Journal ofMedicinu1 Chemistry @ Copgright 1967 by the Ameracan Chemical SoctetzJ
VOLUME10, NUMBER 2
FEBRUARY 27, 196i
Synthesis of Some New 17-Spiro-Substitutecl Steroids DL-ASEF. ~ I O R R ORUTHANS W, 11. HOFER.ASD TOWSLEIP. CCLBERTSOS Research Laboratories, Parke, Dat is and Coinpany, .4nn .-Irbor,X i c h i g u n
Received October 21, IS66 Iodolactoiiization of derivatives of 3P-hydroxypregna-5,20-dieti-lia-acetic acid ( 7 ) ai'forded the corresponding 21-iodo-20p-hydrosy lactones (Sa, 9a, and Sb). Displacement of the iodide by various nucleophiles afforded the corresponding 21-substituted analogs (Sb, 8c, Sf, 9d-h, and 12), and catalytic redriction yielded the 21-tinsubititrited compounds ( S d , Se, and 9c). Other spiro systems were prepared from 3p-hydrosy-jcu-pregii-"0-eii-li~acetic acid (7b) by ozonolysis followed by reduction (18) and osidatioii (19).
ture (10) on the basis of their infrared and nmr spectra. The infrared spectra exhibited carbonyl frequencies (see Table I) at 1775-17% em-' (in the range of y-
The discovery in 1957 that the introduction of a spirolactoiie system a t the c17 position of the steroid nucleus (e.y., la) produced a compound which inhibited the effects of aldosterone' led to the synthesis of steroids having other spiro ring systems at C17. Several of these analogs ( l b , 2 lq3Z,* and 39 have also been reported to be aldosterone inhibitors, while other variations of the spiro ring system (ld,6.7le,74,* 5,9 and 6.O) led to inactive compounds. I n particular, the activity shown by 2 and 3 demonstrated that the 17P-oxygen linkage of the parent compounds (la-c) could be replaced by a carbon linkage in a spirocyclic compound. 111 a preceding paper" we reported a convenient synthesis for a versatile steroid intermediate (7) bearing two functioiialized carbon-linked substituents at C17. We wish to report nom the synthesis of a variety of new 17-spirocyrlic steroids prepared from this intermediate by effecting ring closure between the tmo substituents a t C17. Treatment of the sodium salts of the 17P-vinyl-17aacetic acid derivatives (7a, c, arid d) with iodine afforded the corresponding 21-iodo-20~-hydroxy-17a-acetic acid lactones (8a and 9a and b) in good yield. This ylactone structure was assigned these compounds rather than the isonieric 20-iodo-21-hydroxy &lactone struc-
TABLE I INFRARED FREQCESCIES OF -{-L.~WONES Compd no.
8a 8c 9a 9b 16a
v,
cm-1
177.1 1762 1784 1783 1762
lactones12), and the nmr spectra exhibited multiplets a t ca. 3.4 and 4.7 ppm for the 21- and 20-protons, respectively. (The Czl methylene group, which is attached to an asymmetric carbon atom, exhibits this complex pattern because the two protons are in differing chemical environments.13) Although it is difficult to assign these peaks due to protons on an iodinebearing carbon and to protons on an oxygen-bearing carbon with any degree of certainty, a comparison of this spectrum with those of the derived 21-substituted lactones 8b, d, and f and 9d easily clears up this uncertainty. The spectra (see Table 11) of all these 21substituted lactones (sa, b, d, and f and 9d) show that the one-proton peak a t ca. 4.6, which remains fairly constant in all these spectra, must be due to a proton on the oxygen-bearing carbon, whereas the two-proton peak, which shifts position with varying substitution a t CZ1,must be produced by the two protons on the substituent-bearing carbon. This rules out the isomeric 20-iodo &lactone structure 10. This is corroborated by the nmr spectrum of the 21-unsubstituted lactone 8e (see Table 11). Reductive removal of the iodine atom increases the ratio of these peak areas from 2: 1 to 3 : 1 , confirming that the iodine and not the lactone oxygen was attached to the CH, group.
(1) (a) .I. .I Cella . and C . 11.K a g a n a , J . A m . Chem. Soc., 79, 4808 (1957); Cella, and C . G. Van .4rrnan, Science, 126, 1015 (1957). (2) G. E. .irtli, H. Scliwam, L. H . Yarett, and M. Glitzer, J . M e n ' . Chem.. 6, 61i (1963). (3) (a) D. Uertin and J. Perronnet, Bull. SOC.Chim. France. 564 (1964); (b) \S. F . Johns and E. A . Brown, J . O r g . Chem., $1, 2099 (1966), (4) .\. .I.Patchett, U. S. Patent 3,257,390 (1966). ( 5 ) U . Patelli and R . Sciaky, French Patent 1,383,204 (1965). (6) .A. .I Patcliett, . F . Hofmann, F. F. Giarrusso, H . Schwam. and G . E. Artli, .I. O r g . Chem., 27, 3822 11962). ( i )L. N. Nj-sted and R . R. Burtner, ibid., 27, 3175 (1962). ( 8 ) (a) H.-J. Hess, zbid., 27, 1096 (1962); (b) K . Heusler. Helu. Chim. Acto, 46, 1939 (1962). (9) (a) H . G . Lehmann, Angeu:. Chem. Intern. Ed. E n d . , 4, 783 (1965); (b) N. H. Dyaon, J . .A. Edwards. and J. H. Fried, Tetrahedron Letters, 1841 (1966); (c) G . K . Noersch, D. E . Evans, and G. S. Lewis, J . .Wed. Chem., 10, 254 (1967). (10) (a) E. Farkas and J. .I. Swallov, ibid.. 7 , 739 (1964); (b) G . 11.. Jfoersch and P.L. Creger. J . Helerocgclic Chem., 2, 207 (1965). (11) D. F. Morrow, T. P. Crilbertson. and R. M. Hofer, J . 078. Chem.. 32, 361 (1967)
(12) L. J. Bellamy, "The Infrared Spectra of Complex Jfolecules," John Wiley and Sons, Inc.. Ken, York, N Y., 1954, p I53 (13) R. H. Bible, J r . "Interpretation of S J I R Spectra," Plenum Press, New I-ork. N. 7i., 1065, p T1.
133
la, X = Y = O b,
X =O; Y = H2
c, X = 0;Y = AH
W H
d,X=NR;Y=O e,
X = NR; Y = HY
4
0
LNR
6
AS; R = H b, 5a-H; R = H c, A 5 ; R = Ac d, 5a-H; R = Ac
7a,
1 7 - S P I H O - S U B S T I T C T E D STEK0II)S
13.5
serum cholesterol levels i n rats.I8 The lactone l l d exhibited no progestational activity either orally or subcutaneously in the Clauberg assay at doses as high as 10 mg/kg.
Experimental Sectionl9 10
Ila, X
=I
b, X = O H c, X=OAc d, X = H
12
13
HO
14a, X = H b. X =OH
RO
15
e
H
16a, R = H b, R - A c
O
H
H 17
19
18
qH=CH2
20
orally and subcutaneously, as inhibitors of aldosterone in adrenalectomized rats. l 6 Compounds 7a and b, l l b , c, and d, 18, and 20 were found t o be ineffective orally in preventing litters in mice,17 and in lowering (16) The procedure used was a modification of t h a t developed by C. AI. K a n a n a , F. AI. Sturtevant, and C. G. Van Arman, J . Phnrmacol. Ezpll. T h e r a p . , 126, 123 (19.59). (1;) R. 9. Thompson, M.Sturtevant, and 0. D. Bird, Science, 118, 657 (1953).
The physical properties and methods of preparation of the compoiuid.; are listed in Tahle 111. Procedure A.--A solution of 10.4 g of 3~-hydrosyprcnga-5,02dien-l7u-acetic acid (7a)" in 310 ml of methanol was treated first, wit,h a solut,ion of 8.3 g of KHCOB in 200 ml of water and then with a solution of 7.9 g of iodine and 12.4 g of KI in 7 5 ml of water. The mixture was stirred in the dark a t room temperature for 1 hr, and then poiired into water. The precipitate was filtered, warhed with diltite SaHS03 solrition and with water, dried, and recrystallized. Procedure B.-A solut,ion of 4.90 g of 38,208-dihydroxy-21iodopregn-5-en-liu-acetic acid lactone ( s a ) in 100 ml of dimethylformamide (IIMF) was treated with 3.8 g of potasriiim acetate, and the mixture was stirred and refluxed for 1 hr. The cooled mixture was poured into water and t,he precipitate was filtered, dried, and rerrystallized. Procedure C.-A solut,ion of 230 mg of 21-acetoxy-3p,20Pdihydroxypregn-5-en-lia-acetic acid lactone (8b) in 30 ml of ethanol was treated wit,h 1.22 ml of 1.00 S S a O H solution and refluxed for 2 hr. The cooled solution was concentrated t.0 dryness under reduced pressure. The solid residue wa* suspended in 25 nil of water and warmed on a steam bath. The sodium 3p,20p,21-trihydroxypregn-5-en-l7u-acetatewent into solution as another precipitak began to form. After 1-5 min on the steam bath, the mixt,ure was cooled and filt,ered, and t,he crude product was recrystallized. Procedure D.-A solution of 10.0 g of 3p120p-dihydroxy-21iodopregn-5-en-1 iu-acetic acid lactone (8a) ill 1200 ml of 95yo ethanol wa> treated with 1.0 g of 20% Pd-C and 2.0 g of sodium acetate, aiid the mixture was hydrogenated a t 3.5 kg/cm* until 1 equiv of hydrogen was absorbed (ca. 25 min). The catalyst was removed by filtration and the filtrate was conceiit,rated and poiired iiito water. The precipitat,e was collected aud recrystallized. Procedure E.--,4 solution of 2.06 g of 3p-acetoxy-20p-h?.dros!.2l-iodopregn-5-en-17u-acetic acid lactone (9a) i n 100 ml of I)\IF was t,reated with a solution of 1.25 g of N a y a in 8 ml of water and heated on a steam bath for 1 hr. The solution was poured into concentrated salt solution, and t'he precipitat,e was filtered, washed, dried, and recrystallized. Procedure F.--A solution of 2.35 g of 3&acetosy-2l-azido-20phydroxypregn-5-en-l7a-acetic acid lactone (9d) i n 60 ml of ethyl acetate and 60 ml of methanol was added to a siispension of 0.90 g of 20"; Pd-C in 60 ml of methanol. The resulting mixttire was stirred under hydrogen a t atmospheric pressure for 3 hr. The solution was filtered, and the filtrate was concentrated to drynear under reduced preswre. The crystalline residue afforded a clean, sharp iiifrared spectrum which was transparent at 2108 ( N 3 )and a t 1650 cm-1 (lactam), and exhibited peaks a t :3400 (XH), 1780 (lacto:~e),aiid 1735 em-' (3-OAc). Procedure G.-A solution of 200 mg of 3p-acetosy-21-amiiio20p-hydroxypregn-5-en-17u-acetic acid lact,one (9f) i n 20 ml of tetrahydrofuran (TTTF) was treated with 92 mg of p-toluenesulfonic acid moiiohydrate and 0.20 ml of isoamyl nitrite. The inixtrire was stirred overnight a t room temperature u!ider an atmobphere of nitrogen. I t was conceiitrated under reduced pressure and poiired iiito water. The precipit,ate \vas filtered, washed, and dried; Amax 2 i 3 mp ( e 477), 261 (670), and 22" (8020); umnX 1786 (lactone), 1732 (3-04c), 1600 (CJ15), 1368 and 1178 cm-l (SO1). Procedure H.--A flask contaiiiing 2.18 g of dry 34-acetoxy-21aniiiio-2Op-hyciroxgpregii-5-eri-lia-aceticacid lactone (9f) was (18) G. Rodney, XI. L. Illack, and 0. D. K r d , Biorhern. I~hnrmncol..14, 445 (1965). (19) .\nalj-ses and physical d a t a are listed in Table 111. llelting points xere determined on a Fisher-Johns hlock and are corrected. The ultra\-iolet spectra were riin in methanol. The nrnr spectra were obtained on a Varian A-60 instrument in CDCh, and the shifts are expressed as r)arts per million downfield from lle4Si used as an internal standard. ;\I1 compounds had infrared spectra which agrerd with the assigned structures. The crude materials obtained from theEeneraIiaed prorediires were purified by recrystallixation from tlie appropriate solvent noted in Table 111.
1%
.I(
-- 2fi
K 4s
74.16
b tih
26 31,
. T i IO
ti. ti9 26 07e
74.2:;
h.4:;
March 1967
137
17-SPIRO-SUBSTITUTED STEROIDS
Method
of Compd
21-hcetoxy-206-hydroxy-3-oxopregn4-en-li'a-acetic acid lactonep ( l l c ) 208-Hydroxy-3-oxo-
Starting mate- Yield, rial 70
oc
H
C
H
q
8b
10'
187-189
11
72.43
8.27
i2.28
8.36
VI.
Sd
65
221-223
E
77.49
9.05
7 i . 38
9.13
wepn
hIp,
Solvent"
Other
C
Other
pregn-4-en-lis-ace-
tic acid lactone8 (1ld) '72.25 9.95 3 . 3 i h i 2 . 2 5 8.98 3.47h P *5S >300 3~-.lcetouy-21-aniiuo- H 9f 20p-hydroxypregn.j-en-licu-acetic acid lactam (12) i 6 . 1 9 10.57 '76.05 10.58 240-242 11 2-( 3$,20p-Dihydroxy- I Sd 77 pi egn-5-en-] iwy1)ethanol (14a) i2.97 10.12 72.54 9 . 9 8 273-275 11 Sb 79 2-(3p1208,21-TrihyI droxypregn-%en1'70-y1)ethaiiol (lib) 11 76.70 9.36 i 6 . i 5 9.16 239-241 14b 34 38,21-Dihydro\y-lior- J pregn-5-ene-l i p carboxylic acid lactone (16a) 74.31 8.69 200-202 11 i 4 . 5 7 s.s7 16a 76 33-Acetoxy-21-hyq droxy-1ia-pregn-5ene-li&carboxylic acid lactone (16b) i 6 . 2 6 9.89 i6.11 9.83 2 12-213 Et-\V 67 3p120p-Dihydroxy-2l- K 17 nor-5a-pregnan-lioracetic acid lactone (18) D-E 73.71 S.44 73.44 8.39 243-245 75 lip-Carboxy-3-oxoL 17 5or,17a-pregnan-21oic anhydride (19) 3.63h 179- 180 B-H 78.29 9.73 3.63* 78.12 9.70 40 S,S-Dimethyl-3-oxo- o pregna-4,zO-dien1ia-acetamidet (20) -1= acetonitrile, B = CeH6, 1) = CHzClz, E = ether, E t = ethanol, H = hexane, 11 = methanol, P = pyridine, W = water. Run as a 1% solution in methanol. e Iodine c See preparation of 5e in ref 11. 5 Run as 1% solutions in CHC18unless otherwise noted. S analysis. analysis. f Isolated by fractional crystallization of the mother liquors from the recrystallization of 8d. 0 See ref 15. f Because of anticipated problems with 0 + S i .Ilso prepared in 89% over-all yield from Sa by procedure E followed by acetylation. acyl migration at higher temperatiires, the product was not recrystallized biit was used directly for the succeeding reactionh. I; S analysis. Xmax 240 mp ( E 15,800). C. Djerassi, Org. Reactions, 6, 207 (1951). p Amax 240 mp See ref 14. 1 A, 240 mp ( c 16,100). ,,X,, ( E 15)400). Q See preparation of 6b in ref 11. 7 Obtained by acetylation of the mother liquors from the recrystallization of l l b . 240 mp ( s 16,300). Xnlax 241 mp ( e 17,100). 0
8
heated at 220" in a Roods metal bath. An atmosphere of nitrogen was maintained over the steroid. ilfter 3.5 hr, the flask %-as cooled and the uiireacted starting material was washed out with boiling chloroform. The insoluble residue was recrystallized. Procedure 1.-A solution of 0.54 g of 3@,2Op-dihydroxypregn5-en-lior-acetic acid lactone (Sd) in 50 ml of T H F was treated n i t h 0.50 g of LiAlH4, and the mixture was stirred and refluxed overnight. The excess reagent was decomposed with ethanol, and the mixture was poured into dilute HC1. The precipitate was filtered, washed, dried, and recrystallized. Procedure J.-A suspension of 1.14 g of 2-(3@,2Op,21-trihl dioxypregii-5-en-l7~-yl)ethanol (14b) in 162 ml of dioxane n as cooled and treated with a solution of 1.62 g of periodic acid in 33 ml of water. The mixture was stirred a t 0' overiiight, allowed to warm to room temperature, and poured into concentiated salt solution. The precipitate was filtered, washed, dried, and recrystallized from methanol, affording 0.85 g ( 8 2 % ) of 3p,2l-dihydroxy-17a-pregn-5-ene-l7~-carboxaldehyde hemiacetal form (15), mp 194-210". The infrared spectrum of this material was transparent in the 6-p region, indicating that this hydroxyaldehyde existed completely in the cyclic hemiacetal form. This intermediate was not further characterized and the stereochemistry produced a t C20 was not determined.
-1solution of 0.83 g of 15 in 63 ml of ethanol was treated with a solution of 1.0 g of AgN03 in 9 ml of water. The solution war stirred and treated dropwise with a solution of 1.25 g of KaOH in 25 ml of water. The resulting mixture was stirred and refluxed overnight. The mixture was filtered and the precipitate was washed with 125 ml of ethanol. The filtrate and w-ashings were combined, treated with 3 ml of 12 S HCl, and refluxed for 2 hr. The cooled solution was concentrated under reduced pressure and poured into water. The precipitate was filtered and recrystallized. Procedure K.-A solution of 0.25 g of 3p,20,20-trihydroxy-21nor-5a-pregnan-lior-acetic acid lactone (17)" in 20 ml of ethanol was treated with 2 drops of 50% NaOH solution and 200 mg of XaBH4 and left a t room temperature for 1 hr. The solution was poured into dilute HC1, and the precipitate was filtered, washed, and dried. The infrared spectrum indicated some hydroxy acid to be present as well as lactone, so the crude material was dissolved in 50 ml of ethanol, treated with 4 drops of 12 S HC1, and refluxed for 1 hr. The cooled solution was concentrated to dryness under reduced pressure, and the reaidue was recrystallized, Procedure L.-A solution of 0.62 g of 3pJ20,20-trihydroxy-21nor-5or-pregnan-l7~~-aceticacid lactone (17)" in 65 ml of acetic acid was treated with 1.9 ml of 4 S chromic acid solution and
Synthetic Estrogens, Implantation Inhibitors, and Hypocholesteroleniic Agents. I. Tetrahyclronaphthalene Series'
The atereuc~hemiati.yof l,%d 1-sutistitiited tetrahSdroiial)hthalene derivatives has beeii $iiidietl. Hacic. cid derivatives have been prepared ill this series to achieve separatioii of esphenolic ethers arid pheiiosyacet trogenic, antifertility, niid h?-pocholesteroleniic nctivitiw. 0111ypartial ieparation of thew biological featruehas beeti attained
pared by catalytic, hydrogenation of the corrcspoiitlii~g 3,4-dihydronaphthalene der~r-ative.~.1 further proot of structure for the cis isomer 3 was accompli4ied by reductive elimination of the phenolic hydroxy group 1 icr the phosphate ester 7 to afford the cis hydrocarbon 1 . which was found to be itlenticd with l,?-diphenyI-l,? 3,4-tetrahydronapht halene prepared :wording t o t Ii(, procedure of Bergmann, et ~ 7 1 . ~ Isolatiuri of the cis iiomer of phenol 11 froin tlic Friedel -Crafts alkylation reaction mixture by eryhtdIizatiori was un~ccessful. Hon ever, hubieqwnt tc removal of most of the trans isomer 12 by crystallizatioii, the reiidual mixture was methylated, and tlit, phenolic methyl ethers 13 arid 14 could be separated by fractional cryitallizatioii from ?-propanol. Again 13 ~ a found to be idcntical with the product of (satslytic hydrogenation of the tvrreiponding 8.4-dihydronaphthalcne clerivxt ivc.. The mobt c.oii~iitciiigvvidencae for the t~hemicalassigiiment of the tis and t~ a m of t lie 1,2-d iiubstitutcd 1,2 , 3 .4-t etrdiydroiiaph t haler ic iwmrrs n-a* fuixislicxl by tho nnir specti:t of' the p r i i ( > 1,nlpO unds. I'igurc 1 1lluitr:ite. the four poysible c~oiitoriii:tti o r i of the tetr2thydrcJiiaphthaleiie derivative : ~ s ~ u i i i i i ithnt g the :~licyrlicring i-: iii tlic p ndo-chair form. The l i u r i forin, 111 w1iic.h the t n x -uh tueiitq arc in the cqiicitorial position- is depic~ted :is -tixc*tiu l?lippiiig t h t ~ k~lllkynron1nt I?i l l l b t l t l > in :tsial I ) o q i t i o i i \ n o r i l t l r(1.ult i i i tlic the,.i/tcidynai,i Iy l P S S \table c~oIlfolmnllon13 I i i tlic, -t;il)lc / r t r r i s foriii A tlir vic.iii:d tri ti:ii*y hyclrogoii atiiiiion c.:wboii:, t x r i d 2 ;trc lo( ated tratiu to c w h o t l t c ~ t 4 3 a ~ i d\V(JUld be c y w t o t l t o ihow I I h r g c coupliiig c o i l Thus, when l-hydroxy-2-phenyl-1,2,3,4-tetrahydro- >tarit i n their iimr doublet ~igiiul. Indeed, ./] for t l i c naphthalene TKSI used to alkylate phenol, the cis and ('II hydrogen iignal n :L\ found to be approxiniately 10 trans product's (3 and 4) could readily be isolated cpq, which rorihriiis tlic ii ans diaxial relationship of tho b y fractional crystallization. The cis isomer (3) was C1 hydrogen atonis. \Vherea* nmr clearly establiqheconformation A for the trans isomer, the coupling conidentical wit'h the product obt'aiiied by demethyla-tant ,TI = j cpa foi- thc. t i s iioiner cannot distinguish tion of 5 (see Table I) which, in turn, was prebetweeii the two c~onfoini:itioiis C :urd D.
Several years ago a number of 3-pyridyl substituted dihydro- and tetrahydronaphthalerie derivatives prepared in our laboratories were shown to inhibit the 1lp- or the 17-hydroxylase enzyme systems in the biosynthesis of adrenal cortical and gonadal steroid hormones. The present report deals with the synthe chemistry. arid endocrine-screening results of a number of tetrahydronaphthalerie derivatives. Chemistry.-Catalytic reduction of 1,2-disubstituted 3,4-dihydronaphthalenes rewlted in tetrahydronaphthalene derivative\ in which the substituent5 on the carbon atoms 1 and 2 are in the cis configuration. However, Friedel-Crafts-type alkylation of phenol by means of the carbonium ion produced by the action of a Lewis arid 011 l-hydroxy-3-substit~ited 1.2,8,4-tetrahydronaphthalene afforded a mixture of para-alkylated phenols from which both the cis and tr.ans isomers of 1,1?-disiibstituted tctrahydroIiaphthaleiies could be isolated.
1
a
\
(L
(1) .L cornniunication concerning tlie synthesis and antifertility activity of compounds 16 and 16 described in this paper has been published: \V. L. Hencae, R. TV. J. Carney, L. I. Barsky, A , A , Renzi. L. Dorfman, and G . desterens, Bzperientia, 91, 261 (1965). (2) \V. I,. I
