New digitalis steroids. Synthesis of 17alpha;-amino 5beta;,14beta;-steroids by thermolysis of 17beta;-azidocarbonyloxymethyl derivatives

摘要

1755J. CHEM. SOC. PERKIN TRANS. I 1995 New digitalis steroids. Synthesis of 17a-amino 5p,l4p=steroids by thermolysis of 17~-azidocarbonyloxymethylderivatives Giorgio Fedrizzi, Luigi Bernardi, Giuseppe Marazzi, Piero Melloni and Marco Frigerio * Prassis Istituto di Ricerche Sigma-Tau, Via Forlanini 113, 20019 Settimo Milanese, (MI), Italy An efficient procedure for the synthesis of otherwise difficult to access 17~amino derivatives of the digitalis series is described. The key reaction is the stereospecific thermocyclisation of 3P-acetoxy- 17P-azido- carbonyloxymethyl-5~-androstan-l4~-ol to (1 7R)-3P-acetoxy- 14P-hydroxyspiro5P-androstane-17,4'-3b oxazolidin-2'-one 4. Natural cardiac glycosides, such as digoxin, digitoxin and ouabain, are well known drugs used for the treatment of congestive heart failure, their pharmacological activity being mediated by inhibition of Na+,K+-ATPase.2 As a part of a medicinal chemistry study, we wanted to introduce an amino substituent in the 17a position of the digitalis steroidal skeleton (general formula 1j to study its influence on the binding of the R 1 R = CHZOH.CHO,COzH steroid to the Na' ,K+-ATPase. No 17-amino derivatives of cardiac glycosides are known; only 3p-or 14P-amino derivatives have been described in the literature. 17-Amino steroids, possessing a C/D trans ring junction, are classically prepared by Strecker reaction on 17-ox0 derivatives, usually in high yield^.^ However, in our hands, using the same reaction conditions with the 17-oxo-S~-androstane-3~,14p-diol and its 17-benzylimino derivative did not lead to any reaction.An attempt to perform an cr-amination on the 170- formyl- as well as the 17P-carboxy-SP-androstane-3P,14P-diol with hydroxylamine-0-sulfonic acid ' did not give any products. It was felt that the approach of the reagents to the 17-carbon atom could be hampered by the steric hindrance of the vicinal quaternary carbon atom, associated with the C/D cis junction. We thus considered that an intramolecular reaction, where the reactant is forced to stay in close proximity to the 17a position, rather than an intermolecular one, would be a good strategy for a successful attack. The photolysis or thermolysis of acyl azides to acyl nitrenes was chosen as a suitable reaction for this purpose.It is known that CH-insertion by acyl nitrenes proceeds with retention of configuration, and, therefore, a 17x-amino derivative was expected to be formed from a 17~-azidocarbonyloxymethyl substituent. The reactions shown in Scheme 1 were planned for testing this hypothesis. Compound 29 was treated with triphosgene to give the corresponding chloro carbonate 3a, which was directly transformed into acyl azide 3b by treatment with NaN, (72 overall yield). Thermolysis of 3b in tetrachloroethane (140 "C, 1 h) gave the desired oxazolidinone 4 in 70 yield, together with the oxazinone by-product 5 (18). The ratio of the two isomeric products 4 (oxazolidinone) and 5 (oxazinone) reflects the doHi ~ ' F O-Ad H H 2 EL3" R=C1 3b R=N* amp;or+amp;-OH OH AcO AdH H 4 5 Scheme 1 Reagents and conditions: i, triphosgene, pyridine, CH,CI,, room temp.; ii, NaN,, acetone, room temp.; iii, tetrachloroethane, 140 "C known preference of nitrenes to react with tertiary C-H bonds and to form five-uersus six-membered rings.8 The 17R absolute configuration of compound 4 was confirmed by the strong NOE observed between 13-Me and 20-H.The stereochemistry of compound 5 at C(16) was assigned on the basis of its chemical behaviour. In fact, under mild basic conditions (KOH, room temp., 72 h) urethane 5 undergoes an intramolecular transesterification with the 140-OH. Thus, the relative stereochemistry of 14-OH and 16-NH groups must be cis.Oxazolidinone 4 was then converted into the 140-ethoxymeth- oxy ether 7,which was quantitatively hydrolysed to amino alcohol 8 with KOH in ethanol (Scheme 2). Amino alcohol 8, after protection of the amino group as the Boc derivative, was oxidized to the corresponding aldehyde 10 with pyridinium dichromate and this was in turn converted into carboxylic acid 11 by KMnO, oxidation. Direct hydrolysis of oxazolidinone 4 with KOH in EtOH at reflux did not give the desired 17a-arnino-l7~-hydroxymethyl compound, but led to ether 12. The peculiar behaviour of urethane 4 towards basic hydrolysis, suggests that the 14p-hydroxy group is so close to C-20 that the intramolecular nucleophilic attack of the 140-alcoholate on the urethane carbonyl group is preferred to intermolecular action of potassium hydroxide.The displacement of the specific ,H-ouabain binding from the Na' ,K+-ATPase receptor, purified according to Jorgh- ensen lo and Brown and Erdmann, l1 was evaluated to test the affinity of some of the new derivatives for the digitalis receptor. 9 10 11 Scheme 2 Reagents and conditions: i, KOH, EtOH, room temp.; ii, DHP, TsOH, dioxane, room temp.; iii, chloromethyl ethyl ether, DIPEA, CH,Cl,, reflux; iv, KOH, EtOH, reflux; v, Boc,O, NaOH, Bu'OH, room temp.; vi, PDC, CH,Cl,, room temp.; vii, KMnO,, NaH,PO,, Bu'OH, room temp.; viii, TsOH, MeCN-H,O NH2 HOW H 12 Compound 6shows a weak but significant binding to Na+,K+- ATPase (IC,, = 1.0 x lo-' mol drn-,), while amino acid 11 possesses an IC,, value lower than 1.0 x lo4 mol dm-3.Experimental Mps were determined on a Buchi 535 apparatus and are uncorrected. IR spectra (KBr) were recorded on a Perkin-Elmer 1310 spectrophotometer. 'H and 13C NMR spectra were obtained at 300.13 and 75.48 MHz respectively, on a Bruker AC-300 instrument. Chemical shifts are expressed in ppm (6) downfield from tetramethylsilane (TMS) as internal standard. J Values are given in Hz. Multiplicity of carbon signals was determinated using the DEPT-135" experiment; all spectra were recorded in CDCl,, unless otherwise specified. Mass spectra were obtained on an INCOS-SOB Finnigan spectrometer in the DEP-EI mode at 70 eV. Elemental analyses were performed by Redox, Cologno Monzese, Italy.All reactions were carried out under a nitrogen atmosphere. Dichlorometh- ane was dried over 4 8, molecular sieves. Purification by flash chromatography was performed according to the methodology of Still et a.'' J. CHEM. soc. PERKIN TRANS. 1 1995 3~-Acetoxy-l7p-azidocarbonyloxymethyl-5p-androstan-14p-ol 3b Triphosgene (5.7 g, 19.2 mmol) and pyridine (4.7 cm3, 5.8 mmol) were added to a solution of the alcohol 2(14 g, 38.5 mmol) in dry dichloromethane (540 cm3). The reaction mixture was stirred for 3 h at room temperature, then a second portion of triphosgene (1.7 g, 5.8 mmol) was added and the reaction mixture stirred for 3 h. The organic solvent was evaporated under reduced pressure, the residue was dissolved in acetone (540 cm3) and then sodium azide (12.5 g, 192 mmol) was added and the reaction mixture was stirred for 2 h at room temperature.The solid was filtered off, the solvent removed under reduced pressure and the residue purified by flash chromatography (cyclohexane-ethyl acetate, 85: 15) to give the title compound 3b (12 g, 72), mp 144-146 "C (decomp.) (Found: C, 63.9; H, 8.25; N, 9.6. Calc. for C,,H,,N,05: C, 63.7; H, 8.1; N, 9.7); vrnax/cm-l 3510, 2190, 2140, 1760 and 1730; ~5~5.08 (1 H, m, 3-H), 4.42 (1 H, dd, J 6.7 and 11.2, CHHO),4.27(1 H,dd, J8.2and 11.2,CHHO),2.06(3 H, s, COMe) and 0.97 (6 H, s, 10-Me and 13-Me). (17R3p-Acetoxy-14p-hydroxyspiro5p-androstane-l7,4'-oxazolidin-2'-one 4and (16S,17R)-3~-acetoxy-14p-hydroxy-3',6',16,17-tetrahydro-2'H- 1,30xazino4',5' :16,173-58-androstan-2'+ne 5 A round bottomed flask containing a suspension of acyl azide 3b (10.0 g, 23.1 mmol) in tetrachloroethane (800 cm3) was placed in an oil bath preheated at 140deg;C.The mixture was stirred for 1 h, until the evolution of nitrogen ceased. Tetrachloroethane was evaporated to dryness using the addition of propanol (4 x 200 cm3) to make the evaporation easier. The solid residue was purified by flash chromatography (dichloromethane-ethyl acetate, 55 :45) to give the title compounds 4(6.58 g, 70) and 5 (1.50 g, 18). For 4:mp 250 "C (Found: C, 68.25; H, 8.55; N, 3.5. Calc. for C,,H,,NO,: C, 68.1; H, 8.7; N, 3.45); v,,,/cm-' 3490, 3280, 1740 and 1710; ~5~6.11 (1 H, s, CONH), 5.08 (1 H, m, 3- H), 4.78 (1 H, d, J9.5, CHHO), 4.15 (1 H, d, J9.5, CHHO), 2.06 (3 H, s, COMe), 0.98 (3 H, s, Me) and 0.94 (3 H, s, Me).For 5: mp 241-244 "C (Found: C, 68.3; H, 8.5; N, 3.65. Calc. for C2,H3,N0,: C, 68.1; H, 8.7; N, 3.45); v,,,/cm-' 3440 and 1715;6, 5.30 (1 H, br d, J2.0, CONH), 5.08 (1 H, m, 3-H), 4.67 l H, dd, J 10.5 and 10.8, C(6')HHO, 4.17 I H, dd, J5.7 and 10.8,C(20)HHO,4.11 (1 H,dddd, J2.072.5,8.8and9.0, 16- H), 2.49 l H, dd, J9.0 and 15.0, C(15)HHJ, 2.26 (1 H, ddd, J 5.7,8.8 and 10.5, 17-H), 2.06 (3 H, s, OCOMe), 1.82 I H, dd, J 2.5 and 15.0, C(lS)HH, 1.02 (3 H, s, Me) and0.95 (3 H, s, Me). (17R)-3P, 14p-Dihydroxyspiro 5p-androstane-17,4'-oxazolidin -2'-one 6 Aqueous potassium hydroxide (4 mol dm-3; 5 cm3, 20 mmol) was added to a stirred solution of the acetate 4(3.5 g, 8.64 mmol) in methanol (22 cm3).After 24 h at room temperature, the solvent was evaporated and the residue triturated with water to give the title compound 6(2.98 g, 95), mp 250 "C (Found: C, 69.2; H, 9.15; N, 3.65. Calc. for C2,H3,N0,: C, 69.4; H, 9.15; N, 3.85); v,,,/cm-' 3440,3260 and 1730;6,5.10 (1 H, br s, CONH), 4.87 (1 H, d, J9.5 CHHO), 4.16 (1 H, d, J9.5, CHHO), 4.14 (1 H, m, 3- H), 0.97 (3 H, s, Me) and 0.94 (3 H, s, Me); amp;(MeOD) 12.1 (q), 20.1 (t), 20.4 (t), 23.9 (q), 26.6 (t), 27.8 (t), 29.8 (2 C, t), 31.5 (t), 33.3 (t), 34.9 (t), 35.5 (s), 35.8 (d), 36.3 (d), 41.4(d), 49.0(s), 66.8 (d), 71.2 (s), 77.0 (t), 84.1 (s) and 160.8'(s); m/z 363 (M+, 0.8), 345 (3.9, 327 (5.4), 312 (9.2), 266 (16.9) and 251 (100).(17R)-14p-Ethoxymethoxy-3p-(RS)-tetrahydropyran-2-yloxyspiroSp-androstane-l7,4'-0xazolidin-2'-one 7 3,4-Dihydro-2H-pyran (DHP) (3.5 cm3, 38.5 mmol) and toluene-p-sulfonic acid (PTSA) (10.5 mg, 0.055 mmol) were added to a stirred suspension of spiro compound 6 (1 g, 2.75 J. CHEM. SOC. PERKIN TRANS. I 1995 mmol) in dioxane (24 cm3). After 18 h at room temperature, the reaction mixture was treated with 5 aq. sodium carbonate (5 cm3) and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and the solvent evaporated to dryness under reduced pressure.Flash chromatography of the residue (ethyl acetate+iichloromethane, 55 :45) gave (17R)- 14P-hydroxy-3P-(RS)-tetrahydropyran-2-yloxy-spiro5 P-androstane-17,4'-0xazolidin-2'-one (1.17 g, 95) (Found: C, 70.0; H, 9.35; N, 3.0. Calc. for C2,H4,N05: C, 69.8; H, 9.2; N, 3.1); ~5~5.88 and 5.81 (1 H, 2 x br S, CONH), 4.86 (1 H, d, J 9.5, CHHCON), 4.62 (1 H, m, OCHO), 4.15 (2 H, d, J 9.5, CHHOCON), 3.96 (1 H, m, 3-H), 3.95-3.40 (2 H, m, CH,O), 0.98 (3 H, s, Me) and 0.94 (3 H, s, Me). Chloromethyl ethyl ether (7.3 an3,78.3 mmol) was added dropwise over 20 min to a stirred solution of (17R)-14P- hydroxy-3P-(RS)-tetrahydropyran-2-yloxy-spiro5 P-andro-stane-l7,4'-oxazolidin-2'-one (3.5 g, 7.83 mmol) and diiso- propylethylamine (DIPEA) (33.5 cm', 196 mmol) in dry di- chloromethane (130 cm3) at 0 "C.The reaction solution was refluxed overnight and then cooled and diluted with ethyl acetate (100 cm3). The organic phase was washed with 5 aq. citric acid (5 x 20 cm3) and water (3 x 20 cm3) and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by chromatography (chloroform-ethyl acetate, 65 :35) to give the title compound 7 (3.05 g, 7773, mp 7683 "C (Found: C, 68.7; H, 9.2; N, 3.0. Calc. for C,,H,,NO,: C, 68.9; H, 9.4; N, 2.8); v,,,/cm-' 3280 and 1700; BH 5.79 and 5.75 (1 H, two br s, CONH), 4.83 (1 H, d, J7.O,OCHHO),4.81 (1 H, d, J9.5, CHHOCON),4.71 (1 H, d J 7.0, OCHHO), 4.65 (1 H, m, OCHO), 4.19 (1 H, d, J 9.5, CHHOCON), 3.95 (1 H, m, 3-H), 3.95-3.40 (4 H, m, OCH,CH3 and OCH,CH,), 1.21 (3 H, t, J 7.0, OCH,CH,), 1.03 (3 H, s, Me) and 0.94 (3 H, s, Me).17a-Amino-l4pethoxymethoxy-l7f3-hydroxymethyl-3~-(RS)-tetrahydropyran-2-yloxyI-5p-androstane 8 Potassium hydroxide (6.68 g, 119 mmol) was added to a solution of urethane 7 (3.0 g, 5.94 mmol) in ethanol 90 (80 cm3). The reaction mixture was refluxed for 8 h and then stirred overnight at room temperature. The solvent was evaporated and the residue diluted with chloroform. The organic phase was washed with 1 mol dm-, hydrochloric acid and with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography of the residue (chloroform-methanol-ammo-nia, 90:lO:l) gave the title compound 8 (2.3 g, 81) as an amorphous solid (Found: C, 70.4; H, 10.1; N, 3.1.Calc. for C2,H4,N0,: C, 70.1; H, 10.3; N, 2.9); v,,,/cm-' 3420 and 3215; dH 4.84 (1 H, d, J 7.0, OCHHO), 4.72 (1 H, d, J 7.0, OCHHO), 4.63 (1 H, m, OCHO), 3.95 (1 H, m, 3-H), 3.79 (1 H, d, J 13.8, CHHOH), 3.95-3.40 (4 H, m, OCH,CH, and OCH,CH,), 3.36 (1 H, d, J 13.8, CHHOH), 1.20 (3 H, t, J7.0, OCH,CH,), 0.96 (3 H, s, Me) and 0.87 (3 H, s, Me). 17a-tert-Butoxycarbonylamino-14p~thoxymethoxy-17p-hydroxymethyL3p-(RS)-tetrahydropyran-2-yloxy-5 p-androstane 9 A mixture of the amino alcohol 8 (2.3 g, 4.80 mmol), aqueous sodium hydroxide (1 mol dmP3; 7.9 cm3, 7.9 mmol) and di-tert- butyl dicarbonate (1.57 g, 7.20 mmol) in tert-butyl alcohol (90 cm3) was stirred at room temperature for 48 h.The solution was then diluted with ethyl acetate, the organic layer washed with 5 aq. sodium dihydrogen phosphate and water, dried over sodium sulfate and evaporated to dryness under reduced pressure. Flash chromatography of the residue (di- chloromethane-ethyl acetate, 75 :25) gave the title compound 9 (2.55 g, 92) as an amorphous solid (Found: C, 68.25; H, 10.15; N, 2.3. Calc. for C,,H,,NO,: C, 68.4; H, 9.9; N, 2.4); 1757 v,,,/cm-' 3430 and 1690; dH4.85 (1 H, d, J 7.0, OCHHO), 4.72 (1 H, d, J 7.0, OCHHO), 4.63 (2 H, m, OCHO and NHCO), 4.13 (1 H, d, J 13.8, CHHOH), 3.95 (1 H, m, 3-H), 3.88 (1 H, d, J 13.8, CHHOH), 3.95-3.40 (4 H, m, OCH2CH3 and OCH,CH,), 1.18 (3 H, t, J 7.0, OCH,CH,), 1.45 (9 H, S, CO,Bu'), 1.08 (3 H, s, Me) and 0.95 (3 H, s, Me). 17a-tert-Butox ycarbon y lamino-14pethox ymethox y-3p-(RS)-tetrahydropyran-2-yloxy -5p-androstane-17p-carbaMehyde 10 A mixture of the alcohol 9 (1 g, 1.73 mmol), pyridinium dichromate (PDC) (9 10 mg, 2.43 mmol) and 4 8,molecular sieves (1.73 g) in dry dichloromethane (15 cm3) was stirred at room temperature for 28 h.The mixture was filtered through a pad of Celite-silica gel, washed with ethyl acetate and the filtrate evaporated to dryness. The residue was purified by flash chromatography (cyclohexane-ethyl acetate, 85 :15) to give the title compound 10(800 mg, 80), mp 74-80 "C (Found: C, 68.8; H,9.45;N,2.55.Calc.forC,,H5,NO,:C,68.6;H,9.6;N,2.4); v,,,/cm-' 3370 and 1715; SH9.61 (1 H, s, CHO), 5.05 (1 H, br s, NHCO), 4.80 (1 H, d, J 7.0, OCHHO), 4.69 (1 H, d, J 7.0, OCHHO), 4.63 (1 H, m, OCHO), 3.98 (1 H, m, 3-H), 3.95-3.40 (4 H, m, OCH2CH3 and OCH2CH2), 1.45 (9 H, s, CO,Bu'), 1.21 (3H, t, J7.0,OCH2CH,),0.96(3H,s,Me)and0.94(3H,s,Me).17a-Amino-3,14(34hydroxy-5p-androstane-17p+ar box ylic acid 11 Sodium dihydrogen phosphate (1.25 mol drn-,; 3.5 cm3, 4.33 mmol) and potassium permanganate (1 mol dm-3; 5.2 cm3, 5.20 mmol) were added under vigorous stirring to a solution of the aldehyde 10 (500 mg, 0.866 mmol) in tert-butyl alcohol (5 cm3) and the mixture was stirred at room temperature for 2.5 h. 5 Aqueous NaHSO, (10 cm3) was added to the mixture which was then stirred for 30 min before hydrochloric acid (0.1 mol dm-,) was added and the mixture extracted with ethyl acetate.The organic phase was washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromato- graphy (cyclohexane-ethyl acetate, 6 :4) of the residue gave 17a-tert-butoxycarbonylamino-14P-ethoxymethoxy-3p-(RS)-tetrahydropyran-2-yloxy-5P-androstane-17 P-carboxylic acid (390 mg, 75) (Found: C, 66.9; H, 9.15; N, 2.55. Calc. for C33H,5N08: C, 66.75; H, 9.3; N, 2.4); 6, 5.63 (1 H, br S, CONH), 4.98 (1 H, d, J 7.0, OCHHO), 4.72 (1 H, d, J 7.0, OCHHO), 4.63 (1 H, m, OCHO), 3.97 (1 H, m, 3-H), 3.95-3.40 (4 H, m, OCH,CH3 and OCH,CH,), 1.45 (9 H, s, CO,Bu'), 1.21 (3 H, t, J7.0,0CH2CH3), 1.03 (3 H, s, Me) and 0.94 (3 H, s, Me); m/z 548 (0.1), 509 (O.l), 458 (8.5), 402 (20.3), 390 (18.3) and 57 (100).A mixture of 17a-tert-butoxycarbonylamino-14P-ethoxy-methoxy-3P-(RS)-tetrahydropyran-2-yloxyl-5P-androstane-178-carboxylic acid (390 mg, 0.657 mmol) and PTSA (100 mg, 0.52 mmol) in acetonitrile-water (85: 15; 50 cm3) was refluxed for 3 h, the mixture was then cooled and evaporated under reduced pressure. The residue was chromatographed (chloroform-methanol-ammonia from 80 :20 :2 to 70 :30 :2) to give the title amino acid 11 (145 mg, 60), mp 250 "C (Found: C, 68.15; H, 9.8; N, 3.85. Calc. for C,,H,,NO,: C, 68.3; H, 9.5; N, 4.0); v,,,/cm-' 3100-2700 and 1660; dH(MeOD) 4.04 (1 H, m, 3-H), 1.08 (3 H, s, Me), 0.97 (3 H, s, Me); amp;(MeOD) 14.6 (q), 21.9 (t), 22.1 (t), 24.3 (q), 27.7 (t), 28.5 (t), 30.7 (t), 32.4 (t), 33.6 (t), 33.9 (t), 34.2 (t), 36.1 (d), 36.3 (s), 37.3 (d), 42.1 (d), 50.8 (s), 67.6 (d), 75.5 (s), 86.2 (s) and 177.6 (s); mjz 333 (3.2), 316 (5.8), 306 (4.4), 298 (2.7), 288 (6.2) and 274 (100).(14R,17R)-17a-Amino-14,17-epoxymethano-5p-androstan-3p-01 12 Potassium hydroxide (3.45 g, 61.5 mmol) was added to a stirred solution of urethane 4 (0.5 g, 1.23 mmol) in ethanol 90 (1 1 cm3). The mixture was refluxed for 4 h. The solvent was 1758 evaparated and the residue diluted with ethyl acetate. The organic phase was washed with hydrochloric acid (1 mol dm-3) and with water, dried over sodium sulfate and evaporated. Flash chromatography of the residue (chloroforn-methanol, 80:20) gave the title compound 12 (212 mg, 51) mp 162-165 "C (Found: C, 75.35; H, 10.6; N, 4.25.Calc. for C2,H3,N02: C, 75.2; H, 10.4; N, 4.4); v,,,/cm-' 3330, 3280 and 3200; dH4.12 (1 H, m, 3-H), 3.59 l H, dd, J 3.0 and 8.0, C(20)HHO, 3.52 l H, d, J8.0, C(20)HH0, 1.02(3 H, s, Me) and 0.88 (3 H, s, Me); G,(2H,DMSO) 12.9 (q), 19.9 (t), 21 .O (t), 23.8 (q), 26.5 (t), 27.2 (t), 27.9 (t), 27.9 (t), 29.0 (t), 30.7 (t), 33.8 (t), 35.3 (d), 35.7 (s), 36.4 (d), 36.6 (d), 47.7 (s), 63.9 (s), 65.9 (d), 72.7 (d) and 89.1 (s). References I B. F. Hoffmann and J. T.Bigger, Jr, in The Pharmacological Basis of Therapeutics,eds. A. Goodman Gilman, L. S. Goodman, T. W. Rall and F. Murad, MacMillan Publishing Company, New York, 1985, p. 716. J. CHEM. SOC. PERKIN TRANS. I 1995 2 K. R. H. Repke and W. Schonfeld, Trenh Pharmacol. Sci., 1984,5, 393. 3 L. F. Fieser and M.Fieser, in Steroids, Reinhold, New York, 1959, p. 727; R. Thomas, P. Gray and J. Andrews, Adv. Drug Rex, 1992, 31 1. 4 M. P. Georgiadis and S. A. Haroutounian, Synthesis, 1989,616. 5 M. M. Kabat, A. Kurek, M. Masnyk, K. R. H. Repke, W. Schonfeld, J. Weiland and J. Wicha, J. Chem. Res., Synop., 1987,218. 6 I. Ojima, S. Inaba and K. Nakatsugawa, Chem. Lett., 1975,331. 7 S. Yamada, T. Oguri and T. Shioiri, J. Chem. Soc., Chem. Commun., 1972,623. 8 1. Brown and 0.E. Edwards, Can. J. Chem., 1966,45, 2599; 0.E. Edwards and Z. Paryek, Can. J. Chem., 1973,51,3866; P. C. Marais and 0.Meth-Cohn, J. Chem SOC.,Perkin Trans. I, 1987, 1553. 9 C. R. Engel and G. Bach, Steroid, 1964, 593. 10 P. Jorghensen, Biochim. Biophys. Acta, 1974,356,36. 1 1 L. Brown and E. Erdmann, Arzneim.-Forsh.,1984,34, 13 14. 12 W. C. Still, M. Kahn and A. Mitra, J,Org. Chem., 1978,43,2923. Paper 4/07 126C Received 22nd November 1994 Accepted 24th March 1995