Methods for Introducing Oxygen into Position II of ... - ACS Publications

Methods for Introducing Oxygen into Position II of the Steroids S. A . HARRIS and G. E. SITA

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Research Laboratories, Chemical Division, Merck & Co., Inc.,

Rahway, N. J.

A survey is made of the various chemical, enzymatic, and microbiological methods developed to effect this oxygen addi­ tion. Investigations on the rare natural C-11 oxygenated steroids, such as sarmentogenin and gamabufotalin, are men­ tioned and the synthetic approaches are discussed under three broad subdivisions: (1) the shift to C-11 of a C-12 oxygen atom already present in the molecule (bile acids, hecogenin, etc.); (2) the actual introduction of an oxygen atom into those steroids which are devoid of oxygen in ring C and which form the bulk of the abundant naturally occurring compounds, and (3) the total synthesis.

The first observations of the u t i l i t y of cortisone i n the treatment of rheumatoid arthritis by Hench and K e n d a l l , i n September 1948, not only opened up new horizons i n medicine but also brought about a renaissance i n the chemistry of steroids. The chemical problems a r i s i n g from the need to make cortisone more plentiful and less expensive have been met successfully. The period of the last five years has brought forth many scientific publications attesting to the accomplish­ ments of the chemist. Of the 28 steroids thus f a r recognized i n adrenal cortex extracts, only 5 have been determined to be biologically active and only 2 are of medical interest at present. These are ll-dehydro-17-hydroxycorticosterone (other­ wise known as cortisone) and 17-hydroxycorticosterone, now known as hydro­ cortisone.

Cortisone

Hydrocortisone

Steroids, widely spread through animal and plant life, have been known to chemists f o r a long time. Cholesterol, the unsaponifiable portion of animal and vegetable fats and oils, sex hormones, the bile acids, toad poisons, and many other substances usually found i n small quantities throughout organic nature belong to this class of chemical compounds. Because these molecules are complex, their struc­ ture has been unraveled only i n relatively recent times and much has yet to be learned about them. F r o m the molecular standpoint a l l of these substances can be considered as derived from a four r i n g structure made up of 17 carbon and 28 hydrogen atoms, technically known as cyclopentanoperhydrophenanthrene, each r i n g being identified by a letter and each carbon atom b y a number as shown. Instead of l y i n g flat as might be inferred from the schematic representation, the bonds between the carbon atoms form angles i n the t h i r d dimension, i m p a r t i n g a 1

P r e s e n t address, B a r r e t t D i v i s i o n , Allied C h e m i c a l & D y e C o r p . , 40 R e c t o r St., N e w Y o r k , Ν . Y .

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A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

HARRIS and S U A — O X Y G E N IN STEROID POSITION 11

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" p u c k e r e d " structure to the molecule, which i n t u r n is responsible for problems of steric hindrance that arise when attempts are made to attach other atoms to the system. This latter characteristic is particularly important, i n that i t influences the course of many reactions and often produces unexpected results. If, for example, a substituent or functional group is introduced i n the improper spatial configuration, isomers of the desired compounds are produced which often are medicinally quite inactive. It seems to be essential for the C-10 and C-13 methyl groups (generally present i n n a t u r a l l y occurring steroids) to project forward from the general plane of the r i n g system (assuming the so-called beta configuration, which is conventionally represented by a f u l l line). In the natural steroids the same holds true for the hy­ drogen atom at C-8 and the side chain at C-17, whereas the C-9, C-14, and C-17 hydrogens assume the alpha configuration—i.e., they lie behind the general plane of the r i n g system and are usually represented by a dotted line.

Since most of the natural steroids have configurations similar to that of cor­ tisone, i t seemed highly desirable to use one or the other of such natural steroids as starting material f o r a partial synthesis of cortisone. B u t , i n addition to proper steric configuration, the a n t i a r t h r i t i c activity of the adrenal hormones (whether synthetic or otherwise) appears to depend on the presence of certain functional groups at specified places i n the r i n g system. Thus i t would seem that there has to be: a double linkage between C-4 and C-5, oxygens at C-3, C - l l , and C-17, and a basic - C O - C H 2 O H side chain. Absence of one or more of these substituents usually dimin­ ishes or completely eliminates the therapeutic value of the molecule. C - l l Oxygen Function

Of these groups, the C - l l oxygen function is perhaps the most interesting from the standpoint of steroid synthesis. A historical approach to the problem might make this more apparent. The cortisone used by Hench was prepared from a bile acid, named desoxycholic acid, by means of a 30-step conversion process. Desoxycholic acid possesses a n oxygen function i n the form of an O H at C-12 which, through a sequence of reactions, was utilized as a " h a n d l e " to afford the desired C - l l keto compound. The vast amount of research effort responsible f o r this achievement, stemming from several laboratories across the country and drawing on the previous work of numerous other chemists, is p a r t i a l l y reflected i n nearly 250 pages of reports devoted to various aspects of this work (36). F o l l o w i n g the discovery of cortisone's therapeutic value, i t became immedi­ ately apparent that the supply of cattle bile would be inadequate, and a search f o r more abundantly available r a w materials got under way. A t first attention focused on the plant steroid sarmentogenin, because i t possessed an oxygen function at C - l l . A s shown i n a Dutch patent (48), i t can be converted into 3,ll,20-triketo-21-hydroxypregnane, an important compound for the synthesis of cortisone.

Sarmentogenin

3 11,20-triketo-21-hydroxypregnane i

While extensive plant expeditions by Swiss and American laboratories estab­ lished that a number of Strophanthus species contain sarmentogenin, i t became obvious that the a g r i c u l t u r a l program f o r the procurement of sufficient sarmento­ genin would be too formidable to tackle. A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

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The sarmentogenin saga is entertainingly told i n a chapter entitled " T h e Lost Strophanthus" i n Burlingham's, " T h e Odyssey of Modern D r u g Research," pub­ lished i n 1951 by the Upjohn Co. i n connection w i t h the opening of its new phar­ maceutical manufacturing plant (8). Only one other n a t u r a l steroid is known to possess an oxygenated C - l l and that is the toad poison, gamabufotalin (UU), of academic interest only. Another plant steriod—the sapogenin hecogenin (chemically known as 22isoallospirostan-3/3-ol-12-one)—has received considerable attention because i t con­ tains oxygen i n position 12. Hecogenin is readily isolated from certain species of Agave found i n the southwestern parts of U n i t e d States, Mexico, and A f r i c a . It can also be easily recovered from sisal wastes. The conversion of hecogenin to a n 11-keto compound (11-ketotigogenin) was accomplished by the group headed by Djerassi and Rosenkranz (18, 19) employing a modification of the scheme developed by Gallagher and his coworkers (25).

The p r i n c i p a l problem involved i n this conversion is the transfer of the 12-keto group to the 11-position as shown. Introduction of Oxygen Atom

In the meantime, attention had been turned to some of the steroids without oxy­ gen at r i n g C that are readily available i n relatively large quantities—e.g., cholesterol from wool fat, stigmasterol from many fats and oils, ergosterol from yeast, and certain sapogenins, i n particular diosgenin which is readily obtainable f r o m the Mexican yam, Dioscorea macrostachya. The object was to find practical methods by which oxygen could be introduced at C - l l i n r i n g C. A s so frequently happens i n chemistry, the objective was realized i n several laboratories almost at the same time.

A key intermediate i n the utilization of these compounds is a conjugated 7,8:9,A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

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11-diene. These dienes are prepared f r o m the 5,6:7,8-dienes by selective reduction of the 5,6 double bond followed by treatment of the 7,8-ethylene w i t h mercuric acetate (63). The 7,8 double bond (Δ ) may be already present as i n ergosterol or m a y be introduced into a Δ steroid b y the action of ΛΓ-bromosuccinimide followed by dehydrobromination (14). A process involving the shift of a double bond from position 6 has also been used (13). T h e 7,9-dienes are interesting compounds; because they are conjugated, they span rings Β and C, bridging positions 7 and 11. 7

5

AcO'

F o r the conversion of 7,9-dienes, a n interesting observation that the compound reacts w i t h per acids i n a stepwise manner was reported by Chamberlin, Chemerda. and coworkers (10) using ergosterol D and later by the Swiss group of Heusser and J^ger at Zurich (32). The first mole of per acid is absorbed i n a matter of minutes, the second i n a matter of a few hours, and the t h i r d mole requires a day or so f o r consumption. B y controlling the quantity of per acid a mono-, di-, and t r i oxide can be prepared. Dichromate oxidation or hydrolytic rearrangement of the monoepoxide fol­ lowed by oxidation affords the 7 - l l - d i k e t o - A compound which is converted to the 11-ketone by zinc dust and acetic acid, followed by removal of the 7-keto group by a Wolff-Kishner reduction (22). Of the many other reactions that the monoepoxide is capable of undergoing, the following (55, 58) is most interesting for the synthesis of cortisone. 8

This rearrangement was first reported by Swiss investigators and observed independently i n the Merck laboratories (32, 55, 58). When the oxide is treated w i t h boron trifluoride or aluminum chloride (in benzene), i t is rearranged into a A ' - H - k e t o derivative. The reduction of the 8,9 double bond occurs readily w i t h l i t h i u m i n liquid ammonia, the desired configuration at position 8,9 being obtained. The yield is 9 0 % or better. If alcohol is present during the reduction, the 11-keto group is also reduced to the l l a - h y d r o x y l group. A s these methods are most direct i n the utilization of the oxide, they are preferred. Two other attractive routes to 11-keto steroids from the same 7,9-dienes were reported by Stork and others (59) and Djerassi and others (16). Stork and co­ workers obtained a 9,11-epoxy-7-keto compound which, on treatment w i t h alkali, rearranges to the corresponding A -Ha-hydroxy-7-keto compound. The 8,9 double bond is readily reduced, yielding the 7-keto-11 α-hydroxy steroid. The 7-keto group was eliminated by the Wolff-Kishner reaction o r through the thioketal w i t h Raney nickel, Djerassi and coworkers converted a Δ -7-keto steroid into the enol acetate, 8

9

8,e

8,9

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which was oxidized with perphthalic acid to the A ' -7-keto-lla-hydroxy 8

9

compound

(16).

A departure from the Δ approach was announced by Laubach and co­ workers (89), who employed photochemical peroxidation of r i n g C dienes to intro­ duce the 11-oxygen as a C - l l to C-14 peroxide bridge. 7,β(11)

R

R

R

A dehydroergosterol-type triene is catalytically isomerized with liquid sulfur dioxide to yield the Δ ' - t r i e n e , which is then photoperoxidized and the re­ sulting transannular peroxide is rearranged w i t h mild base to the 11-one, 14hydroxy compound. Dehydration followed by hydrogénation affords the Δ ' -11^βΐο steroid. W i t h regard to biological methods for C - l l oxygenation, a new line of attack was opened by the observation of Hechter, Pincus, and others (65) of the Worcester Foundation for Experimental Biology that perfusion of sterols (such as Compound S and desoxycorticosterone) through the adrenal gland causes hydroxylation i n position 11, to produce hydrocortisone and corticosterone. T h i s discovery was further extended by this group to cover a number of steroids including progesterone (to yield 11/3-hydroxyprogesterone, corticosterone, and hydro­ cortisone), Compound S (to yield hydrocortisone), cholesterol (to yield a mixture of cortical hormones), etc. β

β(14)0(11)

8 9

desoxycorticosterone

corticosterone

progesterone

11-hydroxyprogesterone

Compound S

Compound F (hydrocortisone)

It was later found by others (41, 55) that homogenates of the adrenal gland are also effective i n bringing about the 11-hydroxylation reaction. In every case, hydrox­ ylation produced an 11/3-hydroxy steroid which one expects, since the 11 α-hydroxy steroids have not been found i n the glands. Although these reactions can be carried out i n vitro and are remarkable to the organic chemist, they have not been considered completely practical because of the limitation of adrenal gland supplies a n d the instability of the enzyme system. U p to now no direct chemical oxidation has been devised to carry out this step. If the human gland can carry out 11-hydroxylaA Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

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t i o n reactions and the chemist cannot furnish the reagent to accomplish this same transformation, possibly the microbe may provide the tool. In A p r i l 1952, Peterson and M u r r a y of the U p j o h n Research Laboratories (50) reported that steroids can be 11-hydroxylated using microorganisms. Thus, a comm o n mold of the order of Mucorales (Rhizopus arrhizus) oxidizes progesterone to lla-hydroxyprogesterone and to a dihydroxyprogesterone, later found to be 6 a , l l a - d i hydroxyprogesterone.

k-OH hOH

The U p j o h n publication was followed by several publications on the use of microorganisms for steroid hydroxylations (12, 24). U s i n g an unidentified fungus of the Rhizopus family, the Syntex group (40) carried out the microbial oxidation o f progesterone to lla-hydroxyprogesterone i n 4 5 % yield. The same authors con­ verted lla-hydroxyprogesterone to pregnane-ll,20-dion-3a-ol acetate which pre­ v i o u s l y had been converted to cortisone. COCH

COCH,

COCH,

3

CrQ

[H]

3

This synthesis from progesterone requires 10 steps or, starting w i t h diosgenin, 14 steps required. It is the shortest synthesis of cortisone (starting w i t h a p l a n t •material) reported to date. The Squibb research group (24) observed that Aspergillus niger is also effective i n microbial oxidation of steriods. The same hydroxylation was carried out w i t h 17-hydroxyprogesterone. With the latter, the expected lla,17a-dihydroxyprogesterone was obtained (15% yield) along w i t h 17a-methyl-D-homo-A -androstene-lla, 17a-diol-3,17-dione ( 2 5 % ) . 4

C0CH 0H

C0CH 0H

2

2

,-0H

HO. Aspergillus

25%

•

U

H

niger

~~

The microbial oxidations described above produced i n a l l instances the u n ­ n a t u r a l l l a - h y d r o x y derivatives. Golingsworth (12) reported that Streptomyces

A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

A D V A N C E S IN CHEMISTRY SERIES

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fradiae converted Compound S to hydrocortisone i n small yield. In this instance 11/3 -hydroxylation occurs and similates the adrenal gland i n this respect. Microorganisms are capable of hydroxylating certain steroids i n other positions than the 11 and 6 positions. Thus, Perlman, Titus, and F r i e d (49) observed that an unidentified actinomycete oxidized progesterone to 16a-hydroxyprogesterone. A dihydroxyprogesterone as yet unidentified was also formed. Total Synthesis

Three groups of workers have now completed total syntheses of steroidal com­ pounds capable of being converted into cortisone. Robinson i n 1951(0,) succeeded in synthesizing epiandrosterone. Simultaneously Woodward (64) and his associates at H a r v a r d U n i v e r s i t y announced the successful synthesis of methyl-3a-acetoxy-A etiocholenate. 9(11)

0

Epiandrosterone

COOCH

Methyl-3ar-acetoxy-A

9t,1)

3

-etiocholenate

These syntheses intersected previously published p a r t i a l synthesis of cortisone from n a t u r a l occurring steroids and hence constitute the first formal total synthesis of cortisone. A complete total synthesis of cortisone by an uninterrupted series of reactions was accomplished by Sarett (54) and coworkers of Merck & Co., Inc. The following chemicals were put together i n a stereospecific manner to yield the 21-carbon atom skeleton of cortisone: ethoxypentadiene, benzoquinone, methyl v i n y l ketone, metha l l y l iodide, and ethoxyacetylene magnesium bromide. The benzoquinone furnished the 11-oxygen atom of 11-keto-progesterone, which was the first steroid intermediate obtained i n this synthesis. This was converted into dehydrocorticosterone and then into cortisone. I n this synthesis c^-cortisone was prepared as well as the n a t u r a l stereoisomer.

11-ketoprogesterone

Dehydrocorticosterone

Conclusion

Today a number of different practical methods are available for the synthesis and production of 11-oxygenated steroids. A l l these methods are only a little more than 2 years old as f a r as scientific publications are concerned; They have i n part been responsible for the widespread availability of cortisone. Today cortisone is available i n every hospital and corner drugstore i n this country and i n many other countries. This r a p i d development from the "laboratory c u r i o s i t y " of 3 years ago to the stage of widespread availability is a tribute to modern technology and assures the ultimate goal—the availability of this drug to everyone who needs i t . The following bibliography gives additional references to the methods of intro­ ducing oxygen into position 11 of the steroids. Bibliography

(1) (2) (3) (4)

A r n a u d i , C., Experientia, 7, 81-9 ( M a r c h 1951). B i r c h , A . J., Ann. Rept. Progr. Chem., 48, 204-8 (1952). Budziarek, R., Hamlet, J. C., and S p r i n g , F . S., J. Chem. Soc., 1953, 778-82. Budziarek, R., Johnson, F . , and S p r i n g , F . S. Ibid., 1952, 3410-14.

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(5) Budziarek, R., Newbold, G. T., Stevenson, R., and S p r i n g , F . S., Ibid., 1952, 2892-900. (6) Budziarek, R., and S p r i n g , F. S., Ibid., 1953, 956-9. (7) Budziarek, R., Stevenson, R., and Spring, F . S., Ibid., 1952, 4874-8. (8) B u r l i n g h a m , R., "Odyssey of Modern D r u g Research," Upjohn Co., Kalamazoo, Mich., 1951. (9) Cardwell, H. M. E., Cornforth, J. W., Duff, S. R., Holtermann, H . , and Robin­ son, Robert, Chemistry & Industry, 1951, 389-90. (10) Chamberlin, E. M . , Ruyle, W . V . , Erickson, A . E., Chemerda, J. M., A l i m i n o s a , L . M . , Erickson, R. L., Sita, G. E . , and Tishler, M . , J. Am. Chem. Soc., 73, 23967 (1951). (11) Ciba Foundation, Chemistry & Industry, 1951, S N 1 - S N 1 1 (June 23, 1951). (12) Colingsworth, D . R., B r u n n e r , M. P., and Haines, W . J., J. Am. Chem. Soc., 74, 2381-2 (1952). (13) Dauben, W . G., E a s t h a m , J. F . , and Michaeli, R. Α., Ibid., 73, 4496 (1951). 4496 (1951). (14) Djerassi, C., Chem. Revs., 43, 271-317 (1948). (15) Djerassi, C., Batres, E . , Velasco, M . , and Rosenkranz, G., J. Am. Chem. Soc., 74, 1712-15 (1952). (16) Djerassi, C., Mancera, 0 . , Stork, G., and Rosenkranz, G., Ibid., 73, 4496-7 (1951). (17) Djerassi, C., Mancera, O., Velasco, M . , Rosenkranz, G., and Stork, G., Ibid., 74, 3321-3 (1952). (18) Djerassi, C., Martinez, H . , and Rosenkranz, G., J. Org. Chem., 16, 303-8 (1951). (19) Djerassi, C., Ringold, H . J., and Rosenkranz, G., J. Am. Chem. Soc., 73, 5513-14 (1951). (20) Eppstein, S. H., Peterson, D . H., Leigh, Η. M . , M u r r a y , H. C., Weintraub, Α., Reineke, L . M . , and Meister, P . D., Ibid., 75, 421-2 (1953). (21) Fieser, L . F . , and Herz, J. E., Ibid., 75, 121-4 (1953). (22) Fieser, L . F . , Herz, J. E . , and H u a n g , W . Y . , Ibid., 73, 2397 (1951). (23) Fieser, L . F . , Schneider, W . P., and H u a n g , W . Y . , Ibid., 75, 124-7 (1953). (24) F r i e d , J., Thoma, R. W., Gerke, J. R., Herz, J. E . , Donin, M . N . , and Perlman, D., Ibid., 74, 3962-3 (1952). (25) Gallagher, T . F . , Recent Progr. in Hormone Research, 1, 83-98 (1947). (26) Haines, W . J., Ibid, 7, 255-306 (1952). (27) Hayano, M . , and Dorfman, R. L., J. Biol. Chem., 201, 175-88 (1953). (27A) Hench, P. S., K e n d a l l , E. C., Slocumb, C. H . , and Polley, H . F., Proc. Staff Meetings Mayo Clinic, 24, 181-97 (1949). (28) Herzog, H . L., Jernik, Μ. Α., and Hershberg, Ε. B . , J. Am. Chem. Soc., 7 5 , 269-72 (1953). (29) Herzog, H . L., J e r n i k , Μ. Α., Perman, P . C., Nobile, Α., and Hershberg, Ε. B . , Ibid., 75, 266-9 (1953). (30) Heusler, K., and Wettstein, Α., Helv. Chim. Acta, 36, 398-408 (1953). (31) Heusser, H . , A n l i k e r , R., and Jeger, O., Ibid., 35, 1537-41 (1951). (32) Heusser, H . , Eichenberger, K., K u r a t h , P., Dallenback, H. R., and Jeger, O., Ibid., 34, 2106-32 (1951). (33) Heusser, H . , Heusler, K., Eichenberger, K., Henegger, G. G., and Jeger, O., Ibid., 35, 295-307 (1952). (34) Heusser, H . , Savey, G., A n l i k e r , R., and Jeger, O., Ibid., 35, 2090-5 (1952). (35) Heymann, H., and Fieser, L . F . , J. Am. Chem. Soc., 74, 5938-41 (1952). (36) J. Biol. Chem., M a r c h 1946. (37) K a h n t , F . W., et al., Experientia, 8, 422-4 (1952). (38) K e n d a l l , E . C., Chem. Eng. News, 28, 2074-9 (1950) (39) Laubach, G. D., Schreiber, E . C., Agnello, E . J., Lightfoot, Ε. N . , and B r u n ings, K . J., J. Am. Chem. Soc., 75, 1514-5 (1953). (40) Mancera, O., Zaffaroni, Α., Rubin, Β. Α., Sondheimer, F . , Rosenkranz, G., and Djerassi C., Ibid., 74, 3711-12 (1952). (41) M c G i n t y , D . Α., S m i t h , G . N., Wilson, M . L., Jr., and W o r r e l , C. S., Science, 112, 506 (1950). (42) Meister, P. D., Peterson, D. H., M u r r a y , H. C., Eppstein, S. H . , Reineke, L . M . , Weintraub, Α., Reineke, L . M . , and Leigh, Η. M . , Ibid., 75, 416-18 (1953). (43) Meister, P . D., Peterson, D . H., M u r r a y , H. C., Spero, G . B . , Eppstein, S. H . , Weintraub, Α., Reineke, L . M . , and Leigh, Η. M . , Ibid., 75, 416-18 (1953). (44) Meyer, K., Helv. Chim. Acta, 32, 1599-607 (1949). (45) Oliveto, E . P., Clayton, T., and Hershberg, E . B . , J. Am. Chem. Soc., 75, 486-8 (1953). (46) Oliveto, E . P., and Hershberg, Ε. B . , Ibid., 75, 488-90 (1953). A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

ADVANCES

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IN CHEMISTRY SERIES

(47) Oliveto, E . P., Herzog, H . L., and Hershberg, Ε. B., Ibid., 75, 1505-7 (1953). (48) Organon, Ν. V., Dutch Patent 65,613 ( A p r i l 15, 1950). Compounds of the adrenal cortical hormone series. (49) Perlman, D., Titus, E . , and F r i e d , J., J. Am. Chem. Soc., 74, 2126 (1952). (50) Peterson, D. H . , and M u r r a y , H . C., Ibid., 74, 1871-2 (1952). (51) Peterson, D. H., M u r r a y , H. C., Eppstein, S. H . , Reineke, L . M . , Weintraub, Α., Meister, P. D., and Leigh, Η. M . , Ibid., 74, 5933-6 (1952). (52) Peterson, D . H . , N a t h a n , A . H . , Meister, P. D., Eppstein, S. H . , M u r r a y , H. C., Weintraub, Α., Reineke, L . M . , and Leigh, Η. M . , Ibid., 75, 419-21 (1953). (53) Romo, J., Stork, G., Rosenkranz, G., and Djerassi, C., Ibid., 74, 2918-20 (1952). (54) Sarett, L . H . , Arth, G. E . , Lukes, R. M . , Beyler, R. E . , Poos, G. I., Johns, W . F., and Constantin, J. M . , Ibid., 74, 4974-6 (1952). (55) Schoenewaldt, E . , T u r n b u l l , L., Chamberlin, E. M . , Reinhold, D., E r i c k s o n , A . E . , Ruyle, W . V . , Chemerda, J. M . , and Tishler, M . , Ibid., 74, 2696 (1952). (56) Shoppee, C. W., Vitamins & Hormones, 8, 255-308 (1950). (57) Sita, G. E., Merck Rept., 60, No. 3, 26-8 (1951). (58) Sondheimer, F., Y a s h i n , R., Rosenkranz, G., and Djerassi, C., J. Am. Chem. Soc., 74, 2696-7 (1952). (59) Stork, G., Romo, J., Rosenkranz, G., and Djerassi, C., Ibid., 73, 3546-7 (1951). (60) Sweat, M . L., Ibid., 73, 4056 (1951). (61) Tishler, M . , Record Chem. Progr. (Kresge-Hooker Sci. Lib.), 13, 160-77 (1952). (62) Tschesche, R., and Korte, F., Angew. Chem., 64, 633-8 (1952). (63) Windaus, Α., and Auhagen, E . , Ann., 472, 185-94 (1929). (64) Woodward, R. B., Sondheimer, F., and Taub, D., J. Am. Chem. Soc., 73, 4057 (1951). (65) Zaffaroni, Α., Hechter, O., and Pincus, G., Ibid., 73, 1390-1 (1951). RECEIVED

S e p t e m b e r 13,

1954.

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