COMMUNICATIONS TO THE EDITOR
1064
Vol. 77
(111) and Ce(1V) possess opposite ionic charges in HzS04 ~ o l u t i o n s ,the ~ observed spontaneous exchange rate does not seem t o differ greatly from that found for the nitric acid system,8 in which both exist as cations. For this reason, a kinetic investigation of the spontaneous cerium exchange in H2S04 is also planned. (7) T. J. Hardwick and E. Robertson, Can. J . Ckem., 29, 828 (1951). (8) J. W. Gryder and R. W. Dodson, THISJ O U R A A L , 73, 2890 (1951).
UNIVERSITY OF CALIFORNIA GEORGE E. CHALLENGER Los ALAMOSSCIENTIFIC LABORATORY BURTONJ. MASTERS Los ALAMOS,SEW MEXICO RECEIVED JANUARY 13, 1965
1
\ I 5
0
.
.
T i m e in m i n u t e s . , I . , , IO
,
I I5
.
.
I ,
/
I
20
Fig. 1.
TABLE I DOSIMETRY AKD EXCHANGE DATAAT 0' Observed rate of ferrous oxidation in 0.4 M HISO(: 77.7 wnole/liter-minute G F ~ ( I I I = ) 14 ions/100 ev. (assumed for low energy X-rays) Radiation-
Rate Ce(1V) induced exreduction change rate Medium
0 . 8 NHzSOi 1.0 " 9 0 3
GC~(III)
&change
(pmoles/l.-
(pmols/l.-
min.)
(ions/100 ev.)
(ions/100
18.2 46.1
17.8 9.6
3.28 8.32
3.2 1.7
min.)
ev.)
All experiments were performed a t 0 ' in order to minimize the contribution from the spontaneous thermal exchange process. GoH values of 2.232.58 have been reported in the literature5 for similar irradiation conditions a t room temperature. This is certainly in the same range as our Gexchange value found in HzS04 and is highly suggestive that the inclusion of equation (1) in the ceric sulfate reduction mechanism is indeed valid. In the H N 0 3 system, the high GC~(III)and low Gexchange values are consistent with the above interpretation if it may be assumed that GOH = 3.2, equal to the observed Gexchange in the HzS04 system. Since Gexchange in "0s is only 1.7, there remain about 1.5 OH radicals per 100 ev. which are free to react with the system in some other manner. If any of the following reactions occur, all of which are energetically possible under the experimental conditions employed, the additional reducing power of the solution would be sufficient to account for the large value of GC~(III) in nitric acid. E o = -0.1@ OH $. NOaH + HOz + HNOz
+ + Hz0 + H + = 2H202 + HNOz E" = +0.22 30H + Nos- + Hz0 + H + = 3HzO2 + NO =i
20H
t- NO3-
E o = $0.24
We are currently engaged in extensive studies of the radiation-induced exchange in both the Ce(II1)Ce(1V) and Tl(III)-Tl(I) systems. Although Ce(5) T. J. Hardwick, Discussions Favaday SOL.,12, 203 (1952). (6) W. Latimer, "Oxidation Potentials," 2nd ed., Prentice-Hall Inc., New York, IC.Y., 1952, pp. 45-50, 93.
STEROIDS AND RELATED PRODUCTS. 11.' THE SYNTHESIS OF 1~-DEHYDRO-~~C~-METHYLCORTICOSTERONE ACETATE
Sir:
The important biological properties of 17-methylated estradiolP2testosterone3a,b,Cand other androgens, such as A5-3,R,17P-dihydroxy-17a-methyla n d r o ~ t e n e ~and ~ , ~the recently described 17aamethyl-~-homotestosterone~and 17a-methyl-19nortestosterone,6 of p r o g e ~ t e r o n eand ~ ~ desoxy~~~~ corticosterone1s8asb made the synthesis of 17methyl adducts of 11-oxygenated adrenal cortical hormones desirable. I now wish to record the synthesis of 11-dehydro- 17a-methylcorticosterone acetate (IV), a biologically active homolog of 11dehydrocorticosterone acetate and analog of cortisone acetate. Reaction of 3a-acetoxy-l1,20-diketopregnane (I) with one mole of bromine gave a product from which the 17-monobromo derivative Ia9 [m.p. 168-170", [a]"D 0.8' (c 0.864, CHCli); calcd. for C23H3304Br: C, 60.92; H, 7.34; Br, 17.63. Found: C, 60.86, 61.14; H, 7.47, 7.43; Br, 17.51, 17.451, a dibromide to which, according to present evidence, structure I b should be assigned [m.p. 177', 22.3' (c 1.121, CHC13); calcd. for C23H3204Br2: C, 51.89; H, 6.06; Br, 30.03. Found: (1) Paper I of this series: Ch. R. Engel a n d G. Just, THISJ O U R N A L , 76, 4909 (1954). (2) B. C. Bocklage, H. J. Nicholas, E. A. Doisy, Jr., W.H. Elliott, S. A. Thayer and E. A. Doisy, J . Biol. Chem., 202, 27 (1953). (3) (a) L. Ruzicka, M. W. Goldberg and H. R. Rosenberg, IIelz'. Chim. A c t a , 18, 1487 (1935); (b) K. Miescher and E. Tschopp, Schweiz. M e d . Wochenschrift, 68, 1258 (1938); (c) cf. also E. J. Foley. Pvoc. Soc. E x $ . B i d . M c d . , 76, 811 (1950); A. T. Kenyan, K. Knowlton and I. Sandiford, A n n . I n t . Med., 20, 632 (1944). (4) C f . for instance E. Henderson and M. Weinberg, J . Clin. E n d o cvinol., 11, 641 (1951); see also t h e literature discussed in a recent paper by P. M. Hyde, W. H. Elliott, E. A. Doisy, Jr., and E. A. Doisy [ J . Bioi. Chem., 207, 287 (195411. ( 5 ) H. Heusser, Nagi Wahba and F. Winternitz, H e l v . C h i m . A c t a , 37,1052 (1954). ( 6 ) C. Djerassi, L. Miramontes, G . Rosenkranz and F. Sondheimer, THISJ O U R N A L , 76, 4092 (1954). (7) (a) P1. A. Plattner, H. Heusser and P. T h . Herzig, Helw. Chim. A c t a , 32, 270 (1949); (b) H. Heusser, Ch. R. Engel, P. T h . Herzig and PI. A. Plattner, ibid., 53, 2229 (1950); (c) Hs. H. Giinthard, E. Beriger, Ch. R. Engel and H. Heusser, i b i d . , 36, 2437 (1952). ( 8 ) (a) H. Heusser, E. Beriger and Ch. R. Engel, ibid., 37, 2166 (1954); (b) cf. also a forthcoming publication on t h e biological activities of this substance, (9) Compare P. L. Julian, Recent Propy. in Hormone Research, 6 , 195 (1951). Recently, H. V. Anderson, E. R. Garrett, F. H. Lincoln Jr., A. H. h'athan and J. A. Hogg reported [THIS JOURNAL, 7 6 , 74.3 (1954)] t h e preparation of I a b y t h e action of hypobromous a r i d ( ' 1 1 the 17-enol acetate of I.
Fel 20, 1955
COMMUNICATIONS TO THE EDITOR
1065
of Wilds' method.12 The crude acid chloride reacted with diazomethane, giving the diazo ketone COOR ' c=o IIIc, which, upon decomposition with hydrochloric acid, yielded the chloroketone IIId [m.p. 151', [ C Y ] ~ 48.1' ~D (c 0.890, CHCI3); calcd. for C~H3103Cl: C, 69.73; H, 8.25; C1, 9.36. Found: C, 69.93; H, 8.38; C1, 9.32. Yield from I11 65-70701. The chloride IIId was converted to the iodide IIIe and thence, using a method previously described, l t S a with silver acetate in boiling pyridine, in the pres11, R = R ' = H 1.R = R' = H ence of small amounts of acetic anhydride and IIa, R = H, R' = CHa Ia, R = Br, R' = H IIb, R = Ac, R ' = CHa I b , R = R ' = Br under nitrogen, to the keto1 acetate IIIf [m.p. ~ (c 1.051, CHC13); calcd. R CH~OAC 191.5-192.5', [ a I z 445.9' I I for C24H3405: C, 71.61; H, 8.51. Found: C, c=o c=o 71.67; H, 8.44. Yield from I I I d 65-70%]. Introduction of the A4-double bond, according to Kendall's procedure,13 through the 4-bromide (m.p. 163-164') and the A4-3-semicarbazone (m.p. 210215') of IIIf, gave 11-dehydro-17a-methylcorticosterone acetate (IV) [m.p. 157-158', [ a I z 4 D 170' (c 0.79, CHCI3); 237 mp (log a 4.44); &f;IxClr 1750 and 1720 cm. -l (21-acetoxy-20-ketone 111. R = OH IIIc. R = CHNs IV 111,R = OCHa IIId; R = CHzCi doublet); 1710 cm.-' (11-ketone); 1670 and 1620 IIIe, R = CHd IIIb, R = C1 cm.-l (A4-3-ketone doublet) ; calcd. for C24H3206: IIIf, R = CH~OAC C, 71.97; H, 8.05. Found: C, 7 2 . 2 3 ; H, 7.96. C, 51.85; H, 6.24; Br. 29.821 and the starting Yield from IIIf approximately 60701. material I were isolated. The crude, not easily The adrenal cortical activity exhibited by the separable bromination product was subjected to a new hormone analog, 11-dehydro-17a-methylcorrearrangement of the Aston-Greenburg typelOa,b,c ticosterone acetate, will be the subject of a separate and, after debromination and reacetylation, methyl communication. 3 a-acetoxy- 11-keto- 17a-methyletianate (I Ib) [m.p. I wish to express sincere thanks to the Canadian 184', [ ( Y ] ~ ~63.7' D (c 0.982, CHCI3); calcd. for Life Insurance Officers Association for financial C24H3606: C, 71.25; H, 8.99. Found: C, 71.21; support; to the Ciba Company Limited, Basel, H, 8.801 obtained in approximately 4oY0 yield from Switzerland, for the generous gift of starting mathe neutral fraction of the reaction product. From terial, t o Dr. E. H. Venning, Royal Victoria Hosthe acid fraction the hydroxy acid I1 [m.p. 285- pital, Montreal, for the biological tests; to Dr. 286', [ C ~ ] ~29.5' ~ D (c 1.099, dioxane); calcd. for: R. N. Jones, National Research Council, Ottawa, C21H3204: C, 72.38: H, 9.26. Found: C, 72.34; for the infrared spectral analysis; and to Dean H, 9.041 was isolated. The pure monobromide I a J. B. Collip for his continued encouragement. gave under similar conditions a higher yield of ester The author also wishes to express his appreciation I I b and acid TI. Refluxing of I I b with methanolic Mr. J. F. Alicino, Metuchen, New Jersey, who potassium hydroxide gave the hydroxy ester I I a to carried out the micro analyses. [m.p. 165', [CZ]*~D 41.5' (c 1.012, CHCI,); calcd. (12) A. L. Wilds, U. S. Patent 2,538,611. A. L. Wilds and C. H . for C22H3404: C, 72.80; H, 9.45. Found: C, Shunk, THISJOURNAL, 70, 2427 (1948). Compare also R. Adams 72.78; H, 9.301, also obtained upon methylation and L. H. Ulich, ibid., 42, 599 (1920). of acid I1 and easily reacetylated to the ester IIb. (13) W. F. McGuckin and E. C. Kendall, ibid., 74, 5811 (1952). Prolonged treatment of the latter with methanolic COLLIPMEDICAL RESEARCH LABORATORY potassium hydroxide in a sealed tube a t 170' gave a UNIVERSITY O F WESTERN ONTARIO CH. R.ENGEL ONTARIO, CANADA high yield of the free acid 11. Oxidation of acid I1 LONDON, RECEIVED JANUARY 14, 1955 with chromic acid afforded the keto acid I11 [m.p. 288.5', [ a I z 2 D 45.1' (c 0.941, dioxane); calcd. for C21H3004: C, 72.80; H , 8.73. Found: C, 72.68; FORMATION OF A NEW DINUCLEOTIDE FROM H, 8.75. Yield 85-90y0], further characterized by COZYMASE BY ENZYMIC DESTRUCTION OF its methyl ester IIIa [m.p. 185', [ ( r I z 3 ~ 49.8 (c THE "ONIUM" LINKAGE 1.002, CHC13); calcd. for C22H3204: C, 73.27; Sir : H, 8.95. Found: C, 73.49; H, 8.811 which was Recently it has been shown' that certain enzyalso obtained by chromic acid oxidation of IIa. matically catalyzed syntheses derive their energy Acid I11 was transformed to its chloride IIIb with from the reduction of quaternary ammonium or oxalyl chloride, using Reichstein's modificationll sulfonium salts, rather than from the usual mecha(10) (a) 3. G.Aston and R. B . Greenburg, THISJOURNAL, 6'2,2590 nism of cleavage of energy-rich phosphate esters. (1940). (b) See also Al. Faworsky, J . p 7 a k f . Chem., [2]88,658 (1913). One such "onium" salt, viz., cozymase (DPN) (c) Comparable rearrangements of 17-bromo-20-ketosteroids have been was proposed as a suitable substrate from which to described by R. E. Marker and R. B . Wagner [THISJOURNAL,64, 216, 1273 (19431; P1. A. Plattner, H . Heusser and S. F. Boyce [Helv. derive dinucleotides by this mechanism. We wish Chrm. Acta, 81,603 (1948)j; H . Heusser, Ch. R. Engel, P . T b . Herzig to record the realization of such a reaction. The and PI. A. Plattner [ i b i d . , 33, 2229 (1950)l. substrate was DPN and the acceptor amine was (11) F . Reber, A. Lardon and T . Reichstein, ibid., 37, 45 (1954). CHzR'
I
A. T.ardon and T. Reichstein, ibid., 37, 388,443 (1954).
(1) D. W.Woolley. N a f u r c , 171,323 (1953).
