236
COMMUNICATIONS TO THE EDITOR
SCH2CeH5 I, I1 = P - N O ~ B Z I1,R-H
s I
I11
1
CHzCsHs IV. R -p-NOzBz V,R=H
1 \'J R - I 4 \'IT,R=.k
VI11
IX
X,R=H XI,R=Ac
The optical rotation of the mixture of p-nitrobenzoates derived from the reaction of sodium benzyl mercaptide and the epoxide (111) indicated that approximately a BO: 40 mixture of I1 and V, respectively, was formed in the ring-opening of 111, as the result of predominant attack at C.2. I n order to provide chemical proof of structure, the diols (I1 and IV) were desulfurized with Raney nickel, affording, after acetylation, the acetates VII, isolated as a liquid by preparative gas c h r ~ m a t o g r a p h yand , ~ XI as a solid, m.p. 63-64'. The n.m.r. spectra of the desulfurized compounds were in complete agreement with their assignments as 2-deoxy- and 3-deoxyglycosides, respectively. Thus the C.1 proton signal of the 2-deoxy acetate (VII) appeared as a pair of doublets while that of the 3-deoxyacetate (XI) was found as a well-resolved doublet. These acetates were deacetylated to the deoxyfuranosides (VI andX), and hydrolyzed to the free sugars (VIII and IX). The a-benzylphenylhydrazone of 2-deoxy-~-threo-pentose (VIII) agreed in properties with the derivative reported in the literaturelo and the a-benzylphenylhydrazone of 3-deoxy-~-threo-pentose ( I x ) , a new sugar, was a crystalline solid, m.p. 86-87'. Clearly the assumption of invariable predominant opening of a 2,3-anhydrofuranoside a t C.3 can lead to an incorrect structure assignment. Studies are in progress to determine whether the disulfonate esters of I1 and V will provide a common episulfonium ion intermediate for further transformations.
Vol. 85
a t C-lg have increased the antiinflammatory potency of the parent compound. We wish to report a number of compounds having a methyl group a t C-16 in combination with a AWmethyl group showing pronounced activity, which is retained to a substantial degree by the corresponding 21-desoxy derivatives. Particularly interesting are X of 6,16a-dimethylthe [3,2-c]-2'-phenylpyra~ole~~ A6-hydrocortisone and the corresponding 2 1-deoxy derivative XVI which show anti-inflammatory activities in rats of 550 and 350 times hydrocortisone, respectively. Furthermore the [3,2-~]-2'-phenylpyrazole XI1 of 9a-fluoro-6,16a-diniethyl-A6-hydrocortisone is by far the most potent corticoid ever reported. This compound is 2000 X hydrocortisone in the rat systemic granuloma assay. Although the introduction of a double bond between C-6 and C-7 causes a reduction of the glucocorticoid activity of hydrocortisone by a factor of two," this is not observed with 16a-methylated steroids.l 2 For example the antiinflammatory activity of Sa-fluoro-16a-methy1-lj4,6-pregnatriene-1I@,17a,2l-triol-3,20-dione 2 l-acetate (A6-dexamethasone), I, m.p. 204-209'; ff23D 4-55' (CHC13) : ultraviolet ":::A 219, 248, 298 nip, E 13,000, 9,850, 11.500; (Anal. Found: C, 66.21; H , 6.73), 11 by prepared in low yield from dexa~nethasonel~) chloranil dehydr~genation'~was approximately equal to the parent compound. A similar result was ob11/3, tained with 9 a-fluoro-16a-methyl-4,6-pregnadiene17a,21-triol-3,20-dione 21-acetate 111, m.p. 235-241 O : CPD +112' (CHC13); ultraviolet ":tA 281 mp, E 27,100; (Anal. Found: C, 66.56; H, 7.33), prepared from 16c~-methylhydrocortisonevia chloranil dehydrogenation14a t C-6 followed by dehydration a t C-1113and elaboration of the C-ring fluorohydrin s y ~ t e m . ~ ~ ~ ~ Combination of the A6-function with a C-6 methyl group afforded a number of surprisingly active antiinflammatory agents. Reaction of 6a,16a-dimethyl- 17a,20,20,21-bismethylenedioxy-4-pregnene-l1/3-01-3-one~~ with ~hloranil.'~ afforded the C-6 unsaturated derivative IV, m.p. (dec.) 294-295'; a 2 5 +35' ~ (CHC13) ; ultraviolet At:," 290 mp, E 22,900; (Anal. Found: C, 69.95; H, 8.03), which after reaction with 60% formic acid" and acetylation a t C-21 afforded 6,16a-dimethyl-4,6pregnadiene-l1/3,17a,21-triol-3,20-dione 21-acetate, V, m.p. 208-210'; a 2 6+180° ~ (CHC13); ultraviolet ":::A
(3) G. E. Arth, D. B. R. Johnston, J. Fried, W. W. Spooncer, D. R. Hoff and L. H. Sarett, ibid., 80, 3160 (1958). (4) D. Taub, R. D. Hoffsommer, H. L. Slates and N. L. Wendler, ibid., 80, 4435 (1958). (9) The desulfurization of 11, b u t not of V, led t o appreciable amounts of (5) E. P. Oliveto, R. Rausser, A. L. h-usshaum, W. Gebert, E. B. Hershfurfuryl acetate. berg, S. Tolksdorf, M. Eider, P. L. Perlman and &I. M. Pechet, ibid., 80, (10) F. Weygand and H. W o k , Ber., 86, 256 (1952); G. Rembarz, ibid., 4428 (1958). 95, 1565 (1962). (6) A. Bowers and H. J. Ringold, ibid.. 80, 4423 (1098). LIFE SCIENCES RESEARCH GIOVANNI C A S I N I ~ ~ (7) J. Fried and E. F. Saho, ibdd., 76, 1455 (1954); 79, 1130 (1957). (8) B. J. Magerlein, R. D. Birkenmeyer and F. Kapan, ibid., 82, 1252 STANFORD RESEARCH INSTITUTE MENLOPARK,CALIFORNIA LEON GOODMAN (1960). (9) H. L. Herzog, A. Nobile, S. Tolksdorf, W. Charney, E. B. Hershherg, RECEIVED KOVEMBER 1, 1962 P. t.Perlman and M. M. Pechet, Science, 121, 176 (1955). (IO) R. Hirschmann, N. G. Steinberg, P. Buchschacher, J. H . Fried, G. 1. Kent and hl. Tishler, 3. A m . Chein. Soc., 85, 120 ( 1 9 6 3 ) ; cf. R. 0. Clinton, 16-METHYLATED STEROIDS. IV. 6,16a-DIMETHYL-A'A. J. Manson, F. W. Stonner, A. L. Beyler, G. 0. Potts and A. Arnold, HYDROCORTISONE AND RELATED COMPOUNDS i b i d . , 81, 1513 (1959). (11) S. Tolksdorf, ?vi. I,. Battin, J. W. Cassidy, R. XI. hlacleod, B. H. Warren and P. I,. Perlman, Proc. SOC. Exfill. B i d . M e d . , 92, 207 (1956). (12) This was first established with 16a-methyl-4,6-pregnadiene-l1~,17a,The unrelenting search for an antiinflammatory 21-triol-3,20-dione acetate, Unpublished results of J. Korntved, D. R. steroid with superior therapeutic properties had led to Hoff and G. E. Arth of these laboratories. intense synthetic effort during the last decade. It has (13) G. E. Arth, J. H. Fried, I). B. R. Johnston, D. 12. Hoff, I*. €1. been shown that a number of substituents on the hydroSarett, R. H. Silber, H. C. Stoerk and C. A. Winter, 3. .4in. Chem. Sac., 80, 3161 (1958). and cortisone molecule, including methyls a t C-2,' (14) E. J. Agnello and G. D. Laubach, ibid., 79, 1257 (1957). 16,3f4,5 fluorine a t C-6'j, g7 and 16s and a double bond (15) R. F. Hirschmann, R. Miller, J. Wood and R. E. Jones, ibid,, 78, 4986 (1956). (1) J. A. Hogg, F. H. Lincoln, R. W. Jackson and W. P. Schneider, J . A m . Chem. SOC.,77,6401 (1955). (16) M. Sletzinger and W, Gaines, to he published. (17) R. E. Beyler, R. M. Moriarty, Frances HoEman and L. H. Sarett, (2) G. B. Spero, J. L. Thompson, B. J. Magerlein, A. R. Hanze, H. C . Ilurray, 0. K. Sebek and J. A. Hogg, ibid.,7 8 , 6233 (1056). J. A m . Chem. Soc., 80, 1517 (1958).
Sir:
62
COMMUNICATIONS TO THE EDITOR
Jan. 20, 1963
23i
used in human subjects showed a separation of anti289 mp, e 23,100; (Anal. Found: C, 69.56; HI 7.80). inflammatory and adrenal suppressing activity as Selenium dioxide dehydrogenationla of V afforded 6,16a - dimethyl - 1,4,6 - pregnatriene - ll/3,17aJ21- compared to their eosinopenic and hyperglycemic activities. aZ4D triol-3,20-dione 21-acetate VI, m.p. 179-183'; $94' (CHC13); ultraviolet AzgBxOH 228, 248, 304 mp, The 21-desoxy derivative of compound I was preE 14,100, 9,200, 10,800; (Anal. Found: C, 69.54; pared by hydrolysis of the 21-acetatel formation of the H, 7.73). Mesyl chloride-pyridine dehydration', C-21-mesylate, replacement of the mesylate with yielded 6,16a-dimethyl-l ,4,6,9(1l)-pregnatetraene-17a1 iodide and reduction of the C-21-iodide with sodium 21-diol-3,20-dione 21-acetate, m.p. 208-216'; aZ3D bisulfitez0 to yield Sa-fluoro-16a-methyl-1,4,6-pregna-148' (CHCI3); ultraviolet A"H,: 230, 253, 308 mp, triene-llp,l7a-diol-3,20-dioneX I I I , m.p. 245-250'; E 15,000, 9,000, 10,500; (Anal. Found: C, 73.28; 220, 248, 29s a Z 4+17' ~ (acetone); ultraviolet AZ:,"" H, 7.60). Elaboration of the C-ring fluorohydrin mp, E 12,000, 9,000, 11,600; (ilnal. Found: C, 70.25; system7,15afforded 9a-fluoro-6, 16a-dimethyl-l14,6-preg- H, 7.55). A similar sequence starting with I11 afnatriene-lip, l'ia,21-triol-3,20-dione21-acetateVII, m.p. 11j3,17aforded 9a-fluoro-16a-methyl-4,6-pregnadiene~ (acetone) ; ultraviolet A:;(i" 225, 240-247'; a 2 3 +42' diol-3,20-dione XIV, m. . 255-265'; a Z 4 +%' ~ 245, 302 mk, E 14,400, 9,800, 10,600; (Anal. Found: (acetone); ultraviolet Agfi 281 rnp, E 26,400; (Anal. C, 67.02; H, 6.58). Found; C, 71.15, H, 8.06); compound V afforded Introduction of the Sa-fluorine into IV7+'3~'b as 6,16a-dimethyl-4,6-pregnadiene-l lp,17adiol-3,20-dione above afforded 9~~-fluoro-6,16~~-dimethyl17a,20,20,21XV, m.p. 228-238'; C Y ~ +117' ~ D (CHCI,); ultraviolet bismethylenedioxy-4,6-pregnadiene-l1~-ol-3-one (VIII , 290 mp, E 24,400; (Anal. Found: C, 73.93; m.p. dec. 279-283'; C+D - 19' (CHCI,) ; ultraviolet H, 8.37) ; compound X afforded 6,16a-dimethyl-4,6AMBO= 288 mp, €23,200; (Anal. Found: C, 67.06; HI pregnadiene-1 lp, 17a-diol-20-one- [3,2-~]-2'-phenyIpyra7.22), which after reaction with 60% aqueous formic ~ (CHCI,); ultrazole XVI, m.p. 219-222'; a Z 4-70' acid17 afforded 9a-fluoro-6,16a-dimethyl-4,6-pregna-violet ",A:;: 281, 315 mp, E 17,100, 20,800; (A?zal. diene- 11/3,17a,2 1- tri01-3~20-dione I X , m. p. dec. 247Found: C, 75.95; H, 7.57); compound XI afforded 254'; a 2 5 ~+44' (pyridine) ; ultraviolet XEgBxOH 288 6,16a - dimethyl - 4,6 - pregnadiene - llp,17a - diolmp, E 24,400; (Anal. Found: C, 67.52; H, 7.51). 20-one- [3,2-~]-2'-p-fluorophenylpyrazoleXVII, m.p. The interesting biological results obtained with 16aa24~ -51' (CHC13); ultraviolet ":A:: 209-214'; methylhydrocortisone-(3,2-c)-2'-phenylpyrazole10 sug281, 312 mM, E 15,900, 19,800; (Anal. Found: C, gested the preparation of the corresponding compounds 73.67; H, 7.17). in the 6, 16a-dimethyl-As-hydrocortisone series. Table I lists the anti-inflammatory activitiesz1of the Formylation of I V with ethyl formate and sodium hydride afforded 2-hydroxymethylene-17 CY, 20,20,21TABLE I bismethylenedioxy - 6,16a - dimethyl - 4,6 - pregnaSystemic Systemic Systemic diene-llp-ol-3-one, m.p. 198-205'; a z 6-~197' (CHCompound granuloma Compound granuloma Compound granuloma CIS); ultraviolet 295 mp, r 15,100: (Anal. Found: C, 68.12; HI 7.32). Reaction of the hydroxyI 150 VI1 121 XI11 20 methylene compound with phenylhydrazine yielded I1 162 IX 50 XIV 2 17a,20,20,21 - bismethylenedioxy - 6,16a - dimethylI11 29 551 XV 18 4,6-pregnadiene-11p-01- [3,2-c]-2'-p henylpyrazole , m.p. V 40 XI 600 XVI 348 258-262'; a 2 4 ~ - 123' (CHCI,) ; ultraviolet A",: VI 7122 XI1 2000 XVII 464 283, 315 mp, E 17,200, 20,800; (Anal. Found: C, 72.22; H, 7.08; N, 5.11). Hydrolysis of the bisCH,R methylenedioxy protecting group with 60y0 aqueous formic acid, l7 then acetylation, afforded 6,16a-dimethyl - 4,6 - pregnadiene - 11&17a,21 - triol - 2021-acetate X, double m.p. one [3,2-~]-2'-phenyIpyrazole ~ (CHCL); ultra160-165' and 229-230'; a 2 3+14' violet 283, 315 mp, E 15,700, 19,000; (Anal. Found: C, 72.55; H, 7.28). Similarly the reaction of the 2-hydroxymethylene compound with p-fluorophenylhydrazine and hydrolysis of the bismethylenedioxy protecting group afforded 6,16a - dimethyl - 4,6 - pregnadiene - 116,17a,21- triol20-one [3,2-c]-2'-p-fluorophenylpyrazole XI, m.p. 197(acetone); ultraviolet hM,:.OH 280, 203'; a 2 5 ~-26' 0 313 mp, E 15,800, 19,300; (Anal. Found: C, 71.29; I1 X, R = OCCHs; R' = H ; X = H H, 7.16). XI, R = OH; R ' = F; X = H Starting with VIII, formylation, phenylpyrazole forR' = H ; X = F XII, R = OH; mation and hydrolysis of the bismethylenedioxy proR'=H; X = H XVI, R = H ; tecting groups afforded 9a-fluoro-6,16a-dirnethyl-4,GXVII R = H; R'=F; X = H pregnadiene - ll@,l7a,21 triol - 3,20 - dione - [3,2 - c ] 2'-phenylpyrazole X I I , m.p. dec. 241-245'; C Y ~ ~ D - ~ ~ ' (20) J. Fried, K. Florey, E. F . Sabo, J. E. Herz, A. R . Restivo, A. Borluan (CHCI3); ultraviolet A::"," 283, 314 mp, E 17,700, and F. M. Singer, J . Am. Chem. SOC.,77, 4181 (1955). 20,900; (Anal. Found: C, 71.34; H, 6.60). (21) Modification of the method of R. Meier, W. Schuler and P. Desaulles, Experienfia, 6, 469 (1950). Intact male Holtzman rats (ca. 125 g . ) are The preparation of a number of 21-desoxy derivatives dosed orally each day for one week. in this series appeared to be of interest since Liddle and (22) I t is interesting to note that the double bond isomer of VI, B-methylhave reported that a group of 21-desoxy steroids ene-16cr-methyl-l,l-pregnadiene-ll~,l7~,2l-triol-3,2O-dione 21-acetate (un6
-
(18) Ch. hleystre, H. Frey, W, Voser and A. Wettstein, Hclu. Chim. A d a , 58, 734 (1956). (19) G. W. Liddle and M. Fox,"Inflammatiun and Diseases of Connective Tissue," edited by L, C. Mills and J. H. Moyer, W. B. Saundrrs Co., Philadelphia, Pa., 1YG1, p. 302.
published results of J. H . Fried and A. N. Nutile of this laboratory), was about 1.2 X hydrocortisone in the systemic granuloma assay. (23) Dr. E. W. Boland has informed us that compound X (administered orally) has been found to be approximately 78 X hydrocortisone in the supyressiuu of rheumatoid artluitib iu man.
COMMUNICATIONS TO THE EDITOR
238
reported compounds. No evidence of sodium retention was obtained for this series of compounds. FUNDAMENTAL RESEARCH MERCKSHARP& DOHME RESEARCH LABORATORIES DIVISIOXOF MERCK& Co., INC. RAHWAY, NEW JERSEY
J. H. FRIED H. MROZIK G. E. ARTH T. S. BRY N. G. STEINBERG M. TISHLER RALPHHIRSCHMANN
MERCKINSTITUTE FOR THERAPEUTIC RESEARCH S. L. STEELMAN RECEIVED NOVEMBER 30, 19G2 RELATIVE SIGNS OF FLUORINE-19-FLUORINE-1 9 AND HYDROGEN-1-FLUORINE-19 N.M.R. COUPLING CONSTANTS
TABLE I RELATIVE SIGNS OF
F19-F18COUPLING CONSTANTS
kz
( X = H, CF3,C1, Br, I )
85
substituted lJ1,2-trifluoroethanes, which due to asymmetry show ABX n.m.r. spin s y ~ t e m s were , ~ studied. It was determined that the vicinal and geminal coupling constants have different signs in the three ethane derivatives studied a t room temperature and the one which was frozen into its separate conforiner~.~From the four halogen substituted fluoropropanes studied i t was found that the vicinal coupling has a sign different from the geminal and 1,3-couplings. From the data presented above the relative sign relationships between the most commonly encountered F19-F19n .m.r. coupling constants can he tabulated F
F
\c-c
F\C-C/
F\C-C-C
/F
F'
=i
f
Sir: The importance of the relative signs of n.m.r. coupling constants has only recently been realized in the analyses of high resolution n.m.r. spectra. The use of double resonance techniques for the determination of the relative signs of coupling constants is rather more attractive than the previously exploited long and tedious iterative high-resolution approach. I n this communication we wish to give the results of some double resonance studies which have given the relative signs of several important types of FI9-FI9and HI-FI9 coupling constants. I n Table I are summarized results from FI9-F19 double resonance studies on a number of fluorocarbon
L'OI.
f
=k
F-C
i
F-C
)c=c
F
T
\c=c/
F F-C
*
f
T
\c= c
\F
The one assumption involved in this correlation is that the F F>C-C coupling constant has the same sign as that of the :>C=C coupling. This may be a reasonable assumption on grounds that these coupling constants are all fairly large in magnitude (ranging from about 28-224 c.P.s.) and that the contributions to these two types of geminal couplings may be similar. The fact that the F-C-C-F coupling has the same sign as that of the F-C-CF=C coupling with this assumption is interesting and suggests that the contributions to these two types of vicinal coupling may also be similar. Appropriate compounds to test this assumption are in preparation. Table I1 summarizes some results for HI-FI9 couplings obtained either by "-HI or F19-F19decoupling. TABLE I1 RELATIVE SIGNSOF H1-F19 COUPLING CONSTANTS
CH8CH2Fa CHsCHFz CF~CFHZ CFpCFzH CFaCFzCFzH CFzBrCFBrH CF2HCFzCFH2 CF,jCF2CF2Br J12 ?= J?3 'F J i 3 f ( 3 ) ( 2 ) (1) CFaCFzCF21 2 1 2 7 J23 p Jl3 f ( 3 ) ( 2 ) (1) CFjCFClCFClr Jl? =F , J 2 3 3=,J 1 3 ( 3 ) ( 2 ) (1) CFjCClICFsCl J13 f, J1'3 h,J 1 1 ' f (3) ( L l ' ) D. F. Evans, Mol. Phys., 5, 183 (1962). * D. D. Elleman and S. L. Manatt, J . Chem. Phys., 36, 1945 (1962). D. D. Elleman and S. L. Manatt, presented a t Third Conference on Experimental Aspects of N.M.R. Spectroscopy, Mellon Institute, Pittsburgh, Penna., March 2, 1962. S. L. Manatt and D. D. Elleman, J . A m . Chem. Soc., 84, 1305 (1962). p
j
I
1
cc !
F\
c-c/
H f
J
(1) F F (3Ibtc 1 1 4 f> J24 F r J 3 1 f (2) F>.=< 'H (4) A similar assignment of the relative signs of the Hl-F'g couplings in this molecule also has been obtained from highresolution analyses at two frequencies by s. L. Stafford and J. D. Baldeschwieler, J . Am. Chem. SOC.,83, 4473 (1961). D. F. Evans, Afol. Phys., 5, 183 (1962). D. D. Elleman and S. L. Manatt, presented a t Third Conference on Esperimental Aspects of N.M.R. Spectroscopy, Mellori I n stitute, Pittsburgh, Penn., March 2, 1962.
I t was found that the C
