SILIOICOLIN, A NEW COMPOUND ISOLATED FROM
5.52; OCH3, 23.25; mol. wt. (Rast, camphor), 395. The Gaebel test4 for the methylenedioxy group was Sir : pnsitive. The insolubility of silicicolin in water and cold The finding' that an aqueous suspension of the pulverized dried needles of Juniperus silicicola 5% sodium hydroxide solution indicates the absence (Small) Bailey? (Fam. Pinuceae) produced damage of acidic function such as carboxylic acid and phento Sarcoma 37 in mice, prompted a search for the olic hydroxyl groups. The slow solubility of the active agent or agents. After a process involving compound in boiling 5( sodium hydroxide solusuccessive extractions with different organic sol- tion, with separation of a white gelatinous prevents and chromatography with activated alumina, cipitate on acidification, is strong evidence of '1 similar to that described for other junipers,3 a pure lactone group. The ultraviolet spectrum (Fig. l), showing crystalline compound was obtained in 0.11% yield which was highly active against the tumor. XFZ" 293.5 mp (log E 3.68) and Xz:" 258.5 mp (log e 3.01), is similar to that of podophyllotoxin6 292 mp (log E 3.65) and ";::1 260 (log . I < . , , t 3.07)]. Bands in the infrared (Fig. 2 ) a t lis0 cm. (7-lactone) and 1593 cin. - I (aromatic ring) approximate closely the corresponding ones 111 podophyllotoxin (1785 cni. and 1.593 ~ 1 1 1 . -' I Hydroxyl group absorption around 3450 u i i is negligible. JUNIPER US SILK IC 0LA
t
CY 4000 3000
2000
' i ' i ' ; ' !
I500
k _-' l
i ' i ' l b
II
L-..~_I-J 13
I!
14
I5
W A V E l t l i G l N NI[RONI
Fig. 2 -Infrared
absortion spectrum of chloroform.
silicicoliri
iii
The available evidence is consistent with the assumption that silicicolin is a lignan, perhaps the previously unknown desoxypodophyllotoxir~.~ Structural and biological studies are in progress.
X,mp Fig. 1.---Ultraviolet ahsorption spectrum of silicicoliri in 95yo ctlia1101,
4 G. 0 . Gaebel, .4vrh. $ h a r m . , 248, 225 (1910). [S) A. W. Schrecker a n d J I, Hartwell, THISJOCRNAL, in press (1952). Podophyllotoxin itself was first suspected because of its isolation from other species of juniper.8 (6) Compounds of t h e same empirical formula, possibly structurally similar, have been isolated from plants of t h e family Unzbellijerae, b y K . Noguchi a n d M. Kawanami, J . PWarm. SOL.Japan, 60,629 119401, a n d b y 1. hfarion, Con J , Risenvch, 20B,157 (1942). LABORATORY O F CHEMICAL PHARMACOLOGY JONATHAN L.HARTWELL NATIONAL CANCER INSTITUTE SATIOSAI, INSTITUTES OF HEALTH JAMES M. JOHNSOX DCIROTHEA B. FITZCERALD PI-RI,ICHEALTH SERVICE
MI). XORRIS BELKIS The new coinpound, for which we propose the BRTIIESIIA, name silicicolin, crystallizes from absolute ethanol RECEIVED J Y L Y 21, 1952 in large, colorless, transparent prisms, 1n.p. 173.9~175.5' (cor.); [ ( Y ] ' ~ D - 119" (c, 0.40, chloroform). Anal. Calcd. for C Z ~ H Z O C,~ 66.32; : H, 5 . 5 7 ; 3OCHa,23.37; mol. wt., 398.4. Found: C, 66.34; H, lla-HYDROXYSTEROIDS. SYNTHESIS OF A'(1) D. B. Fitzgerald, M. Belkin, SI.D. Felix and 31. K. Carroll, t o be published in J . N a l . Cancer I?ist. (2) Provided through t h e courtesy of Xlr. R A Honniughauseu, Florida Board of Forestry, Tallahassee, F l a . ( 3 ) J, I, IIartwell, J. hf Johnson. D H I'itzgerald and &I, Belkin, ']'HIS
TOI'KVAI ,
in prrw
PREGNEN-1 la, 17a,2l-TRIOL-3,LO-DIONE 11,2 1-DIACETATE (11-EPI-COMPOUND F DIACETATE 1 Sir :
We wish to report a general method for the reduction of the 11 -carbonyl group in steroids to the
1la-hydroxy gr0up.l This method, coupled with and acid hydrolysis of the semicarbazone6 gave our observation that the 11a-hydroxyl group is not A4-pregnen-1l a ,17a,21-triol-3,20-dione 11,21-diaceoxidized readily by N-bromoacetamide, has made tate (11-epi-compound F diacetate), m.p. 223.0possible the preparation of A4-pregnen-lla,l7a,- 225.8, [.ID + l l S O (1% in dioxane), 16,800. 21-triol-3,20-dione 11,21-diacetate (11-epi-Com- Anal. Calcd. for C25H340,: C, 67.24; H, 7.68. pound F Diacetate). Found: C, 67.12; H, 7.85. Etiocholan-3a-01-l1,17-dione2 was reduced with (6) V. R. Mattos and E. C. Kendall, J . Bid. C k e n . , 188, 287 sodium in refluxing n-propyl alcohol in excellent (1951); B. Koechlio, T.Kritchevsky and T. F. Gallagher, ibid., 184, yield to etiocholan-3a,11a,17P-triol(I), m.p. 245- 303 (1950); E. B. Hershberg, J . OYE.C h e m . , 18, 542 (1948). +13" (O.5Y0 in ethanol). Anal. CHEMICAL 247", RESEARCHDIVISIOX HERSHEL L. HERZOC Calcd. for C19H3203: C, '73.98; H, 10.46. Found: SPHERING CORPORATION EUGEXEP. OLIVETO C, 73.82; H, 10.72. The configuration of the 11- BLOOMFIELD, N. J. MARGARET A . JEVNIK E. B . HERSHBERC hydroxyl group was inferred from the acetylation RECEIVED JUNE9,1952 of I, which gave a triacetate, m.p. 161-1A2°, [CX]?~D -2' (0.9% in ethanol). Anal. Calcd. for C25H3806: C, 69.09; H, 8.81. Found: C, 69.31; THE ION-EXCHANGE SEPARATION OF ISOMERIC H, 8.94. Oxidation of I with excess N-bromoacetDINITROTETRAMMINECOBALT(II1)IONS' amide (NBA) in aqueous methanol-acetone soluSir: tion a t room temperature gave, in good yield, etiocholan-11 a-ol-3,17-dione (11),m.p. 143-144' , [ a I z 5 ~ Recently i t has been shown that the octahedral +72" (1% in acetone). Anal. Calcd. for C1&803: complex ions Cr(HzO)e+++,Cr(SCN) (Ht0)5++,and C, 74.96; H, 9.27. Found: C, 74.87; H, 9.24. Cr(SCN)2(H20)4+ are readily separated by an ionThe structure of I1 was established by independent exchange technique.2 The possibility of using synthesis from I . Oxidation of I with chromic this same technique to separate the isomeric cis anhydride in aqueous acetic acid a t room tempera- and trans complexes having the general formula ture afforded etiocholan-3,11,17-trione(111),3m.p. MA4B2+n was suggested a t that time. The iso135-136", [ a ] " ~+151" (1% in acetone). Upon meric dinitrotetramminecobalt(II1) ions have been refluxing I11 with ethylene glycol and +-toluene- ~ r e p a r e d ,and ~ their elution characteristics have sulfonic acid in benzene solution, there was ob- been studied. An elution curve of a mixture of the tained etiocholan-3,11,l7-trione 3,17-bisdioxolane two complex ions is shown in Fig. 1. Since the ~ (1% in chloro- absorption spectra of these complex ions are differ(IV), m.p. 122-123", [ a I z 6+30° form). Anal. Calcd. for C23H3405: C, 70.73; ent,4it is convenient to make use of the spectra in H, 8.77. Found: C, 70.75; H, 9.07. Reduction following the elution and identifying the eluted of IV with sodium in refluxing n-propyl alcohol, species. The more easily eluted ion is the trans followed by hydrolysis of the product with meth- complex. anol-hydrochloric acid, yielded 11, identical in all respects with the sample from NBA oxidation of I . Sodium and n-propyl alcohol reduction of pregn a n - 3 17a-dio1-11,20-dione ~~~ 20-dioxolane4 yielded the corresponding 11a-hydroxy compound (V) , m.p. 213.2-214.0", [ a ] D -13" (1% in acetone). Anal. Calcd. for C23H3806: C, 70.01; H, 9.71. Found: C, 69.70; H, 9.74. Hydrolysis of V with aqueous methanol-hydrochloric acid gave pregnan3a,lla,17a-triol-2O-one (VI) as the monohydrate, [ a ] D +25" (0,5y0in acetone). Anal. Calcd. for CZ1H3404*H20:C, 68.44; H, 9.85. Found: C, 68.14; H, 10.07. Bromination of VI in chloroform a t C-21 followed by acetoxylation according to the method of Gallaghers yielded an oil which was not further purified, but was oxidized a t C-3 with NBA 0 100 200 300 1.00 and then acetylated a t C-11 to give pregnan-lla,Volume of eluant (in ml.) 17a,21-triol-3,20-dione 11,21-diacetate (VII), m.p. 232-233' dec., [a]% $44' (1% in dioxane). Anal. Fig. 1.-Relative optical density of eluant versus volume of Calcd. for C25H3607: C, 66.94; H, 8.09. Found: eluant (in ml,). -350 mp, - - - - - 325 mp. For trans C, 66.59; H, 8.20. Bromination a t C-4 followed complex €350 > €325. For cis complex e325 > e8&0. Kotice by semicarbazone formation, elimination of HBr that the relative optical densities in the first part of the second peak indicate that the trans complex had not been (1) F. Sondheimer, R. Yashin, G. Rosenkranz and C. Djerassi completely eluted when the eluting agent was changed. In(THISJOUKNAL, 74, 2696 (1952)) noted that the carbonyl group and the double bond conjugated with i t in A~-22-isoallospirosten-3~- dividual portions of eluant were 12.5 ml. ol-11-one propionate are both reduced to yield the saturated lla-01 (1) This work has been supported in part by a grant from the U. S. with the aid of lithium, liquid ammonia and alcohol. .4tomic Energy Commission. (2) L. H. Sarett, ibid., 70, 1454 (1948). (2) E. L. King and E. B. Dismukes, THISJOURNAL, 74, 1674 (1952). (3) S. Lieberman and K . Dobriner, 1.Biol. Chcm., 166, 773 (1946) (3) cis: H. Biltz and W. Biltz, "Laboratory Methods of Inorganic (4) The preparation of the various pregnane dioxolanes will be the Chemistry," John Wiley and Sons, New York, N . Y.. 1928, p. 17Y. subject of another paper. (5) T. H. Kritchevsky, D. L.Garmaise and T. F. Gallagher, THIS Irons: S. M. Jorgensen, 2. onorg. Chem., I T , 469 (1898). JOUKNAI., 74, 483 (1952). (4) F. Basolo. THIS J O ~ N A I . , 79, 4393 (1950).
