A new route to steroid ring-c aromatization from 7-oxygenated steroids

摘要

J. CHEM. SOC. PERKIN TRANS. I 1983 A New Route to Steroid Ring-c Aromatization from 7-Oxygenated Steroids Mario Anastasia," Pierangela Ciuffreda, Marina Del PupPo8 and Alberto Fiecchi Institute of Chemistry, School of Medicine, University of Milan, Via Saldini 50,l-20133Milano, Italy 3P-Acetoxy-5 a-cholesta-8,14- d ien -7B-01 (3), 3P-acetoxy-8 a,9 a-epoxy-5a-c holesta n -7 P-01 (6a), and 3~-acetoxy-8a,l4a-epoxy-5a-cholestan-7~-ol(8a) have been aromatized with hydrochloric acid in ethanol to afford a 9 :1 mixture of 12-methyl-I 8-nor-5a817P( H)-cholesta-8,11,13-trien-3~-ol(4)and 12-methyl-I 8-nor-5a-cholesta-8,I 1,I3-trien-3P-ol (5). By the same acidic treatment 3P-acetoxy- 8a,96c-epoxy-5a-cholestan-7a-ol (6c) generates 3~-hydroxy-5a-cholest-8-en-7-one (7a), and 3P-acetoxy-8~,14a-epoxy-5a-cholestan-7~-ol(8c) affords 3~-hydroxy-5a-cholest-8(14)-en-7-one (9a) accompanied by the previously unobserved 3P-hydroxy-5a-cholest-8(14) -en-I 5-one (I Oa).As part of our interest in the synthesis of ring-c benzenoid steroids from readily available precursors we report here a new route to such compounds starting from 7-oxygenated steroids. In a previous paper 'we reported that a number of sterols of the cholestane series, oxygenated in the c-and D-rings, could be converted into ring-c benzenoid steroids by treat- ment with hydrochloric acid or toluene-p-sulphonic acid. The R H RpH+ configuration of the side chain was retained in the molecular rearrangement promoted by toluene-p-sulphonic acid whilst the side-chain configuration was inverted in the rearrange- ment promoted by hydrochloric acid.Despite the different HR HR products obtained in the reactions with the two acids we isolated in both cases two intermediate trienes, 3P-acetoxy-5a- cholesta-7,9( 1 l), 14-triene (1 b) and 3P-acetoxy-5a-cholesta-8,- 11,14-triene(2), thus strongly supporting the mechanism pro- posed by Whalley et aL2 (Scheme 1) for a similar aromatiz- ation. With this mechanism in mind we considered that, on treatment with hydrochloric acid, 3P-acetoxy-5a-cholesta- 8,14-dien-7P-o1(3) should afford the triene (1 b) by elimination of the 7P-hydroxy-group which, on rearrangement and sapon- L R i ification, would give 12-methyl-1 8-nor-5a, 17P(H)-cholesta- 8,11,13-trien-3P-o1 (4) and 12-methyl-1 8-nor-5a-cholesta-8,- 11,13-trien-3P-o1(5).To test this hypothesis, compound (3), prepared by sodium borohydride reduction of 3~-acetoxy-5a-cholesta-8,14-dien- 7-0ne,' was treated with hydrochloric acid in ethanol at room L temperature. Under these conditions the triene (1 b) crystal- Scbeme 1 lized out as needles from a mixture with the corresponding alcohol (la). When the reaction was performed in refluxing ethanol the aromatic sterol (4) was obtained in good yield, together with a small amount of the isomer (5).l In order to check if the acidic treatment of 3B-acetoxy- Since the 8,14-diene system present in compound (3) can be 8a,9a-epoxy-5a-cholestan-7a-ol(6c) and 3B-acetoxy-8a,l4a- obtained by acidic treatment of an 8a,9a- or 8a,14a-epoxide epoxy-5a-cholestan-7a-01(8c) afforded the unsaturated ke- ring, we treated 3~-acetoxy-8a,9a-epoxy-5a-cholestan-7~-oltones without causing ring-c aromatization we subjected both (6a) with hydrochloric acid in refluxing ethanol.In this case the aromatic sterol (4) was obtained in 50 yield, to- gether with the known 3P-hydroxy-5a-cholest-8-en-7-one(7a) and a minor amount of compound (5). Analogous treatment of 3~-acetoxy-8a,14a-epoxy-5a-cholestan-7~-01(8a) afforded the same sterol (4), together with 3~-hydroxy-5a-cholest-8(14)-en-7-one (9a),'v5 3P-hydroxy-5a-cholest-8(14)-en-1 5-one (10a),6 and a small amount of compound (5). The formation of the ketones (7a) and (9a) by acidic treat- ment of compounds (6a) and (8a), respectively, parallels the formation of the analogous 8- and 8( 14)-unsaturated ketones (7b) and (9b) by acidic treatment of the epimeric 8a,9a- epoxy-5a-cholestan-7a-ol(6b) and 8a, 14a-epoxy-5a-choles- tan-7a-01 (Sb).' epoxy-alcohols to the action of hydrochloric acid in ethanol.Thus, compound (6c)afforded the unsaturated ketone (7a) whilst the epoxy-alcohol (8c) was transformed into the ketone (9a), together with the rather unexpected isomeric ketone (10a). Products of ring-c aromatization were not observed in either reaction. The different behaviour of the epimeric 7a- and 7phydroxy- epoxides to acidic treatment can be reasonably explained by inspection of Dreiding models of the appropriate com-pounds. It appears that in the case of the 7a-hydroxycom- pound (6c)the 7P-hydrogen is antiparallel to the C(8)-0 bond and hence, in the opening of the epoxide ring by the acid, it can easily undergo a 1,Zshift from the 7 to the 8B-position with the (therefore preferred) formation of a 9ar-hydroxy-7- 17 AcO h (1) (2) a; R = OH b; R = OAc , 58H17 HOT (3) (4) HOw (5) For compounds (1)--(12), CeH1,= CH(Me)CH2I3CHMe2 ketone which in turn affords the unsaturated ketone (7a) by dehydration.The 7u-hydrogen of the 7p-hydroxy-isomer (6a) cannot undergo such a 1,Zshift and so the opening of the 8u,9a- epoxide ring to give an 8(14)-ene system3 prevails over the direct formation of compound (7a), which in this case can originate only by a non-concerted mechanism.Inspection of the Dreiding model of compound (8c) shows that in this case the 7p-hydrogen does not lie in the same plane as the C(8)-0 bond and so the unsaturated ketone (9a) cannot form by a route similar to that assumed for (7a). It appears reasonable that an acidic opening of the epoxide ring of com- pound (8c) to afford the 14-ene-7~,8u-diol (11) (Scheme 2) could explain the formation of compounds (9a) and (10a). The 7-ketone (9a) could originate from the diol(l1) by a 1,2- shift of the 7P-hydrogen, as occurs in the formation of a steroidal 7-ketone from a 7~,8u-diol,~followed by the con- jugation of the double bond. The ketone (lOa) could be formed by an allylic isomerization of compound (11) to the diol (12) which is known to afford the 8(14)-unsaturated ketone (lOa) in the presence of mineral acid.9 The formation of compounds (9a) and (10a) from the 7p- hydroxy-compound (8a) probably involves a more complex mechanism and the dehydrative elimination of the 7p-hydroxy-group occurs with the opening of the epoxide ring to afford the triene (la).The direct production of the unsaturated ketone (10a) by treatment of compound (8c) with hydrochloric acid was un- expected in view of the previous work of Midgley and Djer- assi.’ These authors subjected the crude reaction mixture from 5a-cholest-7-ene with rn-chloroperbenzoic acid to the action of hydrochloric acid and they isolated 9a-hydroxy-5 a-cholestan- 7-one as well as compounds (9b) and (lob).The formation of J. CHEM. SOC. PERKIN TRANS. I 1983 C8H17 RR’ 16) (71 a; R = OAc R’= p-OH a;R =OH b;R=H,R’=a-OH b;R=H C; R=OAc, R’=a-OH i8H17 R-k R’ (8) a; R = OAc R’ = p-OH b; R = H , R’ =a-OH c ;R = OAC, R‘ = a-OH (101 a;R=OH b;R=H compound (lob) was explained as being due to the action of the organic acid preceding the treatment with hydrochloric acid. Our results suggest that the enone (lob) could also be formed by an opening of the epoxide ring of compound (8b) with mineral acid. Experimental All m.p.s are uncorrected. 1.r. spectra were recorded on a Perkin-Elmer 157 spectrophotometer for solutions in chloro- form or for Nujof mulls. U.V. spectra were recorded on a Varian 635spectrophotometer.‘H N.m.r. spectra were recorded on a Varian XL-100 spectrometer in CDCl3 solutions with Me4Si as internal standard. Mass spectra were recorded on a Varian 112 S mass spectrometer (direct inlet). The progress of all reactions, and eluates from column chromatography (silica gel ; 230-400 mesh), were monitored by t.1.c. on E. Merck silica gel HFZs4 plates; spots were visualized by spraying with 70 sulphuric acid followed by heating. Preparation of 3~-Acetoxy-Sa-cholesta-8,14-dien-7~-ol(3), 3~-Acetoxy-8~,9a-epoxy-5a-cholestan-7~-oI(6a), and 3p-Acetoxy-8a,l4a-epoxy-5u-cholestan-7~-ol(8a), by Reduction of the Corresponding 7-Ketones.-A solution of sodium borohydride (0.8 g) in water (0.5 ml) and methanol (10 ml) was slowly added to a swirled solution of the required 7- ketone (1 g) in methanol (40 ml).The mixture was left at room J. CHEM. SOC. PERKIN TRANS. I 1983 (9aI t (8c I (111 1H+ (10aI (12 I Scheme 2. temperature for 2 h with occasional agitation and was then poured into ice-water and extracted with diethyl ether. The extract was washed successively with water, 5 hydrochloric acid, 5 aqueous sodium hydrogen carbonate, and water and was then dried (Na2S04)and evaporated to dryness to yield a crude product which, on chromatography on silica with hexane-ethyl acetate (7: 3,v/v) as eluant, yielded the desired alcohol. Thus prepared were 3P-acetoxy-5u-cholesta-8,14-dien-7p-ol (3) (from 3p-acetoxy-5u-cholesta-8,14-dien-7-one') (yield 700 mg) which resisted all efforts at crystallization; A,,,ax. (EtOH) 248 nm (log E 4.1); 6 5.6 (1 H,m, 15-H), 4.65 (total 2 H,m, 3-and 7-H), and 0.95 (3 H,1.1 (3 H, s, 19-H3), s, 18-H3); m/z 442 (M+)(Found: C,78.7;H,10.55.C29H4603 requires C,78.73;H,10.40).3~-Acetoxy-8~,9u-epoxy-5u-chole.~tan-7~-ol(6a) (from 3p-acetoxy-8u,9u-epoxy-5u-cholestan-7-one3)(yield550 mg), m.p.177-180 "C (from methanol); ctDZo +1.8"; 6 4.70 (1 H,m, 3-H), 4.00 (1 H, m, 7-H), 2.00 (3 H,m, OAc), 1.18 (3 H,s, 19-H3),and 0.73 (3 H,s, 18-H3);m/z 460(M+)(Found: C, 75.6;H,10.5.C29H4804 requires C,75.65;H, 10.48).3p-Acetoxy-8~,14u-epoxy-5u-cholestan-7~-ol(8a) (from 38-acetoxy-8a,14u-epoxy-5u-cholestan-7-one (yield 550 mg), m.p. 129-131 "C(from methanol); biDzo j)+10";6 4.70 (1 H, m, 3-H),3.95 (1 H,m, 7-H), 2.00 (3 H, s, OAc), and 0.95 total 6 H,2 x 5 (overlapping), 18-and 19-H3;m/z460(M+) (Found: C,75.5; H, 10.35.C29H4804 requires C,75.65;H, 10.48).In all reductions minor amounts of the corresponding 7u-epimers were observed on t.1.c. analysis of the crude reaction mixtures. 3~-Acetoxy-8~,9u-epoxy-5~-cholestan-7u-ol(6c) and 3p- Acetoxy-8u,l4u-epoxy-5u-cholestan-7u-ol(8c).-3p-Acetoxy-5u-cholest-7-ene (1.5 g) was added in portions to a stirred solution of m-chloroperbenzoic acid (1.7g,85) in chloroform (35 ml) at 0"C.After 8 d at 4"Cin the dark the mixture was filtered and the filtrate was washed in turn with 5 aqueous sodium hydrogen sulphite and 5 aqueous sodium hydrogen carbonate.The dried organic phase was evaporated to dryness and the residue was chromatographed on silica gel with hexane-ethyl acetate (7 :3, v/v) as eluant to afford (i) 38-acetoxy-8a,14a-epoxy-5-cholestan-7a-ol(8c) (500 mg), m.p. 121-122 "C (from methanol); aID2O +lo; 6 4.75 (1 H, m, 3-H), 3.65 (1 H,m, 7-H),and 0.95 total 6 H, 2 x s (overlapping), 18-and 19-H3;m/z 460 (M+) (Found: C, 75.7; H,10.5. C29H4804 requires C, 75.60;H, 10.48) and (ii) 3~-acetoxy-8~,9a-epoxy-5~-cholestan-7u-ol(6c) (600mg) m.p. 145-147 "C (from methanol); diDzo +34"; 6 4.75 (1 H,m, 3-H), 4.10 (1 H,m, 7-H), 1.05 (3 H, s, 19-H3), and 0.69(3 H, s, 18-H3);m/z 460(M+)(Found: C,75.8; H, 10.55.CZ9H4804 requires C,75.60;H, 10.48). Reaction with Hydrochloric Acid at Reflux-General pro- cedure.A solution of the steroid (300mg) in ethanol (33 ml) and hydrochloric acid (2ml ;36) was refluxed under nitrogen for 1 h.The solution was concentrated under reduced pressure, diluted with water, and extracted with diethyl ether. The com- bined extracts were washed successively with 5 aqueous sodium hydrogen carbonate and water and were then dried and evaporated to dryness under reduced pressure to yield a residue which was chromatographed on silica (40-63 mesh) with hexane-ethyl acetate (4: 1, v/v) as eluant to separate the aromatic fraction from ketonic compounds. The aromatic fraction was then rechromatographed on silica gel G-Celite- AgN03 (1 : 1 :0.3,w/w) with hexane-ethyl acetate (100: 5, v/v) as eluant to separate 12-methyl-1 8-nor-5u, 17P(H)-cholesta-8,11,13-trien-3P-ol(4) and 12-methyl-1 8-nor-5u- cholesta-8,11,13-trien-3~-ol(5) from compounds (3), (6a), and @a).Treatment of 3~-acetoxy-5u-cholesta-8,14-dien-7~-ol(3). Acid treatment of compound (3)gave, after chromatography, the triene (4)(145 mg) as an oil; h,,,,. (cyclohexane) 225 nm (log c 4.07); vmax.3'500and 3 330 cm-'; 6 6.94(1 H,s, 1 I-H),3.67 (1 H,m, 3-H), 3.30 (1 H, m, 17-H),2.26(3 H,s, 18-H3),1.10 (3 H,m, 19-H3),and 0.55 (3 H,d, J 6 Hz, 21-H3);m/z382 (M+)(Found: C,84.7; H,11.1. C27H42O requires C, 84.82;H,11.14) and the triene (5) (16mg), m.p. 97-99 "C (from methanol); Xmx. (cyclohexane) 225 nm; vmx. 3 500 and 3 330 cm-'; 6 6.93 (1 H,s, 11-H),3.67 (1 H,m, 3-H), 3.15 (1 H,m, 17-H), 2.26(3 H,s, 18-H3),and 1.10 (3 H,s, 19-H3);m/z 382 (M +)(Found: C,84.55; H,1 1 .I.C27H420 requiresC,84.82;H, 11.14).Treatment of 3 p-acetoxy-8 u,9or-epoxy-5u-cholestan-7~-01 (6a).Acid treatment of compound (6a) gave after chro- matography, (i) the aromatic compound (4)(1 10mg), identi- cal with that obtained from compound (3), (ii) the aromatic isomer (5) (12 mg), identical with that obtained from com- pound (3), and (iii) 3P-hydroxy-5u-cholest-8-ene-7-one(7a) (50 mg), m.p. 122-123 "C(from methanol); Amx. 253 nm; v,,,,. 3 340, 1 655, and 1 586 cm-'; ideatical with an authentic sample.4 Treatment of 3P-acetoxy-8~,14u-epoxy-5u-cholestan-7~-ol (8a). Similar treatment of compound (8a) gave, after chroma- tography, (i) the aromatic compound (4) (105 mg), identical with that obtained from compound (3); (ii) the aromatic isomer (5) (10mg), identical with that obtained from com- pound (3), (iii) 3~-hydroxy-5u-cholest-8(14)-en-15-one (1 Oa)(13 mg), m.p.145-146 "C(from methanol); (lit.,6 145-146 "C), identical (n.m.r. and mass spectra) with an authentic sample, and (iv) 3~-hydroxy-5u-cholest-8(14)-en-7-one (9a)(30mg), m.p. 129-1 30 "C(from methanol); alDZo-54",identi-cal (n.m.r. and mass spectra) with an authentic sam~le.~-~ Treatment of 3~-acetoxy-8~,9u-epoxy-5~-cholestan-7u-ol(6c).Similarly, compound (6c) gave after chromatography, the ketone (7a) (120mg), m.p. 122-123 "C, identical (n.m.r. and mass spectra) with an authentic ~ample.~ No aromatic steroids were detected by g.1.c.analysis of the crude product. Treatment of 3~-acetoxy-8a,14u-epoxy-5a-cholestan-7~-01 590 J. CHEM. SOC. PERKIN TRANS. I 1983 (8c). In an identical manner, compound (8c) gave, after chromatography, the ketones (loa) (40mg) and (9a) (100 mg),both identical with authentic samples. No aromatic steroids were observed by g.1.c. analysis of the crude product. Isolation of 3~-Acetoxy-5a-cholesta-7,9(11),14-triene* (lb). -A solution of the alcohol (3) in ethanol (30 ml) and hydro- chloric acid (2 ml; 36) was kept at room temperature for 30 min and was then cooled. Under these conditions 3p-acetoxy-5or-cholesta-7,9(11),14-triene (1b) crystallized out as needles, m.p.90-91 "C,identical (n.m.r. and mass spectra) with an authentic sample.' If the solution was kept for a longer time at room temperature the parent alcohol (la) was obtained together with its acetate (lb). AcknowledgementsWe thank the Minister0 della Pubblica Istruzione and the Consiglio Nazionale delle Ricerche for support. * Sa-Cholesta-7,9(11),14-trien-3~-ylacetate. References 1 M.Anastasia, P. Allevi, A. Fiecchi, and A.Scala, Lipids, 1982,17, 226. 2 R.Edmunds, J. M.Midgley, L. G. Tagg, B. J. Wilkins, and W. B. Whalley, J. Chem. SOC.,Perkin Trans. 1, 1978,76. 3 L. F.Fieser, K.Nakanishi, and W. Y.Huang, J. Am. Chem. SOC., 1953,75,4719. 4 M.Tsuda, E.J. Parish, and G. J. Schraepfer,J. Org. Chem., 1979, 44,1282. 5 M. Anastasia, A. Fiecchi, G. Cighetti, and G. Galli, J. Chem. SOC.,Perkin Trans. 1, 1977,700. 6 M.Anastasia, A. Fiecchi, and A. Scala, J. Chem. SOC.,Perkin Ths. 1, 1979, 1823. 7 I. Midgley and C. Djerassi, J. Chem. SOC.,Perkin Trans. 1, 1973,155. 8 L.Canonica, A. Fiecchi, M. Galli Kienle, A. Scala, G. Galli, E. Grossi Paoletti, and R. Paoletti, Steroids, 1968, 11, 267. 9 R. B. Woodward, A. A. Patchett, D. H. R. Barton, D. A. J. Ives, and R.B. Kelly, J. Chem. SOC.,1957, 1131. Received 7th Jury 1982; Paper 2/1147