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Steroids and related products. L. The synthesis of 17-methoxymethylprogesterone
107
2902
STEROIDS AND RELATED PRODUCTS. L*. THE SYNTHESIS OF 17-METROXYMPXHYLPROGESTERGNE Z. Bo&za-Tomaszewski and Ch. R. Engel**
Department of Chemistry Universite Laval, Qugbec, Canada GIX 7P4
Received:
12-16-81
ABSTRACT A new progesterone analogue, 17-methoxymethylprogesterone, was synthesized from pregnenoloneby two pathways, one involving as intermediate a 17-hydroxymethylatedadduct, the other one by methoxymethylation of a 17,20-lithiumenolate with bromomethoxymethane. The product shows significant progestationalactivity.
As we reported previously (1,2), 17-hydroxymethylprogesterone (l-3) and its esters represent the first progesterone analogues with bulky 17-substituentswhich do not possess marked progestational activity. This in
viva
unexpected result prompted us to investigate further,
not hydrolyzable derivatives of 17-hydroxymethylprogesterone.
We here report the synthesis of an ether derivative of that compound, 17-methoxymethylprogesterone (6).
In a first series of experiments, an intermediate in one of our syntheses of 17-hydroxymethylprogesterone (2), 3,20-bisethylenedioxy17-hydroxymethyl-5-pregnene(4),was methylated in over 9551, yield by treatment with sodium hydride and, subsequently,with iodomethane to its methyl ether 5, which was deketalyzed by the method of Schinz and SchPppi (4) to 17-methoxymethylprogesterone (17-methoxymethyl-4pregnene-3,20-dione)(6). Volume
39,
Number
1
S
-=ROXDO
January,
1982
S
108
TDEOXDb
1 , R=RO =H , R,= CO-CH, la,
R = AC, Rt/R2=
2
=C(OAc)-CH3
I
J
4
3
5
6
CH,
7
6
9
S
WIIEOXDI
109
The desired progesterone analogue 6,could also be obtained by a direct 17-methoxymethylationof the 17,20-lithium enolates 2 of pregnenolone (I$, from which the 17-hydroxymethyldiketal 4 had originated (cf. 2). The mixture of enolates ,2,prepared as previously described (2) by reaction with methyllithium of the geometricallyisomeric enol acetates __ la of pregnenolone acetate, was treated in tetrahydrofuranwith bromomethoxymethane to afford in 36% yield 17-methoxymethylpregnenolone (3&hydroxy-17methoxymethyl-5-pregnen-20-one)(z), together with pregnenolone (1); taking into account the recovery of starting material, the yield of the 17-methoxymethylated adduct 3 amounted to 66%. The product was now transformedby treatment with Jones' reagent and subsequentlywith hydrochloric acid (cf. 5: in 98% yield, into 17-methoxymethylprogesterone (5).
According to tests carried out by Professor F. Labrie at the Centre Hospitalier de 1'UniversitB Laval, 17-methoxymethylprogesterone(6) -" shows approximatelyone fourth the binding activity of progesterone to a progesterone receptor and no significantbinding activities to estrogen, androgen, and glucocorticoidreceptors; it exhibits marked decidwgenic activity in rats and no anti-deciduogenicactivity. Details of these and other biological investigationswill be reported separately. The significant progestational activities of 17-methoxymethylprogesterone seem of interest since they contrast with the properties of 17-hydroxymethylprogesterone and its esters.
It should be noted that Williamson type reactions of derivatives of 17-hydroxymethylatedpregnanes are not suitable for the preparation of 17-alkoxymethylated20-keto steroids since the logical 17l-substituted substrates must be prone to neopentyl rearrangements. This could be confirmed by several experiments, for instance by the reaction of
S
WIOEOXD#
3,20-bisethglenedioxy-l7-tosyloxymethyl-S-pregnene (7), previously synthesized in our laboratory (2), with sodium methoxide in dimethyl sulfoxide. Apart from isolating in approximately 30% yield the product arising from hydrolysis of the tosylate, the 17-hydroxymethyl. derivative 4, we obtained indeed two rearrangement products. On the basis of elemental and spectroscopic analyses (cf. Experimental.), as well as on that of their plausible genesis from a 171-cationic species, we propose for one of them, isolated in 43% yield, the structure of 3,20-bisethylenedioxy-D-homopregna-5,17(17a)-diene(8), and to the other, isolated in 21% yield, that of 3,20-bisethylenedioxy-18-nor-17a-methyl-D-homo-l7a~-pregna-5, 13(14)-diene (9).
EXPERIMENTAL The melting points were taken in evacuated capillaries and the temperatureswere corrected. For flash chromatography (6),silica gel Woelm for chromatography at elevated pressure, particle size 32-63 mn, was used. Thin-layer chromatographywas performed with "DC-Alufolien Kieselgel 60". The i.r. spectra were recorded on a Beckman fR-12 spectrophotometer,the U.V. spectra on a Beckman DK-IA instrument, the n.m.r. spectra,at 60 MHz and at 90 MBz,on Varian A-60 and Bruker KFX-90 spectrometers, tetramethylsilaneserving as internal standard. The microanalyses and mass-spectroscopieswere performed by Dr. G. Schilling, Ayerst Laboratories, Montreal, to whom we express our sincere appreciation.
38-Hy~~-1?-methox~e~hyZ-5-preg~~-2#-one (21. - From 30,3 ml of a 1,45M ethereal methyllithium solution, the solvent was removed in VUCW, under a slight nitrogen pressure. The residue was dissol.ved in 50 ml of absolute tetrahydrofuran,andas described previously (2), a solution of 4 g of a crude, crystalline mixture of the geometrically isomerit 38,20-diacetoxy-5,L7(20)-pregnadienes 1,~,m-p. 137-143' [prepared according to the method of Fieser and Huang-Minlon (7, cf. also 8,9)1 in I.00ml.of absolute tetrahydrofuranwas added dropwise, with vigorous stirring, at O", 2,2'-bipyridyl serving as indicator. When the red color had almost disappeared, a solution of 1,38 g of bromomethoxymethane in 10 ml of absolute tetrahydrofuranwas added and the mixture was stirred for 5 min at O", and subsequently poured into cold 2 N hydrochloric acid, The precipitate was extracted with ether, the ethereal solution was washed with water and was dried over sodium sulfate. Removal of the solvent gave 3,505 g of a foam which was subjected to flash chromatography (6) on silica gel, benzene-ethyl
s
IPLIEOStDII
111
acetate (7:3)serving as eluent. Thus, 1,8 g of preg?zenoZone(31% &$.ro~-5-pre9nen-20-oneJ fJJ, m.p. l83-186', identifiedby the determination of a mixture melting point and by comparison of its infrared spectrun with that of an authentic sample,aswell as 1,3 g (36% yield) of 3&h#roxy-l7-methoxymethyZ-5-pregnen-2O-one (21,m.p. 213-214', were isolated. Considering the recovery of pregnenolone and a 79% yield fn the formation of the mixture of the enol acetates ?LL,the yield of the methoxymethyl ZO-ketone 2 amounted to 66%. A sample was recrystallizedtwice from methanol for analysis; colorless needles, m.p. 214-215', [u]~~ +52O (c, 1,000 in CHC13); vmax (KBr) 3400 (OR), 1705 (ZO-ketone), 1095 cm-' (ether); 6 (60 MHz, CDC13), 0,66 (s, 3 H, 19-M3), 1,00 (s, 3 H, 18-cH3), 2,17 (s, 3 R, CH3CO), 3,3 (s, 3 R, M30), 3,4 (m, 1 H, W/Z = 26 Hz, 3~H), 3,60 (dd, 2 H, v = 31 Rz, 3 = 8 Hz, CR20), 5,36 (m, 1 H, w/z = 9 Hz, 6-H); mass calcd. for Found: 360. c23H3603Z 360. Anal. Calcd. for C23H3603: C, 76,62; H, 10,07. Found: C, 76,62; H, 9,97.
3,20-Biset;tayZenediolcy-I7-methoccymethyZ-5-pre~ne (5).- A solution of 3 g of 3,2O-bisathylenedio~-l7-hydro~ethyl-5-pre~ene ($) (2), m.p. 173-175', in 100 ml of absolute tetrahydrofuranwas refluxed for 2 h with 3 g of sodium hydride (50% suspension in mineral oil). Iodomethane (1,5 g) was added dropwise and with stirring and the mixture was refluxed for 18,s h. After cooling, the excess sodium hydride was destroyed with ice, the organic solution was filtered and was dried over sodium sulfate. Removal of the solvent gave 3,Ol g (97% yield) of 3,2O-bisethylenedio~-l7-methox~thyl-5-pre~ene (s), m.p. 131-132', which melted after one recrystallizationfrom methanol at 132-134O. A sample was recq stallized twice from ether for analysis; colorless needles, m.p. 134-135 ; CCLI~~ +25' (c, 1,000 in CHC13); vmax (KBr): 1105 and 1085 cm-l (ketals); 6 (90 MHz, CDCl ), 0,86 (6, 3 H, 18-a3), 0,98 (s, 3 8, 19-CH3),1,33 (s, 3 H, 2l-CR3s , 3,12 (s, 3 H, CH30), 3,27 (dd, 2 H, v = 12,5 Hz, J = 9,5 Hz, CR20),5,1 (m, 1 B, w/2 = 9 HZ, 6-H) ; mass calcd. for C27H42O5: 446. Found: 446. Anal. Calcd. for C27H42O5: C, 72,61; H, 9,48. Found: C, 72,63; H, 9.48. I?-Metho~methy~progesterone (I7-Methox~methyl-4-p~le~ne-3.20tiketd 5. - A solution of &one1 ret. (af FPCXIi&e Met~o~rne~~~Z
1,06 g of 17-methoxymethyldiketal 5_,m.p. 132-13z", and of 75 mg of p-toluenesulfonicacid in 150 ml of absolute acetone was left at room temperature for 7 h. Ice and potassium bicarbonate were added and the precipitatewas extracted with ether, The ethereal solution was washed with water and was dried over sodium sulfate. Removal of the solvent gave 808 mg (95% yield) of crystalline 17-methoxymethylqgesterone (17-metho~ethyl-4-preg~ne-3,2O-di~e) (G), m.p. 185-189 . Recrystallizationfrom ether raised the melting point to 188-190°. A sample was recrystallizedtwice more from ether for analysis; colorless prisms, m.p. 189-19l.O; [al&1 +l.89O(c, 1,000 in CRC1 ); &,ax (EtOH) 241 nm (log E 4,2); vmax (KBr) 1705 (20-ketone),1a75 and 1625 (A4-3-keto doublet), 1095 cm-l (ether); d (90 MHz, CDC13) 0,69 (s, 3 H, 18-cD3), 1,2 (s, 3 H, 19-C?+), 2,2 (s, 3 H, CH3CO),
112
S
TZlEOXDU
3,3 (s, 3 H, CH30), 3,57 (dd, 2 H, V = 45 Hz, J = 8 Hz, CH20), 5,75 (s, 1 H, 4-H); mass calcd. for C23H3403: 358. Found: 358. Anal. Calcd. for C23H3403: C, 77,05; H, 9,56. C, 76,71; H, 9,52.
Found:
&i From l?-P~eehox~met-hyZpre~noZone 13). - To a solution of 1 g of 17-me~hox~ethylpregnenolone (_3),m.p. 23.3-214',in 150 ml of absolute acetone, 1 ml of Jones' reagent (10) was added at O" in the course of 1 min. The mixture was left at 0' for another 5 min and then poured into ice water. The product was extracted with ether, the ethereal solution was washed with water and was dried over sodium sulfate. Removal of the solvent gave 982 mg of a crystalline product which was dissolved in 40 ml of methanol and 0,5 ml of water containing a drop of concentrated hydrochloric acid. The solution was warmed to 50' for 5 min, cooled and diluted with 300 ml of water. The mixture was extracted with ether, the ethereal solution was washed with water, and was dried over sodium sulfate. Evaporation of the solvent gave 972 mg (98% yield) of crystalline ~7-methox~ethy~progestero~e ($1, m.p. 185-189°. Recrystallizationfrom ether raised the melting point to 188-190°. The identity of the product was established by the comparison of its infrared spectrum with that of a sample of the product described under (a) and by the determination of a mixture melting point.
pregame
Re~~~ge~~~~ of 3,ZU-Bisethytenediox~-l ?-~os~~~x~e~~~~-5il1. - A solution of 300 mg of 3,2~-b~sethy~ened~oxy-~7-
iosy~ox~ethy~-~-~re~ene (7) (21, m-p. 147-149', and of 600 mg of sodium methoxide in 60 ml of absolute dimethyl sulfoxide was heated with stirring, under nitrogen, for 5 h to 75O. The mixture was cooled and poured into 500 ml of an ice cold 10% hydrochloric acid solution and the product was extracted with dichloromethane. The organic solution was washed with water, was dried over sodium sulfate, and taken to dryness. The residue (209 mg) was subjected to flash chromatography (6) on silica gel. Elutions with benzene-ethyl acetate (4:1> afforded 44 mg (21% yield) of 3,ZO-biset~~Zenedio~~-I8-nor-I7a-meth~~-D-hQ~~Iiiz~--pregr~-5,23(24/-dierze /9,)., m.p. 159-160°. The product was recrys-o tallized twice from ether for analysis; colorless prisms, m.p. 160-161 ; Cctl~~ +25o (c? , 1,000 In CHC13), VmaX (KBr) 1105 and 1080 cm-l (ketals); c;(90 MHZ, CDCl > 0,97 fs, 3 H, 17a-CH3), 1,OO (s, 3 R, l-9-CH3),I,38 (s, 3 H, 2%CH3?, 3,77 (s, 8 H, 0~2~20), 5,1 (m, 1 H, w/2 = 9 Hz, 6-H); mass spectrum: m/e 414 (&), 399, 328, 314, 99, 87. Anal. Calcd. for C26H3804: C, 75,32; H, 9,24. Found: C, 74,96; H, 9,06. The same solvent mixture eluted 90 mg (43% yield) of 3,2L'bisethy~e~dius-y-0-h~o-pregrza-S,1?117al -diem i_Bi,m.p. 220-223'. The product was recrystallized twice from ether for analysis; colorless needles, m.p. 223-225O; [a]$,'+32' (c, 1,000 in CHCl3); Vmax (KBr) 1095 and 1038 cm-l (ketals); 6 (90 MHz, CDCH3), 0,96 (5, 3 5, 18-~~31, x,00 (s, 3 H, 19-c~3), 1,46 (s, 3 H, 2l-CH3f, 3,78 (s, 8 H, 0CK2CH20), 5,l fm, 1 H, wl2 = 10 Hz, 6-H), 5,6 (t, 1 H, .Jl= g Hz, J2 = 4 Hz, 17-H); mass spectrum: m/e 414 (&), 399, 328, 314, 99, 87.
S
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113
Anal. Calcd. for C26H3804: C, 75,32; H, 9,24. Found: c, 75,35; H, 9,13. Elutions in the above-describedchromatogramwith benzene-ethyl acetate (7:s) gave 68 mg (31% yield) of 3,20-bLsethyZendioxy-I7hydroxymethyZ-Spregnene (41 (21, m.p. 172-175', identified by the comparison of its infrgred spectrum with that of an authentic sample and by the determination of a mixture melting point. ACKNOWLF,DGEMENTS We express sincere thanks to Professor Fernand Labrie, Centre de Recherches en EndocrinologieMoldculaire, Centre Hospitalier de 1'Universitd Laval, for the biological evaluations summarized in this paper. Our appreciation is expressed to Mrs. D. Thibault, Mrs. Lise LBvesque,and Mrs. G. Fontaine for excellent technical assistance. The research described in this communicationwas performed pursuant to contract No. NICHD-NOl-8-2812with the National Institutes of Health U.S. Department of Health, Education, and Welfare. This support is gratefully acknowledged and we sincerely thank Dr. H. K. Kim of the National Institute for Child Health and Human Development for his very kind cooperation. We further express our appreciation to the Natural Sciences and Engineering Research Council of Canada, the MinistOre de 1'Education du Qugbec, and to Ayerst Laboratories,Montreal, for their participationin the support of the reported investigations. NOTES AND REFERENCES *
Paper XLIX: Engel, Ch. R., M&-and, Y., and Cats, J., J. Org. Chem. 1982, w-w.-. 47 (1982) (in press).
**
To whom correspondenceshould be addressed.
1. Engel, Ch. R. and Mukherjee, D., Steroids, 1977, *-__ 29, 827. 2. Mukherjee, D. and Engel, Ch. R., Can. J. Chem. *__., 1978, 56, 410. 3. Mukherjee, D. and Engel, Ch. R., Steroids, _-...,_ 1979, 34, 597. 4.
Schinz, H. and Schtippi,G., Helv. Chim. Acta, 1-m1 1947, 30, 1483.
5. Engel, Ch. R. and Jahnke, H., Can. J. Biochem. Physiol. ___1957, 35, 1048. 6.
Still, W. C., Kahn, M., and Mitra, A., J. Org. Chem. __-...w 1978, 43, 2923.
7.
Fieser, L. F. and Huang-Minion, J. Am. Chem. Sot. 1949 71, 1840. ,,.".Vf
8.
(a) Marshall, C. W., Kritchevsky, T. H., Lieberman, S., and Gallagher, T. F., J. Am. Chem. Sot. 1948 ."-,,)70, 1947; (b) Gallagher, T. F. and Kritchevsky, T. H., J. Biol. Chem. 1949 79, 507. ..,,,,,
9. Heusser, H., Engel, Ch. R., Herzig, P. Th., and Plattner, Pl. A., Helv. Chim. Acta, 1950, -u-._ 33, 2229.
114
10.
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(a) Bowden, K., Heilbron, J. M., Jones, E. R. H., and Weldon, B. C. L., J. Chem. Sot. 1946, 39; (b) Bowers, A., Halsall, T. G., Jones, E. R. H., s&a"'Lemin,A. J., J. Chem. Sot. 1953, Y-Ye 2548.
2902
STEROIDS AND RELATED PRODUCTS. L*. THE SYNTHESIS OF 17-METROXYMPXHYLPROGESTERGNE Z. Bo&za-Tomaszewski and Ch. R. Engel**
Department of Chemistry Universite Laval, Qugbec, Canada GIX 7P4
Received:
12-16-81
ABSTRACT A new progesterone analogue, 17-methoxymethylprogesterone, was synthesized from pregnenoloneby two pathways, one involving as intermediate a 17-hydroxymethylatedadduct, the other one by methoxymethylation of a 17,20-lithiumenolate with bromomethoxymethane. The product shows significant progestationalactivity.
As we reported previously (1,2), 17-hydroxymethylprogesterone (l-3) and its esters represent the first progesterone analogues with bulky 17-substituentswhich do not possess marked progestational activity. This in
viva
unexpected result prompted us to investigate further,
not hydrolyzable derivatives of 17-hydroxymethylprogesterone.
We here report the synthesis of an ether derivative of that compound, 17-methoxymethylprogesterone (6).
In a first series of experiments, an intermediate in one of our syntheses of 17-hydroxymethylprogesterone (2), 3,20-bisethylenedioxy17-hydroxymethyl-5-pregnene(4),was methylated in over 9551, yield by treatment with sodium hydride and, subsequently,with iodomethane to its methyl ether 5, which was deketalyzed by the method of Schinz and SchPppi (4) to 17-methoxymethylprogesterone (17-methoxymethyl-4pregnene-3,20-dione)(6). Volume
39,
Number
1
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January,
1982
S
108
TDEOXDb
1 , R=RO =H , R,= CO-CH, la,
R = AC, Rt/R2=
2
=C(OAc)-CH3
I
J
4
3
5
6
CH,
7
6
9
S
WIIEOXDI
109
The desired progesterone analogue 6,could also be obtained by a direct 17-methoxymethylationof the 17,20-lithium enolates 2 of pregnenolone (I$, from which the 17-hydroxymethyldiketal 4 had originated (cf. 2). The mixture of enolates ,2,prepared as previously described (2) by reaction with methyllithium of the geometricallyisomeric enol acetates __ la of pregnenolone acetate, was treated in tetrahydrofuranwith bromomethoxymethane to afford in 36% yield 17-methoxymethylpregnenolone (3&hydroxy-17methoxymethyl-5-pregnen-20-one)(z), together with pregnenolone (1); taking into account the recovery of starting material, the yield of the 17-methoxymethylated adduct 3 amounted to 66%. The product was now transformedby treatment with Jones' reagent and subsequentlywith hydrochloric acid (cf. 5: in 98% yield, into 17-methoxymethylprogesterone (5).
According to tests carried out by Professor F. Labrie at the Centre Hospitalier de 1'UniversitB Laval, 17-methoxymethylprogesterone(6) -" shows approximatelyone fourth the binding activity of progesterone to a progesterone receptor and no significantbinding activities to estrogen, androgen, and glucocorticoidreceptors; it exhibits marked decidwgenic activity in rats and no anti-deciduogenicactivity. Details of these and other biological investigationswill be reported separately. The significant progestational activities of 17-methoxymethylprogesterone seem of interest since they contrast with the properties of 17-hydroxymethylprogesterone and its esters.
It should be noted that Williamson type reactions of derivatives of 17-hydroxymethylatedpregnanes are not suitable for the preparation of 17-alkoxymethylated20-keto steroids since the logical 17l-substituted substrates must be prone to neopentyl rearrangements. This could be confirmed by several experiments, for instance by the reaction of
S
WIOEOXD#
3,20-bisethglenedioxy-l7-tosyloxymethyl-S-pregnene (7), previously synthesized in our laboratory (2), with sodium methoxide in dimethyl sulfoxide. Apart from isolating in approximately 30% yield the product arising from hydrolysis of the tosylate, the 17-hydroxymethyl. derivative 4, we obtained indeed two rearrangement products. On the basis of elemental and spectroscopic analyses (cf. Experimental.), as well as on that of their plausible genesis from a 171-cationic species, we propose for one of them, isolated in 43% yield, the structure of 3,20-bisethylenedioxy-D-homopregna-5,17(17a)-diene(8), and to the other, isolated in 21% yield, that of 3,20-bisethylenedioxy-18-nor-17a-methyl-D-homo-l7a~-pregna-5, 13(14)-diene (9).
EXPERIMENTAL The melting points were taken in evacuated capillaries and the temperatureswere corrected. For flash chromatography (6),silica gel Woelm for chromatography at elevated pressure, particle size 32-63 mn, was used. Thin-layer chromatographywas performed with "DC-Alufolien Kieselgel 60". The i.r. spectra were recorded on a Beckman fR-12 spectrophotometer,the U.V. spectra on a Beckman DK-IA instrument, the n.m.r. spectra,at 60 MHz and at 90 MBz,on Varian A-60 and Bruker KFX-90 spectrometers, tetramethylsilaneserving as internal standard. The microanalyses and mass-spectroscopieswere performed by Dr. G. Schilling, Ayerst Laboratories, Montreal, to whom we express our sincere appreciation.
38-Hy~~-1?-methox~e~hyZ-5-preg~~-2#-one (21. - From 30,3 ml of a 1,45M ethereal methyllithium solution, the solvent was removed in VUCW, under a slight nitrogen pressure. The residue was dissol.ved in 50 ml of absolute tetrahydrofuran,andas described previously (2), a solution of 4 g of a crude, crystalline mixture of the geometrically isomerit 38,20-diacetoxy-5,L7(20)-pregnadienes 1,~,m-p. 137-143' [prepared according to the method of Fieser and Huang-Minlon (7, cf. also 8,9)1 in I.00ml.of absolute tetrahydrofuranwas added dropwise, with vigorous stirring, at O", 2,2'-bipyridyl serving as indicator. When the red color had almost disappeared, a solution of 1,38 g of bromomethoxymethane in 10 ml of absolute tetrahydrofuranwas added and the mixture was stirred for 5 min at O", and subsequently poured into cold 2 N hydrochloric acid, The precipitate was extracted with ether, the ethereal solution was washed with water and was dried over sodium sulfate. Removal of the solvent gave 3,505 g of a foam which was subjected to flash chromatography (6) on silica gel, benzene-ethyl
s
IPLIEOStDII
111
acetate (7:3)serving as eluent. Thus, 1,8 g of preg?zenoZone(31% &$.ro~-5-pre9nen-20-oneJ fJJ, m.p. l83-186', identifiedby the determination of a mixture melting point and by comparison of its infrared spectrun with that of an authentic sample,aswell as 1,3 g (36% yield) of 3&h#roxy-l7-methoxymethyZ-5-pregnen-2O-one (21,m.p. 213-214', were isolated. Considering the recovery of pregnenolone and a 79% yield fn the formation of the mixture of the enol acetates ?LL,the yield of the methoxymethyl ZO-ketone 2 amounted to 66%. A sample was recrystallizedtwice from methanol for analysis; colorless needles, m.p. 214-215', [u]~~ +52O (c, 1,000 in CHC13); vmax (KBr) 3400 (OR), 1705 (ZO-ketone), 1095 cm-' (ether); 6 (60 MHz, CDC13), 0,66 (s, 3 H, 19-M3), 1,00 (s, 3 H, 18-cH3), 2,17 (s, 3 R, CH3CO), 3,3 (s, 3 R, M30), 3,4 (m, 1 H, W/Z = 26 Hz, 3~H), 3,60 (dd, 2 H, v = 31 Rz, 3 = 8 Hz, CR20), 5,36 (m, 1 H, w/z = 9 Hz, 6-H); mass calcd. for Found: 360. c23H3603Z 360. Anal. Calcd. for C23H3603: C, 76,62; H, 10,07. Found: C, 76,62; H, 9,97.
3,20-Biset;tayZenediolcy-I7-methoccymethyZ-5-pre~ne (5).- A solution of 3 g of 3,2O-bisathylenedio~-l7-hydro~ethyl-5-pre~ene ($) (2), m.p. 173-175', in 100 ml of absolute tetrahydrofuranwas refluxed for 2 h with 3 g of sodium hydride (50% suspension in mineral oil). Iodomethane (1,5 g) was added dropwise and with stirring and the mixture was refluxed for 18,s h. After cooling, the excess sodium hydride was destroyed with ice, the organic solution was filtered and was dried over sodium sulfate. Removal of the solvent gave 3,Ol g (97% yield) of 3,2O-bisethylenedio~-l7-methox~thyl-5-pre~ene (s), m.p. 131-132', which melted after one recrystallizationfrom methanol at 132-134O. A sample was recq stallized twice from ether for analysis; colorless needles, m.p. 134-135 ; CCLI~~ +25' (c, 1,000 in CHC13); vmax (KBr): 1105 and 1085 cm-l (ketals); 6 (90 MHz, CDCl ), 0,86 (6, 3 H, 18-a3), 0,98 (s, 3 8, 19-CH3),1,33 (s, 3 H, 2l-CR3s , 3,12 (s, 3 H, CH30), 3,27 (dd, 2 H, v = 12,5 Hz, J = 9,5 Hz, CR20),5,1 (m, 1 B, w/2 = 9 HZ, 6-H) ; mass calcd. for C27H42O5: 446. Found: 446. Anal. Calcd. for C27H42O5: C, 72,61; H, 9,48. Found: C, 72,63; H, 9.48. I?-Metho~methy~progesterone (I7-Methox~methyl-4-p~le~ne-3.20tiketd 5. - A solution of &one1 ret. (af FPCXIi&e Met~o~rne~~~Z
1,06 g of 17-methoxymethyldiketal 5_,m.p. 132-13z", and of 75 mg of p-toluenesulfonicacid in 150 ml of absolute acetone was left at room temperature for 7 h. Ice and potassium bicarbonate were added and the precipitatewas extracted with ether, The ethereal solution was washed with water and was dried over sodium sulfate. Removal of the solvent gave 808 mg (95% yield) of crystalline 17-methoxymethylqgesterone (17-metho~ethyl-4-preg~ne-3,2O-di~e) (G), m.p. 185-189 . Recrystallizationfrom ether raised the melting point to 188-190°. A sample was recrystallizedtwice more from ether for analysis; colorless prisms, m.p. 189-19l.O; [al&1 +l.89O(c, 1,000 in CRC1 ); &,ax (EtOH) 241 nm (log E 4,2); vmax (KBr) 1705 (20-ketone),1a75 and 1625 (A4-3-keto doublet), 1095 cm-l (ether); d (90 MHz, CDC13) 0,69 (s, 3 H, 18-cD3), 1,2 (s, 3 H, 19-C?+), 2,2 (s, 3 H, CH3CO),
112
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TZlEOXDU
3,3 (s, 3 H, CH30), 3,57 (dd, 2 H, V = 45 Hz, J = 8 Hz, CH20), 5,75 (s, 1 H, 4-H); mass calcd. for C23H3403: 358. Found: 358. Anal. Calcd. for C23H3403: C, 77,05; H, 9,56. C, 76,71; H, 9,52.
Found:
&i From l?-P~eehox~met-hyZpre~noZone 13). - To a solution of 1 g of 17-me~hox~ethylpregnenolone (_3),m.p. 23.3-214',in 150 ml of absolute acetone, 1 ml of Jones' reagent (10) was added at O" in the course of 1 min. The mixture was left at 0' for another 5 min and then poured into ice water. The product was extracted with ether, the ethereal solution was washed with water and was dried over sodium sulfate. Removal of the solvent gave 982 mg of a crystalline product which was dissolved in 40 ml of methanol and 0,5 ml of water containing a drop of concentrated hydrochloric acid. The solution was warmed to 50' for 5 min, cooled and diluted with 300 ml of water. The mixture was extracted with ether, the ethereal solution was washed with water, and was dried over sodium sulfate. Evaporation of the solvent gave 972 mg (98% yield) of crystalline ~7-methox~ethy~progestero~e ($1, m.p. 185-189°. Recrystallizationfrom ether raised the melting point to 188-190°. The identity of the product was established by the comparison of its infrared spectrum with that of a sample of the product described under (a) and by the determination of a mixture melting point.
pregame
Re~~~ge~~~~ of 3,ZU-Bisethytenediox~-l ?-~os~~~x~e~~~~-5il1. - A solution of 300 mg of 3,2~-b~sethy~ened~oxy-~7-
iosy~ox~ethy~-~-~re~ene (7) (21, m-p. 147-149', and of 600 mg of sodium methoxide in 60 ml of absolute dimethyl sulfoxide was heated with stirring, under nitrogen, for 5 h to 75O. The mixture was cooled and poured into 500 ml of an ice cold 10% hydrochloric acid solution and the product was extracted with dichloromethane. The organic solution was washed with water, was dried over sodium sulfate, and taken to dryness. The residue (209 mg) was subjected to flash chromatography (6) on silica gel. Elutions with benzene-ethyl acetate (4:1> afforded 44 mg (21% yield) of 3,ZO-biset~~Zenedio~~-I8-nor-I7a-meth~~-D-hQ~~Iiiz~--pregr~-5,23(24/-dierze /9,)., m.p. 159-160°. The product was recrys-o tallized twice from ether for analysis; colorless prisms, m.p. 160-161 ; Cctl~~ +25o (c? , 1,000 In CHC13), VmaX (KBr) 1105 and 1080 cm-l (ketals); c;(90 MHZ, CDCl > 0,97 fs, 3 H, 17a-CH3), 1,OO (s, 3 R, l-9-CH3),I,38 (s, 3 H, 2%CH3?, 3,77 (s, 8 H, 0~2~20), 5,1 (m, 1 H, w/2 = 9 Hz, 6-H); mass spectrum: m/e 414 (&), 399, 328, 314, 99, 87. Anal. Calcd. for C26H3804: C, 75,32; H, 9,24. Found: C, 74,96; H, 9,06. The same solvent mixture eluted 90 mg (43% yield) of 3,2L'bisethy~e~dius-y-0-h~o-pregrza-S,1?117al -diem i_Bi,m.p. 220-223'. The product was recrystallized twice from ether for analysis; colorless needles, m.p. 223-225O; [a]$,'+32' (c, 1,000 in CHCl3); Vmax (KBr) 1095 and 1038 cm-l (ketals); 6 (90 MHz, CDCH3), 0,96 (5, 3 5, 18-~~31, x,00 (s, 3 H, 19-c~3), 1,46 (s, 3 H, 2l-CH3f, 3,78 (s, 8 H, 0CK2CH20), 5,l fm, 1 H, wl2 = 10 Hz, 6-H), 5,6 (t, 1 H, .Jl= g Hz, J2 = 4 Hz, 17-H); mass spectrum: m/e 414 (&), 399, 328, 314, 99, 87.
S
?FIIEOIDI
113
Anal. Calcd. for C26H3804: C, 75,32; H, 9,24. Found: c, 75,35; H, 9,13. Elutions in the above-describedchromatogramwith benzene-ethyl acetate (7:s) gave 68 mg (31% yield) of 3,20-bLsethyZendioxy-I7hydroxymethyZ-Spregnene (41 (21, m.p. 172-175', identified by the comparison of its infrgred spectrum with that of an authentic sample and by the determination of a mixture melting point. ACKNOWLF,DGEMENTS We express sincere thanks to Professor Fernand Labrie, Centre de Recherches en EndocrinologieMoldculaire, Centre Hospitalier de 1'Universitd Laval, for the biological evaluations summarized in this paper. Our appreciation is expressed to Mrs. D. Thibault, Mrs. Lise LBvesque,and Mrs. G. Fontaine for excellent technical assistance. The research described in this communicationwas performed pursuant to contract No. NICHD-NOl-8-2812with the National Institutes of Health U.S. Department of Health, Education, and Welfare. This support is gratefully acknowledged and we sincerely thank Dr. H. K. Kim of the National Institute for Child Health and Human Development for his very kind cooperation. We further express our appreciation to the Natural Sciences and Engineering Research Council of Canada, the MinistOre de 1'Education du Qugbec, and to Ayerst Laboratories,Montreal, for their participationin the support of the reported investigations. NOTES AND REFERENCES *
Paper XLIX: Engel, Ch. R., M&-and, Y., and Cats, J., J. Org. Chem. 1982, w-w.-. 47 (1982) (in press).
**
To whom correspondenceshould be addressed.
1. Engel, Ch. R. and Mukherjee, D., Steroids, 1977, *-__ 29, 827. 2. Mukherjee, D. and Engel, Ch. R., Can. J. Chem. *__., 1978, 56, 410. 3. Mukherjee, D. and Engel, Ch. R., Steroids, _-...,_ 1979, 34, 597. 4.
Schinz, H. and Schtippi,G., Helv. Chim. Acta, 1-m1 1947, 30, 1483.
5. Engel, Ch. R. and Jahnke, H., Can. J. Biochem. Physiol. ___1957, 35, 1048. 6.
Still, W. C., Kahn, M., and Mitra, A., J. Org. Chem. __-...w 1978, 43, 2923.
7.
Fieser, L. F. and Huang-Minion, J. Am. Chem. Sot. 1949 71, 1840. ,,.".Vf
8.
(a) Marshall, C. W., Kritchevsky, T. H., Lieberman, S., and Gallagher, T. F., J. Am. Chem. Sot. 1948 ."-,,)70, 1947; (b) Gallagher, T. F. and Kritchevsky, T. H., J. Biol. Chem. 1949 79, 507. ..,,,,,
9. Heusser, H., Engel, Ch. R., Herzig, P. Th., and Plattner, Pl. A., Helv. Chim. Acta, 1950, -u-._ 33, 2229.
114
10.
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TIOEOXDI
(a) Bowden, K., Heilbron, J. M., Jones, E. R. H., and Weldon, B. C. L., J. Chem. Sot. 1946, 39; (b) Bowers, A., Halsall, T. G., Jones, E. R. H., s&a"'Lemin,A. J., J. Chem. Sot. 1953, Y-Ye 2548.