10'7
NOTES
TABLE I O-PHENYLKETO STEROIDS PREPIRED BY REACTIONOF DIPHENYLIODOKIUJI CHLORIDE WITH a - A C Y L K E T O STEROIDS
Product 6
1 2
6
3
4
Starting material 16-Ethoxalylestrone methyl etherd 2-Hydroxymethylenetestosteronee 1iB-Hydroxy-2-hydroxymethylene-1 ia-methyl- 5,-androstan%onel 16-Ethoxalyl-3-ethylenedioxyandrost-5-en-1;-onej 20-Ethylenedioxy-21-hydroxy-2hydroxymet hyleneprepn-&en%on& 20-Ethylenedioxy-2-hydroxymethylene. 11,9,17a.21-txihydroxypregn-4-en-3-onek
Yield,
Rfp,
[alii.
L/b
oca
desb
---Chromatography--Adsorbent or support SolventC
Formula
--C, Calcd
%---
%-
Found
-H, Calcd
83 29
83.24
7.83
8.00
Found
8
lli-148
+82
32
194-196
+91
Silica
B-E ( 9 : l )
cZ6n3?o282.37
81.99
8.85
8.99
-29
Celite
H-11 ( l : l I h j i
CwH36O9
82.06
82.28
9.54
9.51
Silica
13-E (9R:R)
C?;HJIOB
79.76
79 68
8.43
8.55
Celite
H-Rl(I : l ? l t m
C:OHIIO'
ii 30
iG.91
8.50
8.81
Florid1
A-E ( 5 :95)
CxHnOs
i2.li
72.55
7.91
7.68
25
1
130-132fl (resolidifies) 157-188 185-187
24
210-211'
9
276-279
+92
CrsHrsOr
a Prodiicts were recrystallized from ether-petroleum ether ( b p 30-60") unless noted otherwise. For 1-2'~;, soliitioii in chloroform. A = acetone, B = benzene, E = ether, H = heptane, 31 = methanol. This work. e F. L. iVeisenborn, I). C. Itemy, and T. L. Jacobs, J . Am. Chem. Sac., 76, 562 (1954). f H. J. Ringold, E. Batres, 0. Halpern, and E. Xec:)echea, ihid., 81, 427 (1959). fl Recrystallized from ethyl acetate-heptane. Upper phase. i For a description of this techniqiie see 11.J. Reiss, It. E. Schaub, (+.It. Allen, Jr., J. F. Poletto, C. Pidacks, R. B. Conrow, and C. J. Coscia, Tetrahedron, 20, 357 (1964). The eluate was collected in 100-in1 fractions and aliquots of each fraction were chromatographed on silica gel plates using a benzene-acetolie-aatei, ( 2 : 1 : 2 ) system: these = 2.76). ' IT. 11. chromatograms were developed with phosphomolybdic acid. The product was foiind in fractiolls 35-47 (T',/V, Kissman, A. S. Hoffman, and ?*I.J. Weias, J . Org. Chem., 26, 973 (1961). H. h1. Kissmaii, A . 8. Hoffman, atld 11.J. \Veiss, ihid., 27. 3168 (1963). Recrystallized from methanol. Prodiict eluted a t peak hold-bark voliime 5.5 (T'",/I'. = 3.13).
14.4
p;
aryl proton resonances at 6 7.16-7.34).
The
a configuration for the 2-phenyl substituent in 2 was
assigned by consideration of the nnir spectrum, which revealed a single-proton resonance at 6 3.62 coupled with the 1P-proton (Jae = 6.5 cps) and the la-proton (Jaa= 13.0 cps). These values for the coupling constant's are in excellent' accord with those reported for 2a-acetoxycholestan-3-one ( J a e = 6.6 cps, Jaa= 13.1 cps).* A similar resonance (Jae= 5.5 cps, Jaa= 13.0 cps) is observed for 1, but. is obscured in the spectra of 3 and 4 by the ketal methylene proton resonances. However, an identical resonance was observed in 2a-phenyldeoxycorticosterone, obtained by acid hydrolysis of ketal 3. The difference noted in Jaefor the saturated derivative 2 and the unsaturated derivatives is most probably a reflection of the change in the dihedral angle between the 2p- and lp-protons imposed by introduction of the double bond into ring A. The values (-6 to +80) observed for the molecular rotation differences ( A M D ) between the 2-phenyl derivat,ives and the corresponding 2-hydrogen compounds also support the a configurat'ion for the ~ u b s t i t u e n t . ~An assignment of configuration to the 16-phenyl derivatives 5 and 6 was not possible. However, the nmr spectrum of 5 indicated the isolation of one epimer, inasmuch as a single sharp resonance was observed for the 18-prot)ons(6 0.93).8 (2) K. I,. Villiamson and W. S. Johnson, J . A m . Chem. Soc., 83, 4623 (1961). For the epimeric 2@-acetoxycholestan-3-one, Jae = 7.4 cps and Jaa= 9.5 cps. (3) These values a r e in general agreement with t h e effect on molecular rotation caused by substitution of halogen,' hydroxy1,s acetoxy,j met,hyl,6 and cyano7 groups a t t h e 2ar position. (4) B. Ellis and V. Petrow, J . Chem. SOC.,1179 (1956). (5) G. Rosenkranz, 0. Mancera, and F.Sondheimer, J . A m . Chem. Soc., 77, 145 (1955). (6) H . J. Ringold and G . Rosenkrana, J . O r g . Chem.. 21, 1333 (1956). ( 7 ) H. R'I. Kissman. A. S . Hoffman, and M . J . Weiss. ibid., 27, 3168 (1962). (8) T h e nmr spectra. of t h e 16-nitro and -cyano derivatives of estrone methyl ether show double resonances for t h e 18-protons, each of which is shifted downfield from t h e position (0.88 ppm) of this resonance in t h e spectrum of estrone methyl ether: R . E . Schaub, H. M. Kissman, and R I . J . K e i s s , ihid., 29, 2775 (1964).
2a-Phenyltestosterone (1) n-as converted into the propionat'e ester, a derivative of greater interest' for assay as a possible anabolic agent. I n this connection, an attempt' to prepare the 2a-phenyl derivative of dihydrotestosterone by reduction of 1 with lithium in liquid ammonia failed, possibly as a result of phenyl substituent involvenient. Finally, we would note the inability to det'ect products in t'he attempted reaction of diphenyliodoniuni chloride u-it,henol awtate 7 and ennmine 8.9
A d
dP a& 7
8
Biology.-In general, it appears that int,roduction of the phenyl group nega,tes the biological effects of t'he parent hormones. Thus, the t,estosterone derivat,ives 1 and 2, as well as the propionate ester of 1, showed no significant, androgenic or anabolic art,ivit!y when assayed (500-pg oral dose) by t'he ventral proRtate-levat,or ani procedure. lo 16&Phenylestrone %methyl ether (5) was less active at a total dose of 1000 pg than estrone mas at' a total dose of 3 pg in an estrogen assay." Also, 5 showed no significant hypocholesterolemic effect when administered to the rat at 0.005% of t'he diet.12 2a-Phenylhydrocortisone 20ketal (4)mas inactive following a single subcutaneous injection of 900 pg/rat' in an antiphlogistic-thymus in(9) T h e reaction of 1-(N-morpholin.vl)c~cloliexenewith diphenyliodonium chloride is reported t o give a low yield of 2-phenylcyclohexanone: 11. E. Kuehne, J . A m . Chem. SOC..84, 837 (1962). (10) This assay is a modification of that reported by L. G. Hershberper, E. G. Shipley, and R. IC. Meyer. Proc. Soc. E z p t l . B i d . .Wed.. 83, 175 (1953). (11) R. I. Dorfman and A. S. Dorfman. Bndoerinologu, 6 5 , 6.5 (1954). (12) For a description of this assay see S. Gordon, E. LV. Cantrall, \Ir. P. Cekleniak, H. J. Alhers, E;. RIaiiw, R. M . Stolar, and R . Bernstein. Steroids. 4, 267 (1961).
