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76
this base has been shown to be identical to the bufotenine picrate obtained from piptadenia peregrin^.^
hydrofuran solution to give ferrocene. The absorption spectra in tetrahydrofuran show complex and very sharp bands reminiscent of those of the lanthanide ions in aqueous solutions; this resemRESEARCH LABORATORIES THEUPJOHNCOMPANY NERRILL E. SPEETER blance is shown also in their magnetic properties. KALAMAZOO, ~IICHIGAN WILLIAMC. ANTHOSY The remaining lanthanide elements will probably RECEIVED JUNE 14, 1954 form similar compounds. I n the "actinide" series where similar behavior is to be expected we have prepared a brown dicyclopentadienyl chloro comCYCLOPENTADIENYL COMPOUNDS OF Sc, Y, pound of uranium. La, Ce AND SOME LANTHANIDE ELEMENTS In the transitional series we have shown that Sir: dicyclopentadienyl manganese4 is ionic. It has a The cyclopentadienyl ring is unusual in the magnetic moment corresponding to five unpaired number of metals with which i t forms organo- electrons when magnetically dilute, and forms metallic compounds. This property arises from conducting solutions in liquid ammonia. The the fact that the ring may be attached to a metal formation of the ionic dicyclopentadienylmanin three ways. (a) by the two electron covalent ganese, rather than a covalent bis-cyclopentabond, which may be referred to as the "sandwich dienylmanganese, must be attributed not to a high bond," to many transitional rnetals,lab; (b) by a electropositive nature of the metal, but to the covalent bond between a metal and a single carbon exceptional stability of the manganous ion, which atom of the ring. The silicon cyclopentadienyl has the 3d shell half filled. It may be noted, howcompounds2 may be of this type, ( c ) by ionic ever, that since the negative charge will be disbonds. tributed over the anion, the most likely packing in The ability of electropositive elements to form the crystal will have the cation between the planes ionic cyclopentadienyl compounds is of a more of the rings in a "sandwich" configuration similar general nature than has been realized previously, to that of ferrocene.la although compounds such as cyclopentadienyl(4) G Wilkinson and F, A Cotton, Chelnzrlry and I n d u s t r y ( L o n d o n ) , sodium have long been known.3 The elements 11, 307 (1954). scandium, yttrium, lanthanum and the lanthanide ~IALLINCKRODT LABORATORY G. ITILKINSON UNIVERSITY elements provide an ideal test case, since no organo- HARVARD J. M. BIRMINGHAM MASSACHUSETTS metallic compounds of these elements have been CAMBRIDGE, 10, 1954 RECEIVEDNOVEMBER confirmed. The anhydrous metal chlorides were stirred with cyclopentadienyl sodium in tetrahydrofuran soluSTEROIDS. LXIII.' SYNTHESIS OF A4-19-NORtion. The solvent was removed and the residues P R E G N E N E - ~ ~ ~ , ~ ~ G , ~ ~DIONE - T R I (19OL-~,~~ heated a t 200-250" in vacuum. TricyclopentaNORHYDROCORTISONE) AND RELATED 19-NORADRENAL HORMONES dienyl metal compounds of the formula (C6Hj)&t, where M may be Sc, Y , La, Ce, Pr, Nd, Sm and Gd, Sir : were obtained as sublimates in yields of the order The observation that removal of the C-19 angular of 65%. Typical analyses are' &-Found. C, 73.7; methyl group in the case of progesterone,2adesoxyH, 6.0; Sc, 18.3; required: C, 74.0; H, 6.2; Sc, corticosterone*b and 17a-ethynylte~tosterone~~ re18.5; Ce-Found: C,51.6; H,4.1; Ce,42.S; required: sulted in a marked increase in hormonal activity C, 53.7; H, 4.5; Ce, 41.8; Xd-C, 51.8; H, 4.6; has encouraged us to undertake the more comKd, 41.2; required: C, 53.1; H, 4.5; Kd, 42.5. plicated task of preparing similar derivatives of 11Snz-Found. C, 51.3; H, 4.2; Sm, 43.3; required, oxygenated hormones. We should now like to C, 52.2; H,4.3; Sm,43.5. announce the successful synthesis by a combined The compounds are all crystalline solids, ther- chemical-biochemical procedure of the 19-nor mally stable to a t least 400°, which sublime above analog (111) of the most important adrenal hormone 220' a t mm.: Sc, straw color, m.p. 240"; Y , A4-pregnene-1I@, 17a,2 l-triol-3,20-dione (hydropale yellow m.p. 295"; La, colorless, m.p. 395'; cortisone or Compound F) and of some related Ce,orange,m.p.435'; Pr, palegreen,m.p.420°; iz'd, substances. pale blue, m.p. 380'; Snz, orange, m.p. 36.3"; Alkaline hydrogen peroxide oxidation of 3Gd, pale yellow, m.p. 350'. The compounds de- hydroxy- 17-acetyl-1,3,5,16-e~tratetraene~ gave the compose with water giving cyclopentadiene and corresponding 16a,l7a-epoxide [m.p. 234-23G". the hydroxide. They are insoluble in hydrocarbon [a]"D +124O (all rotations in CHC13); found: solvents but dissolve readily in tetrahydrofuran and C, 76.72; H, 7.881 which upon conversion to the glycol dimethyl ether. They react only slowly 3-methyl ether (m.p. 141-144') followed by hydrowith air. Tricyclopentadienylcerium is an ex- gen bromide opening, catalytic debromination to ception, in that it is blackened instantaneously by 3 -methoxy-1Ta-hydroxy-1 $-acetyl- 1,3,5-estratriene even traces of oxygen; it is also unusual in giving a (1) Paper LXII, F. Sondheimer, 17. Velasco and G. Rosenkranz, blue green vapor. The ionic nature of the com- T I ~ IJOURNAL. S in press. (2) (a) C . Djerassi, L. Miramantes and G. Rosenkranz, i b i d . , 75, pounds is indicated by their instantaneous and (1953); (b) A. Sandoval, L. Miramontes, G. Rosenkranz, C. Djequantitative reaction with ferrous chloride in tetra- 440 rassi and F. Sondheimer, i b i d . , 7 6 , 4117 (1953); (c) C.Djerassi, L. (1) f a ) J D Dunitz and L E Orgel, A'afurc, 171, 121 (193), (b) T V h l o f i t t , THISJ O U R N A L 76, 3386 (19%) (2) K C Friscii, rhid , 75, 0050 (1953) (3) J Thiele, BPY 3 4 , 08 (1901)
Miramontes, G. Rosenkranz and F. Sondheimer, i b i d . , 7 6 , 4092 ( I 954). ( 3 ) C. Djerassi, G. Rosenkranz, J. Iriarte, J. Berlin and J. R o m o ,
i b i d . , 7 3 , 1523 (1951).
Dec. 5 , 1954
COMMUNICATIONS TO THE EDITOR
c,
(m.p. 150-152', [ a I z 0 D f45'; found: 77.02; H, 8.30) and then ketalization with ethylene glycol furnished the corresponding 20-cycloethylene ketal (m.p. 124-126', [~]*OD4-43', no c=O band in infrared; found: C, 74.20; H, 8.61). Birch reduction and subsequent acid hydrolysis yielded 19nor- 17a-hydroxyprogesterone (I) (m.p. 204-206', [ c x ] ~ ~+41°, D XE\:H 240 mp, log e 4.23; found: c, CHzR''
I
CEO
I, R 11, R 111, R IV, R V, R VI, R VII, R
= R" = H, R' OH = H, R ' = R " = OH = OH(@),R' = R" = OH = 0, R' = R" = OH = R' = R" H = R' = H, R" = OH = OH@), R' = H, R" = OH
d/ 75.58; H , 8.98). Microbiological oxidation* a t C-2 1 led to A4-19-norpregnene- 17cr,21-diol-3,20dione (11) with m.p. 178-180', which showed the red color with concd. sulfuric acid and with triphenyltetrazolium chloride typical of the parent hormone (Reichstein's Substance S). It was characterized as the 21-monoacetate, m.p. 241-243', [ a l Z 0+goo, ~ 240 mp, log E 4.22; found: C, 70.63; H, 8.35. Incubation of either I or I1 with adrenal homogenates6 gave crystalline A4-19norpregnene-1 16,17cr,21-triol-3,20-dione (111) (19norhydrocortisone), m.p. 255-257', [ O ( ] ~ O D +112' (MeOH), 241 mp, log E 4.23, 240, 282, 385 and 470 mp,6 v","Bj,9' 3500, 3380 and 3230 crn.-' (multiple OH absorption), 1707 cm.-l (20-ketone) and 1670 cm.-' (A4-3-ketone);' red color with triphenyltetrazolium chloride; found : C, 68.84; H, 8.22; movement ratio8 (CHCI3HCONHZ) 0.40. Chromium trioxide oxidation of 19-norhydrocortisone (111) on a micro scale led to 19-norcortisone (IV), m.p. 230-232',
Xz2,H
Xz2H
XzzH
(4) Cf.A. Wettstein, C. Meystre and E. Vischer, Helv. Ckim. Acta, 37, 1548 (1954). (5) A. Zaffaroni, U. S. Patent 2,671,752. (6) Cf. A. Zaffaroni, Recent Propress i n H o r m a v e Research, 8 , 51 (1953). (7) By courtesy of Dr. R. N. Jones, National Research Council, Ottawa. ( 8 ) This is expressed as the ratio of the movement of the 19-norsteroid compared with the parent hormone on paper in the indicated solvent system. I n agreement with theory, it was found that the norsteroids are less mobile in paper chromatograms and that this becomes particnlarly pronounced with llp-hydroxy nor-steroids (cf. movement ratios of 0.80 and 0.72 for 19-nor-desoxycorticosterone and 19-nor.a b. respectively) since the latter function now is not subject t o hindrance by the angular methyl group. Thus in contrast to hydrocortisone, 19-norhydrocortisone forms a diacefale with acetic anhydridepyridine (2 hr., 2 5 9 as was established on a micro scale by the characteristic mobility ratios on paper (cf. A. Zaffaroni and R. B. Burton, J . Biol. Chcm., 193,749 (1981)).
. !.
6211
238 mp, log E 4.21: X2;o4 280, 340, 415 and 490 mp,6 red color with triphenyltetrazolium chloride, movement ratios (CHCl3-HCONH2) 0.73. The formation by 19-norhydrocortisone of a diacetatea and oxidation to a ketone proves that the new hydroxyl group cannot be tertiary, while the ultraviolet absorption spectrum of 19-norcortisone eliminates position 6. Unequivocal proof for the C-11 location of the hydroxy group in I11 was provided by sodium bismuthate oxidation to A4-19-norandrostene-3,17dione-116-01 (m.p. 193-197', v:xC1' 1739 and 1670 cm.-'; found: C, 75.22; H, S.12); dehydration (p-toluenesulfonic acid-benzene) gave an oil which on the basis of its spectral behavior ( v ~ ~ ~ ' ' 1740 and 1665 cm.-', XgzH 302 mp, log e 4.0) must have been predominantly A4-9(10)19-norandro~tadiene-3,17-dione.~ The formation of this substance is explainable only from an 1l-hydroxy19-nor-steroid. The 1lp-configuration is based rather securely on molecular rotation differences'O and on the argument that in contrast to microbiological oxidation (11a-hydroxylation predominating), adrenal incubation in all recorded cases results in 116-hydroxylation. Similar incubation of 19-norprogesterone (V) 2a or 19-nordesoxycorticosterone (VI) 2b has yielded 19-norcorticosterone [ C ~ ] ~ O D +l55' (EtOH), (VII), m.p. 195-197', XEi:H 241 mp, log E 4.21, 285, 390 and 475 mp;6 found: C, 72.06; H, 8.45; movement ratio8 (CeHtj-HCONHz) 0.35. The above-described experiments thus complete the synthesis of the remaining 19-nor analogs of the important steroid hormones. The results of various biological experiments will be published by other investigators.
X z :
JOINTCONTRIBUTION FROM A . ZAFFARONI RESEARCH LABORATORIES H. J. RINGOLD G. ROSENKRANZ SYNTEX, S. A. FRANZ SONDHEIMER MEXICO,D. I?., A N D DEPARTMENT OF CHEMISTRY G. H. THOMAS WAYNEUNIVERSITY CARLD JERASSI DETROIT, MICHIGAN RECEIVED NOVEMBER 8, 1954 CH3 (9) S Julia, Bull. SOC.C h i m . Fvnrzce. 780 (1954), reports XEi:H 320 m p , log e 4.15 for
@ '
(@
(10) The [MID shift in passing from 111 to hydrncortisone is 4-196 and from I11 to 11-epihydrocortisone is 4-34. Since the [MID contribution of the C-19 methyl group in steroidal hormones lies in the range f 1 5 0 t o +ZOO (A. L. Wilds and N. A. Nelson, THISJOURNAL, '75, 5366 (1953); A. Sandoval, G. H. Thomas, C. Djerassi, G. Rosenkranz and F. Sondheimer. ibid., in press), the ll&hydroxy configura. tion for 111 is clearly indicated.
