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COMMUNICATIONS T O THE EDITOR
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sospermine derivatives.6 When dihydrodemeth- have been investigating the effect of methyl suboxygeissospermine (C39Hd8N40si m.p. 182-184', stitution elsewhere in the hydrocortisone molecule. irom reduction of I with sodium in ammonia) We have also shown4 t h a t the 6a-fluor0 group powas heated with selenium, alstyrine was formed. tentiates the biological activity of hydrocortisone. On the other hand, decarbomethoxygeissospermine The present report concerns the synthesis of a (Cg8H46N40,m.p. 254-255') obtained by treat- series of highly active hydrocortisone analogs conment of I with methanolic potassium hydroxide, taining both the 6a-fluoro and 16a-methyl gr0ups.j gave, as expected, a desmethylalstyrine which 1Ga-Methylprogesterone6 was converted by microwas further degraded to o-aminopropiophenone and bial fermentation7 to 1la-hydroxy-16a-methyl4-methyl-5-ethylpicolinic acid (m.p. 156-158'). progesterone, m:p. 161-163', [ a ] +149' ~ (chf.) The latter was identical with a synthetic sample which was oxidized with sodium dichromate to prepared from 2-methyl-5-ethylpyridine-4-carboxal-1Ga-methyl-11-ketoprogesterone, m:p. 183-1 85', dehyde' by WolfF-Kishner reduction, condensa- [ a ]+225' (chf.), A,, 238 mp (15,800). This was tion with benzaldehyde, and oxidation to the subjected to a process involving diglyoxalation, picolinic acid. bromination and Faworskii rearrangement with The above evidence definitely establishes the sodium methoxide8 to give a mixture of methyl structure of the Ca-substituent as a p-aldehydo- 3,ll-diketo-1Ga -methyl - 4j17(20) - [cis1- pregnadienester. Its position is fixed a t C16 by the nature of Zl-oate, m.p. 175-17G0, [ a ] D +165' (chf.), the various alstyrines produced, and these also A,, 232.5 mp (23,750) and methyl 3,11-diketoestablish the remaining skeletal structure of geis- 16a- methyl - 4,17(20) - [trans]- pregnadien - 21 - oate, soschizine. Confirmation of the indolic N-H and m.p. 192-195", [ a ] D f 131' (chf.), Xmax 232.5 enolic 0-H was provided by infrared bands a t 2.90 mp (24,100). The 3-ethylene-ketal of the trans and 3.30 p, respectively, which were shifted to ester then was epoxidized with peracetic acid to 3.88 and 4.00 after exchange in deuterium meth- give methyl 3-ethylenedioxy-5a,6a-oxido-l l-ketooxide. Thus structure I1 is established for geis- 16a-methyl- 17(20)-[ trans ] -pregnen-21-oate, m .p. soschizine. 187-191', [ a ] -63' ~ ( C h f . ) , Amax 225 mp (13,850). On reaction with hydrogen fluoride the oxide was (6) Preliminary studies showed t h a t similar alstyrines were obtained from I and 11. However, greater availability and higher yields of opened and the ketal lost, giving methyl 5,-hyalstyrines made t h e geissospermine derivatives more suitable. Since droxy - 6p - fluoro - 3 , l l -diketo - 16a -methyl - 17(20) geissoschizoline (in common with most indoline alkaloids) fails t o [trans]-pregnen-21-oate, m.p. 230-234', [a]D yield alstyrines under these conditions, t h e products obtained must - 6' (chf .), Xma, 224 mp (13,850). Reketalization arise from t h e indolic portion of the geissospermine derivatives. (7) F. D. Popp and W. E. McEwen, THIS JOURNAL,80, 1181 (at C-3) with ethylene glycol, lithium aluminum hy(1958). dride reduction and acetylation of the resulting 21(8) National Science Foundation Postdoctoral Fellow, 1958-1959. alcohol produced 3-ethylenedioxy-G/3-fluoro-l6aH. RAPOPORT methyl-17(20) - [trans]-pregnene - 5a,ll/3,21-triol, DEPARTMENT OF CHEMISTRY R. J. WIXDGASSEN~ UNIVERSITY OF CALIFORXIA h-.A. HUGHES 21-acetate, m.p. 17G180°, [Q]D -1' (chf.). OxiBERKELEY, CALIFORNIA T. P. OXAK dation of this material with N-methylmorpholine oxide-peroxideg and a catalytic amount of osmium RECEIVED MAY6, 1959 tetroxide gave 3 - ethylenedioxy - 60 - fluoro5 a , l lp, 17a,21-tetrahydroxy- 1Ga - methylpregnan 6a-FLUORO-16a-METHYL ANALOGS 20-one 21-acetate, which was not purified, but was OF CORTICAL HORMONES treated with anhydrous hydrogen chloride in chloroSir : form-e thanol to give 6a-fluoro- 1Ba-methylhydroSince the initial demonstration in these labora- cortisone, 21-acetate (I) m.p. 242-245' (dec.), Xmax tories' of the enhanced adrenal cortical activity of 237 mp (14,950). 6a-Fluoro-16a-methylhydrocorthe 2a-methyl analogs of corticoids, we2 and others3 tisone, m.p. 210-216' , was obtained from this by hydrolysis with potassium bicarbonate in methanol. (1) J. A. Hogg, F. H . Lincoln, R . W.Jackson and W. P. Schneider, Selenium dioxide dehydrogenation of I formed THISJ O U R N A L , 77, 6401 (1955). 6a-fluoro- 16a-methylprednisolone 2 1-acetate (11) , (2) G. B. Spero, J. L . Thompson, B. J. Magerlein, A. R . Hanze, H . C . hlurray, 0. K. Sehek and J. A. Hogg, i b i d . , 7 8 , 6213 (1936); m.p. 173-176', resolidifying and melting again at G . B. Spero, J. L. Thompson, F. H . Lincoln, W. P . Schneider and J. A. 232-234' (dec.). Application of the well-known Hogg, i b i d . , 79, 1515 (1957); G. S.Fonken and J. A. Hogg, Tetuahedvon, 2, 305 (1958); J. C . Babcock and J. A. Campbell, THISJOURNAL, series of reactions'": dehydration a t 11, bromoin press. ( 3 ) G. Cooley, B. Ellis, D. N. Kirk and V. Petrow, J . Chem. Soc., 4112 (1957); A. Bowers and H. J , Ringold, THIS J O U R N A L , 8 0 , 3091 (1958); G. E . Arth, D. B. R. Johnston, J. Fried, W. W. Spooncer, D . R . Hoff and L. H. Sarett, ibid., 8 0 , 3160 (1958); G. E. Arth, J. Fried, D. B. R . Johnston, D . R. Hoff, L. H . Sarett, R . H. Silber, H. S.Stoerk and C. -4. Winter. ibid., 8 0 , 3161 (19%): E . P. Oliveto, R. Rausser, A. L. S u s s b a u m , W . Gebert. E. B. Hershberg, S. Tolksd o r f , M. Eisler and P. I.. Perlman, i b i d . , 80, 4428 (1958); E. P. Oliveto, R . Rausser, L. Weber, A. L . Kussbaum, W. Gebert, C. T. Coniglio, E. B. Hershberg, S. Tolksdorf, M. Eisler, P. L . Perlman and M. M. Pechet, i b i d . , 80, 4131 (1958); D. T a u b , R . D. Hoffsommer, H . L. Slates and K. L. Wendler, i b i d . , 80, 4439 (1958); E. P. Oliveto, R . Rausser, H . L. Herzog, E . B . Hershberg, S. Tolksdorf, M. Eisler, P. L . Perlman and M. M. Pechet, ibid., 80, 6687 (1958); J. A. Zderic, H. Carpio and H . J. Ringold, i b i d . , 81, 432 (1959); J. Fried, G. E. Arth and L. H. Sarett, i b i d . , 81, 1235 (1959); C. H. Robinson, 0. Gnoj and E. P. Oliveto, J . Org, Ckem., 24, 121 (1959).
(4) G. B. Spero and J. A. Hogg, U. S.Patent 2,838.497, June 10, 1958; J. A. Hogg, G. B . Spero, J. L. Thompson, B. J. Magerlein, W. P. Schneider, D . H . Peterson, 0. K. Sebek, H . C . hlurray, J. C. Babcock, R . L. Pederson and J. A. Campbell, Chem. a i i d I n d . , 1002 (1958). See also t h e subsequent reports by A . Bowers and H . J . Ringold, THISJ O G R X A L , 80, 4423 (1958), and J. S. hlills, A. Bowers, C. C . Campillo, C . Djerassi and H . J. Ringold, ibid., 81, 1204 (1959). (5) During t h e preparation of this communication a report appeared b y J. A. Edwards, A. Zaffaroni, H . J. Ringold and C . Djerassi, Pvoc. Chem. Soc., 87 (1959). describing one member of this series. (6) R. E. Marker and H . M. Crooks, Jr., THISJ O U R N A L , 6 4 , 1280 (1942). (7) T h e organism used was R h i s o p z i s nigricans (A.T.C.C. 6227b). (8) J. A. Hogg, P. F. Beal, A. H . Nathan and F. H . Lincoln, U. S. Patent 2,790,814. (9) W. P. Schneider and A. R. Hanze, U.S.Patent 2,769,821 ( S o v . 6, 1956). (10) J. Fried and E. Sabo, THISJOURNAL, 7 6 , 1455 (1954).
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hydrin formation, closure t o the 9,110-oxide and opening with hydrogen fluoride gave 6 c t , 9 ~ ~ difluoro- 16a-methylprednisolone 2 1-acetate (I11), m.p. 2.57-259' (dec.), A;&', 238 mp ( E 16,500). Satisfactory analyses were obtained for the compounds. 'The biological effects of these new hydrocortisone analogs will be reported in detail elsewhere by members of the Upjohn Company Endocrinology Department. As examples of the type of potentiation of activity observed, lie-fluoro-16amethylhydrocortisone acetate (I), Ga-fluoro-llicu~iiethplprednisolone acetate (11), and Cia,Sa-difluoro-1 Ga-methylprednisolone acetate (111) were, 111 L \' V respectively, approximately 40, 160 and 700 times This "inversion" of the two carbon bridge reas active as hydrocortisone in the liver glycogen quires that the B/C junction be cis in one member deposition assay." of the gibberic-allogibberic acid pair while t r a m (11) Irein7 i t i A w I'rw. Soc. E'xp. B i d . M e t i . , 89, 371 (1933). \Ve are indebted in the other. In view of this, it is illuminating !
