January 1969
5
STEHOIUAL.~CTCLIC ETHERS
to yield 2.17 g (9570) of 4d (A and B),mp 228-245'. Khen the thiolactone 4d was chromatographed on silica gel using a 1:l mixture of CHCls-petroleum ether (bp 30-60') for elution, followed by recrystallization of the main fraction from lIeOH, an analytical sample was obtained: mp 247-254'; [ a ]23~-70.23; 325 mp (log E 4.20); (em-') 3610 (OH), 1673 (conjugated C=C); nmr, Table I. A n d . (C23H3002S), C, H. 17~-Hydroxy-17-(5-methoxy.2-thienyl)androst-4-en-3-one (6). --In a three-necked flask under S p , 1 g (0.0025 mole) of diol 2d in 25 ml of PhH was added, and the mixture was brought to reflux temperature while stirring. To the refluxing mixture 1.00 g of dry, recrystallized Al(O-i-Pr)s and 6 ml of MezCO (dried over MgSO1) were added; the mixture was then refluxed with stirring for 19 hr. At the end of the reflux period enough PhH was added to bring the total volume to 100 ml; the solution was then washed with eight 30-ml portions of a 15% solution of potassium sodium
":::P
tartrate followed by four 30-ml portions of H20, and finally concentrated to give a crystalline product (square plates) which was recrystallized (PhH) to yield 0.616 g ( 6 1 5 ) of 6, mp 87-Y8". Further recrystallization (PhH) gave an analytical sample: mp 95-1010; [cY]'~D -46.22; A",',"," 251 mp (log e 4.30), vz::" 3610 (OH), 1660 (conjugated C=O), 1208 and 1234 em-' (2-methoxythienyl). Anal. (C~H3203S)C, H. ~-Mercapto-3-oxoandrost-4-ene-A17~y-croton~c Acid ?-Lactone (5).-When 875 mg of thiolactone 4d \$as treated with -4I(O-zPr)a and hIesCO following the procedure described above, 560 mg of cream-colored solid was obtained which upon recrystallization (MesCO) gave 392 nig (45y0) of thiolactone 5, mp 215-225". Further recrystallization (MelCO) gave the analytical sample: ~ XzF 239 mp (lug E 4.29) and 328 mp 234-236'; [ a ]2 3 -54.64; mp (log E 4.15); ~2;;' (em-') 1673 (overlapping conjugated C=O groups); nmr, Table I. Anal. (C2,Hls02S)C, H.
Steroidal Cyclic Ethers PAUL I ~ U K AASD T HRATMOSDO ~ L A P A S 01yanic Ctierriidry and t'alholoyy Deparlirients, Research Division, Abbolt Laborulories, S o r l h Chicago, I1/znois 60064
Received June %$,1968 Seveial tetrahydiofuian derivatives of the androstane and estrane series were prepared by NaBH4-BF3 etherate reduction of the correiponding 176-hydroxy-16p-acetic acid ?-lactones or by cyclization of the appropriate 16p-(2-hydroxyethyl)-17p-hydroxy steroids. The cyclic ethers were tested for estrogenic, antiestrogenic, antigonadotropic, and androgenic activities. Two of the estrane derivatives exhibited weak estrogenic properties while the remaining compounds were biologically inactive.
The observed antiestrogenic activites of a cyclic et her derivative of 19-nortestosterone, 4', 5'-dihydrospiro [estr-4-ene-17,2'(3'H)-furan]-3-one1and a number of closely related compounds,2 as well as the reported effectiveness of some of these substances as aldosterone antagonist^,^ suggested a study of the biological properties of a series of aridrostanes and estranes having a tetrahydrofuran structure fused t o the D ring. The preparation of these compounds from a number of lactones or their precursors in the androstane4 and estrane5series is reported. NaBHd-BFS etherate reduction6 of 3p1l7P-dihydroxy5a-androstane-l6~-aceticacid y-lactone (1)4 yielded 17/3,3'-epoxy- 16p-ethyl-5 a-andros t an-3P-01 (2a) in 34% yield together with a 46% yield of 160-(2-hydroxyethyl)-5a-androstane-3p117/3-diol (3a). The major reduction product 3a was allowed to react with p-toluenesulfonyl chloride in pyridine to give a mixture containing the mono- and the di-p-toluenesulfonates 3b and 3c. Treatment of the crude p-toluenesulfonate mixture with BO-t-Bu in t-BuOH essentially following the cyclization procedure of Brown,2 led to the formation of the 3p-hydroxy ether 2a and the p-toluenesulfonate 2b. The latter (2b) was cleaved to 2a with sodium in liquid ammonia-ammonium ~ h l o r i d e . ~ (1) G. Bialy, .1. P. 3ferri11, and G. Pincus, Endocrinology, 79, 125 (1966). (2) E. A. Brown, J . .lied. Chem., 10, 546 (1967); U. S. Patent 3,297,686 (1967). (3) G. E. Arth, H. Schwam, L. H. Sarett, and hI. Glitzer. J . M e d . Chem., 6 , 617 (1963); S. H. Pines, R. A. Firestone, L. Re, M. A. Kozlowski, and &I. Sletzinger, Steroids, 8 , 877 (1966); S. H. Pines, U. S. Patent 3,303,205 (1967). ( 4 ) P . Kurath and W. Cole, J . Org.Chem., 26, 1939 (1961). ( 5 ) P. Kurath and IT. Cole, ibad., 26, 4592 (1961). (6) G. R. Pettit and D. ill. Piatak, i b i d . , 27, 2127 (1962); e / . G. R. Pettit, B. Green, T. R. Kasturi, and U. R. Ghatak, Tetrahedron, 18,953 (1962), and
references t o earlier work given in these two papers. (7) 1). B. Uenney arid B. Goldstein. J . Ory. Chem., 21, 4 i 9 (1956); J . Am. Chem. Suc., 79, 49-18 (19S7).
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2a. R =
b. R =
