurance eluted with greater ease from the chromatogram Officers Association. and possessed a higher specific rotation than its (2) This paper is abbreviated from part of the doctoral thesis of G. Just to be presented to the Faculty of Graduate Studies of the University of Western Ontario. (3) L. Ruzicka, M. W. Goldberg and H . R. Rosenberg, Helv. Chim. Acla, 18, 1487 (1935). (4) K . Miescher and E. Tschopp, Schweis. Med. Wochenschriff,68,
1258 (1938). ( 5 ) (a) P1. A. Plattner, H. Heusser and P. Th. Herzig, Helv. Chim. Acta, 32, 270 (1949); (b) H.Heusser, Ch. R. Engel, P. Th. Herzig and PI. A. Plattner, i b i d . , 33, 2229 (1950); (c) Hs. H . Giinthard, E. Beriger, Ch. R. Engel and H. Heusser, i b i d . , 36, 2437 (1952). (6) See also A. Wettstein and F. Renz, Ann. Rev. Biochem., 18, 355
(1949). (7) C f . a forthcoming publication in the "Ilelvetica Chimica Acta."
( 8 ) C f . , for example, V. R. Mattox and E. C. Kendall, THIS JOUR76, 882 (1948); 72, 2290 (1950); J . B i d . Chem., 188, 287 (1951); W. F . McGuckin and E. C. Kendall, THISJOURNAL, 74, 5811 (1952); B. A. Kaechlin, T . H. Kritchevsky and T. F. Gallagher, J . B i d . Chcm., 184, 393 (1950). (9) R . V. Oppenauer, Rec frau. ckim., 66, 137 (1937). (10)T. Reichstein and H. G. Fuchs, Helu. Chim. Acto, 23, 684 (1940). (11) T.Reichstein and W. Schindler, ibid., 23, 669 (1940). (12) J. G. Aston and R . B . Greenburg, THIS JOURNAL,62, 2590 (1940); see also Al. Faworsky, J . p v a k f . Chem., [ 2 ]88, 658 (1913). (13) PI. A. Plattner, H Heusser and S F Royce, Helv. Chim. A c t a , 31, 603 (1948). NAL,
