J . Org. Chem., Vol. 40, No. 21, 1975 3131
11-Oxidized 19-Norandrostanes Estra-4,14-diene-3,11,17-trione(32).T o a solution of 31 (0.400 g, 1.32 m m o l ) in dry pyridine, SOC12 (0.1m l ) was added a t -10'. T h e m i x t u r e was s t i r r e d a t t h i s temperature f o r 10 min a n d water (5 m l ) was added. T h e solvent was evaporated t o dryness u n d e r reduced pressure a n d t h e crystalline 32 was washed w i t h water a n d recrystallized f r o m benzene-hexane mixture. T h e y i e l d of 32 was 0.300 g (80%): mp 130-132O; NMR 6 1.13 (s, 3, CH3), 3,l (s, 2, a t C-16),5.9 ppm ( 8 , 2, a t C-4 a n d C-15);ir 1740, 1705, 1660, 1625 cm-l; u v m a x (95% E t O H ) 238 nm ( E 16,500). Anal. Calcd f o r Cl~Hzo03:C, 76.03;H, 7.09.Found: C, 75.93;H, 7.15. 14@-Estra-4-ene-3,11,17-trione(34). T h e d i k e t a l 8 was reduced by t h e B i r c h m e t h o d by t h e procedure used in t h e case of compound 30. T h e intermediate 33 was n o t isolated in p u r e form, but was hydrolyzed t o compound 34 in m e t h a n o l containing some 10% hydrochloric acid. T h e y i e l d o f 34 was 85%: mp 173-175'; N M R 6 1.18 (s, 3,CH3), 5.9 ppm (s, 1, a t C-4); ir 1730,1700,1660, 1620 cm-l; u v m a x (95% E t O H ) 239 nm ( E 16,000). Anal. Calcd f o r C1BH2203: C, 75.49;H, 7.74.Found: C, 75.38;H, 7.82.
Acknowledgment. I would like t o express my gratitude t o Professor M. K o c h for his help a n d fruitful discussion, and t o Dr. M. Guzewska for her help in t h e preparation of the manuscript. Registry No.-1, 55923-94-9;2, 55871-06-2;3, 55903-62-3;6, 55903-63-4;7, 55925-20-7;8, 55871-07-3; 9, 55903-64-5;10,5590365-6;12, 55871-08-4; 13, 55871-09-5; 14, 55871-10-8;15, 55871-119; 16, 55871-12-0;17, 24510-25-6;18, 24510-29-0;22, 55871-13-1; 23, 55871-14-2; 24, 55871-15-3; 25, 55871-16-4; 26, 55903-66-7; 28,
55871-17-5;29, 55871-18-6;30, 55871-19-7;31, 55871-20-0;32, 55871-21-1; 34,55903-67-8.
References a n d Notes (1)Part VI: A. R. Daniewski, J. Org. Chem., 40, 3124(1975). (2)W. S.Johnson and W. F. Johns, J. Am. Chem. SOC.,79,2005(1957). (3)J. Collins, W. Hess, and F. J. Frank, Tetrahedron Lett., 3363 (1968). 14) . . Part IX: A. R. Daniewski. M. Guzewska. and M. Kocor, J. Org. Chem., 40,3131 (1975). (5) S. N. Ananchenko and I. V. Torgov, Dokl. Akad. Nauk SSSR, 127,553 (1959);S. N. Ananchenko and I. V. Torgov, Tetrahedron Lett., 1553 (1963);G. H. Douglas, J. M. H. Graves, D. Hartley, G. A. Hughes. B. J. McLoughlln, J. Siddall, and H. Smith, J. Chem. SOC., 5072 (1963). (6)We are very much indebted to Dr. H. Smith, Wyeth Laboratories, St. David, Pa., for his generous gifts of the samples.
(7)R. P. Stein, G. C. Buzby. Jr., G. H. Douglas, and H. Smith, Tetrahedron Lett., 3603 (1967). (8) A. J. Birch and G. S. R. Subba Rao, Aust J. Chem., 23,547 (1970). (9)P. de Mayo, "Molecular Rearrangements", Interscience, New York, N.Y., 1963,p 77. (IO) A. R. Daniewski, M. Guzewska, and M. Kocbr, J. Org. Chem., 39,2193 (1974). (11) L. F. Fieser and M. Fieser, "Reagents for Organic Synthesis", Wiiey, New York, N.Y., 1967,p 142. (12)A. A. Akhrem and Y. A. Titov, "Total Steroid Synthesis", Plenum Press, New York, N.Y., 1970,p 59. (13)All melting points are uncorrected. The NMR spectra were determined in CDC13. unless stated otherwise, with a Jeol at 100 MHz using Me& as an Internal standard. The ir spectra were obtained in KBr, unless stated otherwise, with a Unicam SP 200 spectrophotometer. All the reactions were monitored by thin layer chromatography. (14)All the compounds were obtained as racemates and for the sake of simpllcity, prefixes dl or rac have been omitted. For the preparation of opticaiiy active compounds see part VIII. J. Org. Chem., 40, 3135 (1975).Compounds 1, 6,9,and 12 were obtained according to procedures described in ref 1.
Total Synthesis of Steroids. IX.' Synthesis of 1 1-Oxidized 19-Norandrostanes A. R. Daniewski, M. Guzewska, and M. K o c h * Institute of Organic Chemistry, Polish Academy of Sciences, 00-961 Warszawa, Poland Received M a y 1, 1975 Reactions o f rac-3-methoxy-14n-hydroxy-8n-estra-1,3,5(lO)-triene-ll,l7-dione (la) leading t o rac-ll-keto8,14-bisdehydroestradiol3-methylether (20)a n d analogous compounds are described. T h e B i r c h r e d u c t i o n o f 20 followed by hydrolysis a n d Jones oxidation produced rac-19-norandrost-4-ene-3,11,17-trione (22),h a v i n g t h e n a t u r a l geometry a t a l l c h i r a l centers.
T h e total synthesis of a mixture of rac-3-methoxy-14ahydroxy-8a-estra-1,3,5(10)-triene- 11,17-dione ( 1a) and its epimer l b was described earlier? This mixture gave on ketalization a single diketal 2 (Scheme I), whose further transformations are t h e subject of our present communication. T h e diketal 2 was dehydrated with thionyl chloride in pyridine t o form the unsaturated intermediate 3, which was subsequently catalytically hydrogenated to the saturated diketal 4. T h e latter compound was then reduced by the Birch method a n d yielded on hydrolysis t h e 19-norsteroid 6 with cis geometry of C/D ring junction. Acid hydrolysis of the diketal4 afforded a n unseparable mixture of diketones 7a and 7b epimeric a t C-9. Birch reduction of the diketal2, followed by acid hydrolysis produced the 19-nor compound 9, which was dehydrated t o the diene trione 10. T h e synthesis of the 17-hydroxy 19-norsteroid 12 was achieved by Birch reduction, followed by acid treatment, of t h e monohydroxy ketal 11 (Scheme 11); the latter compound has been prepared from the diketal 2 as described before.2 In all cases of Birch reduction described above a n d below, a new chiral center was created a t carbon 10. Ac-
cording to the literature: such a reduction of the aromatic A ring, followed by acid hydrolysis of t h e enol ether groups, leads predominantly t o products with trans geometry of the hydrogen a t C-10 with respect to H-9; consequently the compound 6 is a racemic mixture of 13-isoestranes (or 19nor-13-isoandrostanes, respectively), and therefore compounds 9,10, and 12 have also the geometry as presented. In order t o secure the possibility of changing the configuration a t carbon atoms 8 and 9, we attempted the introduction of the double bond a t the B/C ring junction. In fact, dehydrogenation of la,b with DDQ gave the desired compound* 15 (Scheme III), but only in poor yield (22%); the main reaction product was a 8,14-seco compound, 16. This disappointing result can be explained in the following way. As is known from the l i t e r a t ~ r e ,the ~ DDQ dehydrogenation of saturated ketones consists of @-axialhydride ion abstraction from the ketone enolate, followed by the stabilization of the intermediate carbonium ion by reorganization of electrons t o a,@-unsaturated ketone. In our case, however, the intermediate carbonium ion 14 formed from the enolate IC can stabilize in two competing ways, a and b, as depicted in Scheme 111. T h e tricyclic compound 16 was re-
3132 J. Org. Chem., Vol. 40,No. 21, 1975
Daniewski, Guzewska, and Koc6r
Scheme I Me
MeO
Scheme I1
Me0
MeO
la, X = a-H
& co flR la,X
= a-H b, X = P-H
2
b, X = P-H
4
0 12, R
11 Me0
8
3
1
1
@-fl OH
4
fl
\
Me0
IC
1-u-
\
-n+
/
Me0
16
a+ &
i)H
/
Me0
la, X = a.H b, X = /3-H
Me0
9
\
I
/
14
/
a,dotted line
10
Me0
H
Scheme I11
Me0
/
=
13,R = AC
Me0
\
0
H
/
/
MeO
b, full and dotted line a 1-H'
/
Me0
7a
7b Me0
Me0
17
Me0
5
6
cently described by Harnik e t a1.6 T h e reaction proceeds apparently toward t h e more favored, sterically less strained product 16. We also observed in a separate experiment t h a t t h e rate of the dehydrogenation reaction of compound la is much higher than t h a t of lb. This is caused by t h e tendency t o remove the strong 1,4 interaction between H-9 and t h e angular methyl group in t h e C ring which must assume in la t h e boat conformation. All attempts to cyclize the compound 16 failed; its structure was additionally proved by dehydrogenation t o t h e naphthalene derivative 17, obtained also in our laboratory earlier? A better approach t o t h e compounds with natural geom-
15
etry a t chiral centers 8 and 9 is presented in Scheme IV. Acid hydrolysis of the 17-hydroxy ketal2 18 yielded the hydroxy ketone 19, which according t o its lH NMR spectrum has cis B/C ring junction, and which smoothly underwent t h e dehydrogenation with DDQ t o t h e pentaene 20 in good yield. This compound gave on catalytic reduction a mixture of two products: t h e main product was the desired tetraene 21a (68.2%), with trans C / D ring junction, and t h e minor one appeared t o be 11-oxo-17-dihydroequilenin methyl ether (21b). Its structure was confirmed by t h e oxidation t o the known 11-oxoequilenin methyl ether8*9(23). . T h e tetraene 21a was reduced according t o Birchlo and Smith" t o 11-oxoestradiol methyl ether; however, yields were not satisfactory. Therefore we carried out t h e Birch reduction t o its completion (the styrenic double bond and t h e aromatic system); upon hydrolysis and Jones oxidation of the hydroxyl a t C-17, we obtained compound 22, rac19-norandrost-4-ene-3,11,17-trione, in good overall yield. T h e spectral and analytical data of 22 were identical with
J.Org. Chem., Vol. 40,No. 21,1975 3133
11-Oxidized 19-Norandrostanes
Scheme IV
b, X = P-H
18
I Me
Me0
OH
Me0 19
20
added in small portions to the solution of 1g (2.6 mmol) of the diketal 4 in 20 ml of THF and t-BuOH (3:l) and 200 ml of liquid ammonia. After 3 hr the solution was decolorized by addition of some methanol, and subsequently 7 g of NH&l was added. Ammonia was evaporated, the residual solution was diluted with 100 ml of water, a portion of organic solvents was removed in vacuo, and the remaining solution was extracted with chloroform. The organic solution was evaporated in vacuo after drying with anhydrous MgS04, leaving ca. 1 g of an oil, which was then treated at room temperature with 5 ml of 3 N HC1 in 50 ml of methanol. After 2 hr the solution was worked up in the usual way, giving 0.6 g (82%) of 6 mp 185-190' (from MeOH); uv max (95% EtOH) 240 nm ( e 16,600); ir 1740 (CO at C-17), 1720 (CO at C-ll), and 1670 cm-l (CO at C-3); lH NMR 1.22 (s,3, CH3), 5.98 ppm (s, 1,H-4). Anal. Calcd for C18H2203: C, 75.49; H, 7.74. Found: C, 75.59; H, 7.84. 3-Methoxy-8a,l4@-estra-1,3,5(10)-triene-ll,l7-dione (7a) and 3-Methoxy-8a,9@,14@-estra-1,3,5(10)-triene-l1,17-dione (7b). The solution of 0.5 g (1.3 mmol) of the diketal 4 in 100 ml of methanol and 0.5 ml of 10% HCl was refluxed for 2 hr. The reaction solution was then worked up in the usual manner, and 0.33 g (86%) of the oily mixture of 7a and 7b was obtained. All attempts to separate the epimers by chromatography failed: uv max (95% EtOH) 278 nm ( t 1980) and 285 (1800); ir (film) 1740 (CO at C-17), 1720 cm-l (CO at C-11); 'H NMR 1.15 and 1.20 (2 s, CH3), 3.60 (d, J s , S = 10 Hz, H-9 in 7b), 3.82 (s,3, OCH3), 3.90 (d, J Q ,=~6 Hz, H-9 in 7a), 6.8 (m, H-2, H-4, and H-1 from 7a), 7.2 ppm (d, H-1 from 7b). 3-Methoxy- 1la-hydroxy- 11,l 1,17,17- bis( ethylenedioxy) 8a,g@-estra-2,5(1O)-diene (8). The solution of 0.95 g (2.4 mmol) of the diketa12 2 in 30 ml of THF-t-BuOH mixture (3:l) and 150 ml of liquid ammonia was treated portionwise with 3 g of metallic sodium. After 4 hr the solution was worked up in the standard manner, giving 0.88 g (93%) of 8: mp 159-161' (from MeOH); ir 3520 cm-l (OH); lH NMR 1.12 (s, 3, CH3), 3.60 (s, 3, OCH3), 3.95 (s,8,OCH~CH20),4.80 ppm (s,l,H-2). Anal. Calcd for C23H3206: C, 68.29; H, 7.97. Found: C, 68.60; H,
-
Me0
Me0 21a
I
2lb
I
8.20.
22
23
those described in the literature.12 T h e direct comparison of the melting points and ir spectra with those of an authentic sample kindly supplied by H. Smith confirmed the structure of 22. Further work on the synthesis of optically active compounds of this series is in progress.
Experimental S e c t i ~ n ~ ~ ~ ~ ~ 3-Methoxy-l1,11,17,17-bis(ethylenedioxy)-8a,9@-estra1,3,5(10),14-tetraene (3). The solution of 2.5 g (6.2 mmol) of the hydroxy diketa12 2 in 50 ml of pyridine was treated with 0.5 ml of thionyl chloride and allowed to stand for 20 min at room temperature. The reaction mixture was then poured into 11. of cold water, and the precipitate was filtered and dried, giving 2.3 g (96%) of 3: mp 146-148O (from MeOH); 'H NMR 1.38 (s, 3, CH3), 3.85 (s, 3, OCH3), 4.00 (s, 4, OCH2CH20 at C-17), 5.55 (s, 1, H-15), 6.75 (m, 2, H-2 and H-4), 7.45 ppm (d, 1, J = 9 Hz, H-1). Anal. Calccl for C23H2805: C, 71.85; H, 7.34. Found: C, 71.82; H, 7.30. 3-Methoxy-l1,11,17,17-bis(ethylenedioxy)-8a,9j3,14@-estra1,3,5(10)-triene (4). The solution of 1.0 g (2.61 mmol) of compound 3 in 100 ml of toluene was hydrogenated at room temperature in the presence of 1 g of 10%Pd/CaCO3 catalyst. The equimolar amount of hydrogen was consumed within 4 hr, and the reaction mixture was worked up in the standard manner, giving 1 g (quantitative yield) of the diketal4: mp 154-155' (from benzenehexane); 'H NMR 1.22 (8, 3, CH3), 3.88 (s, 3, OCH3), 4.00 (s, 4, OCHzCHzO at C-17), 6.75 (m, 2, H-2 and H-4), 7.5 ppm (d, 1,J = 9 Hz, H-1). Anal. Calcd for C23H3005: C, 71.48; H, 7.82. Found: C. 71.09; H, 7.72. 13a-Estra-4-ene-3,11,17-trione(6). Metallic sodium (3 g) was
14a-Hydroxy-8a,9~,10a-estra-4-ene-3,11,17-trione (9). Compound 8 was refluxed with 3 N HC1 in methanol for 1 hr, giving in almost quantitative yield the product 9 mp 208-209O (from benzene); uv max (95% EtOH) 241 nm (c 16,350); ir 3400 (OH), 1740 (CO at C-17), 1720 (CO at C-111,1660 cm-' (CO at C-3); 'H NMR 1.20 (s, 3, CH3), 5.95 ppm (s, 1,H-4). Anal. Calcd for C18Hzz04: C, 71.50; H, 7.33. Found: C, 72.01; H, 7.17. 9@,10a-Estra-4,8(14)-diene-3,11,17-trione(10). A solution of 0.4 g (1.3 mmol) of compound 9 in 20 ml of pyridine was dehydrated with thionyl chloride at -70', giving 0.35 g (95%) of 10: mp 180-183' (from MeOH); uv max (95% EtOH) 233 nm ( e 13,900); ir 1740 (CO at C-17), 1700 (CO at C-111, and 1670 cm-' (CO at C-3); 'H NMR 1.13 (s, 3, CH3), 5.90 ppm (s, 1, H-4). Anal. Calcd for C1sHz003: C, 76.03; H, 7.09. Found: C , 76.09; H, 7.09. 17a-Acetoxy-13a-estra-4-ene-3,ll-dione (13). The hydroxy ketal 11 (0.1 g, 0.3 mmol) was reduced with sodium in liquid ammonia as above, and 0.075 g (89%)of oily 12 was obtained. This oil was acetylated with acetic anhydride in pyridine and after the normal work-up 0.084 g (98%) of the acetate 13 was obtained: mp 153-156' (from MeOH); uv max (95% EtOH) 240 nm ( f 16,840); ir 1735 (CO from acetate), 1700 (CO at C-ll), 1660 (CO at C-3), and 1620 cm-l (C=C); 'H NMR 1.1 (s, 3, CHs), 2.0 (s, 3, CH:,COO), 4.8 (t, 1, H-17),5.9 ppm (s, 1, H-4). Anal. Calcd for C20Hz704: C, 72.70; H, 7.93. Found: C, 72.47; H, 8.07. 3-Methoxy-14a-hydroxyestra-1,3,5(lo)$( 9)-t e t r a e n e 11,17-dione (15) and 3-Methoxy-8,14-secoestra-1,3,5(10),8-tetraene-11,14,17-trione (16). The solution of la or l b or a mixture of 1a.b (1 g, 3.2 mmol) and 0.76 g (3.3 mmol) of dichlorodicyanop-benzoquinone (DDQ) in 50 ml of benzene was refluxed for 5 hr. The precipitated hydroquinone (0.75 g, quantitative yield) was then filtered off, and the filtrate was evaporated in vacuo, dissolved in 25 ml of methylene chloride, and washed several times with 10% aqueous NaOH and then with water. The organic layer was then dried with anhydrous MgS04 and filtered and the solvent was evaporated in vacuo. The residue was treated with 10 ml of ether and compound 15 (0.22 g, 22%) precipitated: mp 205-235' dec; uv max (95% EtOH) 203 nm ( e 33,200), 246 (14,650), 287 (3470), 297 (4010) and 318 (4550); ir 3500 (OH), 1740 (CO at C-17), 1650 cm-' (CO at C-11).
3134
J.Org. Chem., Vol. 40, No. 21, 1975
Anal. Calcd for C19H2004: C, 73.06; H, 6.45. Found: C, 73.80; H, 6.38. The filtrate was evaporated and the residue was crystallized from methanol, giving 0.73 g (74%) of 16: mp of dried sample 112116O (lit.6 mp 76-86O solvated and 118-122' after drying in vacuo a t 70O); uv max (95% EtOH) 204 nm ( E 29,600), 247 (14,350), 289 (4040), 313 (3210); ir 1720 (CO a t C-14 and C-17), 1650 cm-l (CO at C-11); 'H NMR (of the MeOH solvate) 1.18 (s, 3, CH3), 3.01 (d, 4, 2 H-15 and 2 H-16), 3.5 (s, CH30H), 3.65 (s, 2, 2 H-12), 3.88 (s, 3, OCH3), 6.73 (m, 2, H-2 and H-4), 7.05 (t, 1, H-8), 7.55 ppm (d, 1,J = 9 Hz, H-1). Anal. Calcd for C1gH2004: C, 73.06; H, 6.45. Found: C, 72.42; H, 6.53. 3-Methoxy-8,14-secoestra-1,3,5,6,8-pentaene-l1,14,17-trione (17). Compound 16 (0.5 g, 1.6 mmol) was dehydrogenated with 0.36 g (1.6 mmol) of DDQ in the manner described above, giving after standard work-up 0.45 g (90%) of compound 17, mp 115' (from ether), spectrally identical with compound prepared earlier? 3.Methoxy-17fl-hydroxy-8a-estra-1,3,5(10),14( 1 5 ) - t e t r a e n 11-one (19). The solution of hydroxy monoketa12 18 (1 g, 2.9 mmol) in 100 ml of methanol and 10 ml of 10% aqueous HCl was left a t room temperature for 2 hr. Standard work-up yielded 0.83 g (95%)of 17 as an oil: ir 3500 (OH) and 1710 cm-' (CO at C-11); IH NMR 1.0 (s, 3, CH3),3.4 (s, 3, OCH3), 4.0 (t, I, H-17), 5.2 (s, 1, H15),6.75 ppm (m, 3, H-1, H-2, H-4). 3-Methoxy-l7fl-hydroxyestra-1,3,5( 10),8,14-pentaen-ll-one (20). Dehydrogenation of 19 (0.8 g, 2.7 mmol) with DDQ (0.61 g, 2.7 mmol) was carried out in the manner described above, giving 0.75 g (95%)of 2 0 mp 134-137'; ir 3400 (OH) and 1650 cm-l (CO); uv max (95% EtOH) 264 nm (c 21,000) and 358 (11,500); lH NMR 1.1 (s, 3, CH3), 3.78 (9, 3, OCH3),4.2 (t, 1, H-17), 5.92 (s, 1, H-15), 6.72 (m, 2, H-2 and H-4), 8.02 ppm (d, 1, J = 9 Hz, H-1). 3-Methoxy-17fl-hydroxyestra-1,3,5( 10),8(9)-tetraen-ll-one ( 2 l a ) a n d 3-Methoxy-17fl-hydroxyestra-l,3,5,6,8(9)-pentaen11-one (21b). The solution of 20 (0.7 g, 2.36 mmol) in 100 ml of toluene was hydrogenated in the presence of 0.7 g of 10% Pd/ CaC03 in the manner described above, giving 0.67 g (96%) of crystals, which were a mixture of 21a and 21b. After chromatography on 70 g of silica gel with hexane-ethyl acetate (3:l) as eluents we obtained (a) 0.16 g (22.8%) of 21b [mp 194-198' (from ether); uv max (95% EtOH) 249 nm (c 23,900), 322 (47001, and 357 (3590); ir 3450 (OH), 1650 (CO), and 1620 cm-I (C=C); lH NMR 0.8 (s, 3, CH3), 3.9 (s, 3, OCH3), 4.1 (t, 1, H-171, 7.12 (m, 4, H-2, H-4, H-6, H-7), and 7.9 ppm (d, 1, J = 9 Hz, H-I); m/e 2961, and (b) 0.48 g (68.2%)of 21a Imp 196-203' (from ether); uv max (95%EtOH) 248 nm ( e 16,850); ir 3420 (OH), 1640 cm-I (CO); 'H NMR 0.88 ( 8 , 3, CH3), 3.75 (s, 3, OCH3), 3.98 (t, 1, H-17), 6.7 (m, 2, H-2 and H-4) and 7.95 ppm (d, 1, J = 9 Hz, H-1); m/e 2981. Estra-4-ene-3,11,17-trione(22). The compound 21a (0.2 g, 0.67 mmol) was reduced with sodium in liquid ammonia in the
Daniewski, Guzewska,
and K o c h
manner described above, and then oxidized carefully by Jones reagent. The product was separated by TLC using a mixture of benzene-methanol-acetone (9:l:l) as eluent to give 0.090 g (50%) of 22: mp 180-185O; uv max (95% EtOH) 240 nm (c 12,600); ir 1740, 1720, 1660, and 1620 cm-'; IH NMR 0.9 (5, 3, CH3) and 5.85 ppm (s, 1, H-4) [lit.12mp 185-189O; uv max 239 nm (c 14,300); ir 1740, 1720,1660, and 1620 cm-I]. 3-Methoxyestra-1,3,5,6,8(9)-pentaene-ll,l7-dione (23). Compound 21b (0.1 g, 0.34 mmol) was oxidized with Jones reagent, giving 0.070 g (77.5%) of 23: mp 218-221O (from MeOH) (lit8 mp 224O, lit.9 mp 195-196'); uv max (95% EtOH) 250 nm (6 27,000), 320 (6460), and 361 (3660) [lit.$ 245 nm (c 13,500), 315 (2500)l; ir 1730, 1670, and 1620 cm-'; lH NMR (CD3COCD3) 0.8 (s, 3, CH3), 3.9 ( 8 , 3, OCH3), 7.3 (m, 4, H-2, H-4, H-6, H-7), and 8.1 ppm (d, 1, J = 9 Hz, H-1). Anal. Calcd for ClgH1803: C, 77.53; H, 6.16. Found: C, 77.19; H, 6.16. R e g i s t r y No,-la, 51606-68-9; lb, 51606-67-8;2,51510-11-3; 3, 51510-17-9; 4, 55903-69-0; 6, 55903-70-3; 7a, 55903-71-4; 7b, 55903-72-5; 8, 55903-73-6; 9, 55903-74-7; 10, 55871-48-2; 11, 51510-15-7; 12, 55871-49-3; 13, 55871-50-6; 15, 55871-11-9; 16, 51270-60-1; 17, 41021-02-7; 18, 51510-14-6; 19, 55871-51-7; 20, 55871-61-9; 21a, 18656-76-3; 21b, 55903-75-8; 22, 21317-72-6; 23, 16373-41-4.
References and Notes (1) Part VIII: A. R. Daniewski, J. Org. Chem., 40, 3135 (1975). (2)A. R. Daniewski, M. Guzewska, and M. Kocor, J. Org. Chem., 39,
2193 (1974). (3)A. A. Achrem and J. A. Titow, "Polnyj Sintiez Steroidow", lzdatielstwo Nauka, Moskwa, 1967,p 5g. (4) The same compound has been obtained by one of us (A. R. Daniewski) by a dlfferent approach: J. Org. Chem., in press. , (5)H. J. Ringold and A. Turner, Chem. hd. (London), 21 1 (1962). (6)M. Harnik, R. Szpigielman, Y. Lederman, J. Herling, and 2. V. J. Zaretskii, J. Org. Chem., 39, 1873 (1974). (7)A. R. Daniewski, M. Guzewska, and M. Kocor, Bull. Acad. Pol. Sci., Ser. Sci. Chim., 2,91 (1973). (8)A. Horeau, E. Lorthioy, and J. P. Guette, C. R. Acad. Scb, Ser. C,269,
558 (1969). (9)A. J. Birch and G. S.R. Subba Rao, Tetrahedron Lett., 2763 (1967). (IO) A. J. Birch and G. S. R. Subba Rao, Aust. J. Chem., 23, 547 (1970). (1 1) R. P. Stein, G. C. Buzby, and H. Smith, Tetrahedron Lett., 3603 (1967). (12)Y. Y. Lin, M. Shlbahara, and L. L. Smith, J. Org. Chem., 34, 3530 (1969). (13)Melting points were measured on a micro hot plate, arid are not corrected. Ir spectra were determined in KBr tablets with an lnfracord instrument, and 'H NMR spectra were measured with a Jeol 100-MHz spectrometer in CDC13 solution (accuracy f0.5 Hz) and are given in 6 values. The microanalyses were performed in our microanalytical laboratory (head 2 . Celler, M.S.). (14) All compounds were obtained as racemates and for the sake of simplicity the prefixes (dlor rac, respectively) have been omitted.
11-Oxidized 19-Norandrostanes Estra-4,14-diene-3,11,17-trione(32).T o a solution of 31 (0.400 g, 1.32 m m o l ) in dry pyridine, SOC12 (0.1m l ) was added a t -10'. T h e m i x t u r e was s t i r r e d a t t h i s temperature f o r 10 min a n d water (5 m l ) was added. T h e solvent was evaporated t o dryness u n d e r reduced pressure a n d t h e crystalline 32 was washed w i t h water a n d recrystallized f r o m benzene-hexane mixture. T h e y i e l d of 32 was 0.300 g (80%): mp 130-132O; NMR 6 1.13 (s, 3, CH3), 3,l (s, 2, a t C-16),5.9 ppm ( 8 , 2, a t C-4 a n d C-15);ir 1740, 1705, 1660, 1625 cm-l; u v m a x (95% E t O H ) 238 nm ( E 16,500). Anal. Calcd f o r Cl~Hzo03:C, 76.03;H, 7.09.Found: C, 75.93;H, 7.15. 14@-Estra-4-ene-3,11,17-trione(34). T h e d i k e t a l 8 was reduced by t h e B i r c h m e t h o d by t h e procedure used in t h e case of compound 30. T h e intermediate 33 was n o t isolated in p u r e form, but was hydrolyzed t o compound 34 in m e t h a n o l containing some 10% hydrochloric acid. T h e y i e l d o f 34 was 85%: mp 173-175'; N M R 6 1.18 (s, 3,CH3), 5.9 ppm (s, 1, a t C-4); ir 1730,1700,1660, 1620 cm-l; u v m a x (95% E t O H ) 239 nm ( E 16,000). Anal. Calcd f o r C1BH2203: C, 75.49;H, 7.74.Found: C, 75.38;H, 7.82.
Acknowledgment. I would like t o express my gratitude t o Professor M. K o c h for his help a n d fruitful discussion, and t o Dr. M. Guzewska for her help in t h e preparation of the manuscript. Registry No.-1, 55923-94-9;2, 55871-06-2;3, 55903-62-3;6, 55903-63-4;7, 55925-20-7;8, 55871-07-3; 9, 55903-64-5;10,5590365-6;12, 55871-08-4; 13, 55871-09-5; 14, 55871-10-8;15, 55871-119; 16, 55871-12-0;17, 24510-25-6;18, 24510-29-0;22, 55871-13-1; 23, 55871-14-2; 24, 55871-15-3; 25, 55871-16-4; 26, 55903-66-7; 28,
55871-17-5;29, 55871-18-6;30, 55871-19-7;31, 55871-20-0;32, 55871-21-1; 34,55903-67-8.
References a n d Notes (1)Part VI: A. R. Daniewski, J. Org. Chem., 40, 3124(1975). (2)W. S.Johnson and W. F. Johns, J. Am. Chem. SOC.,79,2005(1957). (3)J. Collins, W. Hess, and F. J. Frank, Tetrahedron Lett., 3363 (1968). 14) . . Part IX: A. R. Daniewski. M. Guzewska. and M. Kocor, J. Org. Chem., 40,3131 (1975). (5) S. N. Ananchenko and I. V. Torgov, Dokl. Akad. Nauk SSSR, 127,553 (1959);S. N. Ananchenko and I. V. Torgov, Tetrahedron Lett., 1553 (1963);G. H. Douglas, J. M. H. Graves, D. Hartley, G. A. Hughes. B. J. McLoughlln, J. Siddall, and H. Smith, J. Chem. SOC., 5072 (1963). (6)We are very much indebted to Dr. H. Smith, Wyeth Laboratories, St. David, Pa., for his generous gifts of the samples.
(7)R. P. Stein, G. C. Buzby. Jr., G. H. Douglas, and H. Smith, Tetrahedron Lett., 3603 (1967). (8) A. J. Birch and G. S. R. Subba Rao, Aust J. Chem., 23,547 (1970). (9)P. de Mayo, "Molecular Rearrangements", Interscience, New York, N.Y., 1963,p 77. (IO) A. R. Daniewski, M. Guzewska, and M. Kocbr, J. Org. Chem., 39,2193 (1974). (11) L. F. Fieser and M. Fieser, "Reagents for Organic Synthesis", Wiiey, New York, N.Y., 1967,p 142. (12)A. A. Akhrem and Y. A. Titov, "Total Steroid Synthesis", Plenum Press, New York, N.Y., 1970,p 59. (13)All melting points are uncorrected. The NMR spectra were determined in CDC13. unless stated otherwise, with a Jeol at 100 MHz using Me& as an Internal standard. The ir spectra were obtained in KBr, unless stated otherwise, with a Unicam SP 200 spectrophotometer. All the reactions were monitored by thin layer chromatography. (14)All the compounds were obtained as racemates and for the sake of simpllcity, prefixes dl or rac have been omitted. For the preparation of opticaiiy active compounds see part VIII. J. Org. Chem., 40, 3135 (1975).Compounds 1, 6,9,and 12 were obtained according to procedures described in ref 1.
Total Synthesis of Steroids. IX.' Synthesis of 1 1-Oxidized 19-Norandrostanes A. R. Daniewski, M. Guzewska, and M. K o c h * Institute of Organic Chemistry, Polish Academy of Sciences, 00-961 Warszawa, Poland Received M a y 1, 1975 Reactions o f rac-3-methoxy-14n-hydroxy-8n-estra-1,3,5(lO)-triene-ll,l7-dione (la) leading t o rac-ll-keto8,14-bisdehydroestradiol3-methylether (20)a n d analogous compounds are described. T h e B i r c h r e d u c t i o n o f 20 followed by hydrolysis a n d Jones oxidation produced rac-19-norandrost-4-ene-3,11,17-trione (22),h a v i n g t h e n a t u r a l geometry a t a l l c h i r a l centers.
T h e total synthesis of a mixture of rac-3-methoxy-14ahydroxy-8a-estra-1,3,5(10)-triene- 11,17-dione ( 1a) and its epimer l b was described earlier? This mixture gave on ketalization a single diketal 2 (Scheme I), whose further transformations are t h e subject of our present communication. T h e diketal 2 was dehydrated with thionyl chloride in pyridine t o form the unsaturated intermediate 3, which was subsequently catalytically hydrogenated to the saturated diketal 4. T h e latter compound was then reduced by the Birch method a n d yielded on hydrolysis t h e 19-norsteroid 6 with cis geometry of C/D ring junction. Acid hydrolysis of the diketal4 afforded a n unseparable mixture of diketones 7a and 7b epimeric a t C-9. Birch reduction of the diketal2, followed by acid hydrolysis produced the 19-nor compound 9, which was dehydrated t o the diene trione 10. T h e synthesis of the 17-hydroxy 19-norsteroid 12 was achieved by Birch reduction, followed by acid treatment, of t h e monohydroxy ketal 11 (Scheme 11); the latter compound has been prepared from the diketal 2 as described before.2 In all cases of Birch reduction described above a n d below, a new chiral center was created a t carbon 10. Ac-
cording to the literature: such a reduction of the aromatic A ring, followed by acid hydrolysis of t h e enol ether groups, leads predominantly t o products with trans geometry of the hydrogen a t C-10 with respect to H-9; consequently the compound 6 is a racemic mixture of 13-isoestranes (or 19nor-13-isoandrostanes, respectively), and therefore compounds 9,10, and 12 have also the geometry as presented. In order t o secure the possibility of changing the configuration a t carbon atoms 8 and 9, we attempted the introduction of the double bond a t the B/C ring junction. In fact, dehydrogenation of la,b with DDQ gave the desired compound* 15 (Scheme III), but only in poor yield (22%); the main reaction product was a 8,14-seco compound, 16. This disappointing result can be explained in the following way. As is known from the l i t e r a t ~ r e ,the ~ DDQ dehydrogenation of saturated ketones consists of @-axialhydride ion abstraction from the ketone enolate, followed by the stabilization of the intermediate carbonium ion by reorganization of electrons t o a,@-unsaturated ketone. In our case, however, the intermediate carbonium ion 14 formed from the enolate IC can stabilize in two competing ways, a and b, as depicted in Scheme 111. T h e tricyclic compound 16 was re-
3132 J. Org. Chem., Vol. 40,No. 21, 1975
Daniewski, Guzewska, and Koc6r
Scheme I Me
MeO
Scheme I1
Me0
MeO
la, X = a-H
& co flR la,X
= a-H b, X = P-H
2
b, X = P-H
4
0 12, R
11 Me0
8
3
1
1
@-fl OH
4
fl
\
Me0
IC
1-u-
\
-n+
/
Me0
16
a+ &
i)H
/
Me0
la, X = a.H b, X = /3-H
Me0
9
\
I
/
14
/
a,dotted line
10
Me0
H
Scheme I11
Me0
/
=
13,R = AC
Me0
\
0
H
/
/
MeO
b, full and dotted line a 1-H'
/
Me0
7a
7b Me0
Me0
17
Me0
5
6
cently described by Harnik e t a1.6 T h e reaction proceeds apparently toward t h e more favored, sterically less strained product 16. We also observed in a separate experiment t h a t t h e rate of the dehydrogenation reaction of compound la is much higher than t h a t of lb. This is caused by t h e tendency t o remove the strong 1,4 interaction between H-9 and t h e angular methyl group in t h e C ring which must assume in la t h e boat conformation. All attempts to cyclize the compound 16 failed; its structure was additionally proved by dehydrogenation t o t h e naphthalene derivative 17, obtained also in our laboratory earlier? A better approach t o t h e compounds with natural geom-
15
etry a t chiral centers 8 and 9 is presented in Scheme IV. Acid hydrolysis of the 17-hydroxy ketal2 18 yielded the hydroxy ketone 19, which according t o its lH NMR spectrum has cis B/C ring junction, and which smoothly underwent t h e dehydrogenation with DDQ t o t h e pentaene 20 in good yield. This compound gave on catalytic reduction a mixture of two products: t h e main product was the desired tetraene 21a (68.2%), with trans C / D ring junction, and t h e minor one appeared t o be 11-oxo-17-dihydroequilenin methyl ether (21b). Its structure was confirmed by t h e oxidation t o the known 11-oxoequilenin methyl ether8*9(23). . T h e tetraene 21a was reduced according t o Birchlo and Smith" t o 11-oxoestradiol methyl ether; however, yields were not satisfactory. Therefore we carried out t h e Birch reduction t o its completion (the styrenic double bond and t h e aromatic system); upon hydrolysis and Jones oxidation of the hydroxyl a t C-17, we obtained compound 22, rac19-norandrost-4-ene-3,11,17-trione, in good overall yield. T h e spectral and analytical data of 22 were identical with
J.Org. Chem., Vol. 40,No. 21,1975 3133
11-Oxidized 19-Norandrostanes
Scheme IV
b, X = P-H
18
I Me
Me0
OH
Me0 19
20
added in small portions to the solution of 1g (2.6 mmol) of the diketal 4 in 20 ml of THF and t-BuOH (3:l) and 200 ml of liquid ammonia. After 3 hr the solution was decolorized by addition of some methanol, and subsequently 7 g of NH&l was added. Ammonia was evaporated, the residual solution was diluted with 100 ml of water, a portion of organic solvents was removed in vacuo, and the remaining solution was extracted with chloroform. The organic solution was evaporated in vacuo after drying with anhydrous MgS04, leaving ca. 1 g of an oil, which was then treated at room temperature with 5 ml of 3 N HC1 in 50 ml of methanol. After 2 hr the solution was worked up in the usual way, giving 0.6 g (82%) of 6 mp 185-190' (from MeOH); uv max (95% EtOH) 240 nm ( e 16,600); ir 1740 (CO at C-17), 1720 (CO at C-ll), and 1670 cm-l (CO at C-3); lH NMR 1.22 (s,3, CH3), 5.98 ppm (s, 1,H-4). Anal. Calcd for C18H2203: C, 75.49; H, 7.74. Found: C, 75.59; H, 7.84. 3-Methoxy-8a,l4@-estra-1,3,5(10)-triene-ll,l7-dione (7a) and 3-Methoxy-8a,9@,14@-estra-1,3,5(10)-triene-l1,17-dione (7b). The solution of 0.5 g (1.3 mmol) of the diketal 4 in 100 ml of methanol and 0.5 ml of 10% HCl was refluxed for 2 hr. The reaction solution was then worked up in the usual manner, and 0.33 g (86%) of the oily mixture of 7a and 7b was obtained. All attempts to separate the epimers by chromatography failed: uv max (95% EtOH) 278 nm ( t 1980) and 285 (1800); ir (film) 1740 (CO at C-17), 1720 cm-l (CO at C-11); 'H NMR 1.15 and 1.20 (2 s, CH3), 3.60 (d, J s , S = 10 Hz, H-9 in 7b), 3.82 (s,3, OCH3), 3.90 (d, J Q ,=~6 Hz, H-9 in 7a), 6.8 (m, H-2, H-4, and H-1 from 7a), 7.2 ppm (d, H-1 from 7b). 3-Methoxy- 1la-hydroxy- 11,l 1,17,17- bis( ethylenedioxy) 8a,g@-estra-2,5(1O)-diene (8). The solution of 0.95 g (2.4 mmol) of the diketa12 2 in 30 ml of THF-t-BuOH mixture (3:l) and 150 ml of liquid ammonia was treated portionwise with 3 g of metallic sodium. After 4 hr the solution was worked up in the standard manner, giving 0.88 g (93%) of 8: mp 159-161' (from MeOH); ir 3520 cm-l (OH); lH NMR 1.12 (s, 3, CH3), 3.60 (s, 3, OCH3), 3.95 (s,8,OCH~CH20),4.80 ppm (s,l,H-2). Anal. Calcd for C23H3206: C, 68.29; H, 7.97. Found: C, 68.60; H,
-
Me0
Me0 21a
I
2lb
I
8.20.
22
23
those described in the literature.12 T h e direct comparison of the melting points and ir spectra with those of an authentic sample kindly supplied by H. Smith confirmed the structure of 22. Further work on the synthesis of optically active compounds of this series is in progress.
Experimental S e c t i ~ n ~ ~ ~ ~ ~ 3-Methoxy-l1,11,17,17-bis(ethylenedioxy)-8a,9@-estra1,3,5(10),14-tetraene (3). The solution of 2.5 g (6.2 mmol) of the hydroxy diketa12 2 in 50 ml of pyridine was treated with 0.5 ml of thionyl chloride and allowed to stand for 20 min at room temperature. The reaction mixture was then poured into 11. of cold water, and the precipitate was filtered and dried, giving 2.3 g (96%) of 3: mp 146-148O (from MeOH); 'H NMR 1.38 (s, 3, CH3), 3.85 (s, 3, OCH3), 4.00 (s, 4, OCH2CH20 at C-17), 5.55 (s, 1, H-15), 6.75 (m, 2, H-2 and H-4), 7.45 ppm (d, 1, J = 9 Hz, H-1). Anal. Calccl for C23H2805: C, 71.85; H, 7.34. Found: C, 71.82; H, 7.30. 3-Methoxy-l1,11,17,17-bis(ethylenedioxy)-8a,9j3,14@-estra1,3,5(10)-triene (4). The solution of 1.0 g (2.61 mmol) of compound 3 in 100 ml of toluene was hydrogenated at room temperature in the presence of 1 g of 10%Pd/CaCO3 catalyst. The equimolar amount of hydrogen was consumed within 4 hr, and the reaction mixture was worked up in the standard manner, giving 1 g (quantitative yield) of the diketal4: mp 154-155' (from benzenehexane); 'H NMR 1.22 (8, 3, CH3), 3.88 (s, 3, OCH3), 4.00 (s, 4, OCHzCHzO at C-17), 6.75 (m, 2, H-2 and H-4), 7.5 ppm (d, 1,J = 9 Hz, H-1). Anal. Calcd for C23H3005: C, 71.48; H, 7.82. Found: C. 71.09; H, 7.72. 13a-Estra-4-ene-3,11,17-trione(6). Metallic sodium (3 g) was
14a-Hydroxy-8a,9~,10a-estra-4-ene-3,11,17-trione (9). Compound 8 was refluxed with 3 N HC1 in methanol for 1 hr, giving in almost quantitative yield the product 9 mp 208-209O (from benzene); uv max (95% EtOH) 241 nm (c 16,350); ir 3400 (OH), 1740 (CO at C-17), 1720 (CO at C-111,1660 cm-' (CO at C-3); 'H NMR 1.20 (s, 3, CH3), 5.95 ppm (s, 1,H-4). Anal. Calcd for C18Hzz04: C, 71.50; H, 7.33. Found: C, 72.01; H, 7.17. 9@,10a-Estra-4,8(14)-diene-3,11,17-trione(10). A solution of 0.4 g (1.3 mmol) of compound 9 in 20 ml of pyridine was dehydrated with thionyl chloride at -70', giving 0.35 g (95%) of 10: mp 180-183' (from MeOH); uv max (95% EtOH) 233 nm ( e 13,900); ir 1740 (CO at C-17), 1700 (CO at C-111, and 1670 cm-' (CO at C-3); 'H NMR 1.13 (s, 3, CH3), 5.90 ppm (s, 1, H-4). Anal. Calcd for C1sHz003: C, 76.03; H, 7.09. Found: C , 76.09; H, 7.09. 17a-Acetoxy-13a-estra-4-ene-3,ll-dione (13). The hydroxy ketal 11 (0.1 g, 0.3 mmol) was reduced with sodium in liquid ammonia as above, and 0.075 g (89%)of oily 12 was obtained. This oil was acetylated with acetic anhydride in pyridine and after the normal work-up 0.084 g (98%) of the acetate 13 was obtained: mp 153-156' (from MeOH); uv max (95% EtOH) 240 nm ( f 16,840); ir 1735 (CO from acetate), 1700 (CO at C-ll), 1660 (CO at C-3), and 1620 cm-l (C=C); 'H NMR 1.1 (s, 3, CHs), 2.0 (s, 3, CH:,COO), 4.8 (t, 1, H-17),5.9 ppm (s, 1, H-4). Anal. Calcd for C20Hz704: C, 72.70; H, 7.93. Found: C, 72.47; H, 8.07. 3-Methoxy-14a-hydroxyestra-1,3,5(lo)$( 9)-t e t r a e n e 11,17-dione (15) and 3-Methoxy-8,14-secoestra-1,3,5(10),8-tetraene-11,14,17-trione (16). The solution of la or l b or a mixture of 1a.b (1 g, 3.2 mmol) and 0.76 g (3.3 mmol) of dichlorodicyanop-benzoquinone (DDQ) in 50 ml of benzene was refluxed for 5 hr. The precipitated hydroquinone (0.75 g, quantitative yield) was then filtered off, and the filtrate was evaporated in vacuo, dissolved in 25 ml of methylene chloride, and washed several times with 10% aqueous NaOH and then with water. The organic layer was then dried with anhydrous MgS04 and filtered and the solvent was evaporated in vacuo. The residue was treated with 10 ml of ether and compound 15 (0.22 g, 22%) precipitated: mp 205-235' dec; uv max (95% EtOH) 203 nm ( e 33,200), 246 (14,650), 287 (3470), 297 (4010) and 318 (4550); ir 3500 (OH), 1740 (CO at C-17), 1650 cm-' (CO at C-11).
3134
J.Org. Chem., Vol. 40, No. 21, 1975
Anal. Calcd for C19H2004: C, 73.06; H, 6.45. Found: C, 73.80; H, 6.38. The filtrate was evaporated and the residue was crystallized from methanol, giving 0.73 g (74%) of 16: mp of dried sample 112116O (lit.6 mp 76-86O solvated and 118-122' after drying in vacuo a t 70O); uv max (95% EtOH) 204 nm ( E 29,600), 247 (14,350), 289 (4040), 313 (3210); ir 1720 (CO a t C-14 and C-17), 1650 cm-l (CO at C-11); 'H NMR (of the MeOH solvate) 1.18 (s, 3, CH3), 3.01 (d, 4, 2 H-15 and 2 H-16), 3.5 (s, CH30H), 3.65 (s, 2, 2 H-12), 3.88 (s, 3, OCH3), 6.73 (m, 2, H-2 and H-4), 7.05 (t, 1, H-8), 7.55 ppm (d, 1,J = 9 Hz, H-1). Anal. Calcd for C1gH2004: C, 73.06; H, 6.45. Found: C, 72.42; H, 6.53. 3-Methoxy-8,14-secoestra-1,3,5,6,8-pentaene-l1,14,17-trione (17). Compound 16 (0.5 g, 1.6 mmol) was dehydrogenated with 0.36 g (1.6 mmol) of DDQ in the manner described above, giving after standard work-up 0.45 g (90%) of compound 17, mp 115' (from ether), spectrally identical with compound prepared earlier? 3.Methoxy-17fl-hydroxy-8a-estra-1,3,5(10),14( 1 5 ) - t e t r a e n 11-one (19). The solution of hydroxy monoketa12 18 (1 g, 2.9 mmol) in 100 ml of methanol and 10 ml of 10% aqueous HCl was left a t room temperature for 2 hr. Standard work-up yielded 0.83 g (95%)of 17 as an oil: ir 3500 (OH) and 1710 cm-' (CO at C-11); IH NMR 1.0 (s, 3, CH3),3.4 (s, 3, OCH3), 4.0 (t, I, H-17), 5.2 (s, 1, H15),6.75 ppm (m, 3, H-1, H-2, H-4). 3-Methoxy-l7fl-hydroxyestra-1,3,5( 10),8,14-pentaen-ll-one (20). Dehydrogenation of 19 (0.8 g, 2.7 mmol) with DDQ (0.61 g, 2.7 mmol) was carried out in the manner described above, giving 0.75 g (95%)of 2 0 mp 134-137'; ir 3400 (OH) and 1650 cm-l (CO); uv max (95% EtOH) 264 nm (c 21,000) and 358 (11,500); lH NMR 1.1 (s, 3, CH3), 3.78 (9, 3, OCH3),4.2 (t, 1, H-17), 5.92 (s, 1, H-15), 6.72 (m, 2, H-2 and H-4), 8.02 ppm (d, 1, J = 9 Hz, H-1). 3-Methoxy-17fl-hydroxyestra-1,3,5( 10),8(9)-tetraen-ll-one ( 2 l a ) a n d 3-Methoxy-17fl-hydroxyestra-l,3,5,6,8(9)-pentaen11-one (21b). The solution of 20 (0.7 g, 2.36 mmol) in 100 ml of toluene was hydrogenated in the presence of 0.7 g of 10% Pd/ CaC03 in the manner described above, giving 0.67 g (96%) of crystals, which were a mixture of 21a and 21b. After chromatography on 70 g of silica gel with hexane-ethyl acetate (3:l) as eluents we obtained (a) 0.16 g (22.8%) of 21b [mp 194-198' (from ether); uv max (95% EtOH) 249 nm (c 23,900), 322 (47001, and 357 (3590); ir 3450 (OH), 1650 (CO), and 1620 cm-I (C=C); lH NMR 0.8 (s, 3, CH3), 3.9 (s, 3, OCH3), 4.1 (t, 1, H-171, 7.12 (m, 4, H-2, H-4, H-6, H-7), and 7.9 ppm (d, 1, J = 9 Hz, H-I); m/e 2961, and (b) 0.48 g (68.2%)of 21a Imp 196-203' (from ether); uv max (95%EtOH) 248 nm ( e 16,850); ir 3420 (OH), 1640 cm-I (CO); 'H NMR 0.88 ( 8 , 3, CH3), 3.75 (s, 3, OCH3), 3.98 (t, 1, H-17), 6.7 (m, 2, H-2 and H-4) and 7.95 ppm (d, 1, J = 9 Hz, H-1); m/e 2981. Estra-4-ene-3,11,17-trione(22). The compound 21a (0.2 g, 0.67 mmol) was reduced with sodium in liquid ammonia in the
Daniewski, Guzewska,
and K o c h
manner described above, and then oxidized carefully by Jones reagent. The product was separated by TLC using a mixture of benzene-methanol-acetone (9:l:l) as eluent to give 0.090 g (50%) of 22: mp 180-185O; uv max (95% EtOH) 240 nm (c 12,600); ir 1740, 1720, 1660, and 1620 cm-'; IH NMR 0.9 (5, 3, CH3) and 5.85 ppm (s, 1, H-4) [lit.12mp 185-189O; uv max 239 nm (c 14,300); ir 1740, 1720,1660, and 1620 cm-I]. 3-Methoxyestra-1,3,5,6,8(9)-pentaene-ll,l7-dione (23). Compound 21b (0.1 g, 0.34 mmol) was oxidized with Jones reagent, giving 0.070 g (77.5%) of 23: mp 218-221O (from MeOH) (lit8 mp 224O, lit.9 mp 195-196'); uv max (95% EtOH) 250 nm (6 27,000), 320 (6460), and 361 (3660) [lit.$ 245 nm (c 13,500), 315 (2500)l; ir 1730, 1670, and 1620 cm-'; lH NMR (CD3COCD3) 0.8 (s, 3, CH3), 3.9 ( 8 , 3, OCH3), 7.3 (m, 4, H-2, H-4, H-6, H-7), and 8.1 ppm (d, 1, J = 9 Hz, H-1). Anal. Calcd for ClgH1803: C, 77.53; H, 6.16. Found: C, 77.19; H, 6.16. R e g i s t r y No,-la, 51606-68-9; lb, 51606-67-8;2,51510-11-3; 3, 51510-17-9; 4, 55903-69-0; 6, 55903-70-3; 7a, 55903-71-4; 7b, 55903-72-5; 8, 55903-73-6; 9, 55903-74-7; 10, 55871-48-2; 11, 51510-15-7; 12, 55871-49-3; 13, 55871-50-6; 15, 55871-11-9; 16, 51270-60-1; 17, 41021-02-7; 18, 51510-14-6; 19, 55871-51-7; 20, 55871-61-9; 21a, 18656-76-3; 21b, 55903-75-8; 22, 21317-72-6; 23, 16373-41-4.
References and Notes (1) Part VIII: A. R. Daniewski, J. Org. Chem., 40, 3135 (1975). (2)A. R. Daniewski, M. Guzewska, and M. Kocor, J. Org. Chem., 39,
2193 (1974). (3)A. A. Achrem and J. A. Titow, "Polnyj Sintiez Steroidow", lzdatielstwo Nauka, Moskwa, 1967,p 5g. (4) The same compound has been obtained by one of us (A. R. Daniewski) by a dlfferent approach: J. Org. Chem., in press. , (5)H. J. Ringold and A. Turner, Chem. hd. (London), 21 1 (1962). (6)M. Harnik, R. Szpigielman, Y. Lederman, J. Herling, and 2. V. J. Zaretskii, J. Org. Chem., 39, 1873 (1974). (7)A. R. Daniewski, M. Guzewska, and M. Kocor, Bull. Acad. Pol. Sci., Ser. Sci. Chim., 2,91 (1973). (8)A. Horeau, E. Lorthioy, and J. P. Guette, C. R. Acad. Scb, Ser. C,269,
558 (1969). (9)A. J. Birch and G. S.R. Subba Rao, Tetrahedron Lett., 2763 (1967). (IO) A. J. Birch and G. S. R. Subba Rao, Aust. J. Chem., 23, 547 (1970). (1 1) R. P. Stein, G. C. Buzby, and H. Smith, Tetrahedron Lett., 3603 (1967). (12)Y. Y. Lin, M. Shlbahara, and L. L. Smith, J. Org. Chem., 34, 3530 (1969). (13)Melting points were measured on a micro hot plate, arid are not corrected. Ir spectra were determined in KBr tablets with an lnfracord instrument, and 'H NMR spectra were measured with a Jeol 100-MHz spectrometer in CDC13 solution (accuracy f0.5 Hz) and are given in 6 values. The microanalyses were performed in our microanalytical laboratory (head 2 . Celler, M.S.). (14) All compounds were obtained as racemates and for the sake of simplicity the prefixes (dlor rac, respectively) have been omitted.
