Aromatization of some 4,5-epoxy-3-hydroxysteroids

摘要

1972 1889Aromatization of Some 4,5-Epoxy-3-hydroxysteroidsBy D. Baldwin and J. R. Hanson,*The School of Molecular Sciences,The Universityof Sussex, Brighton BN1 9QJTreatment of the epimeric 17~-acetoxy-4,5-epoxyandrostan-3~-ols with hydrogen bromide in glacial acetic acidgave 17~-acetoxy-4-rnethyloestra-l,3,5(1O)-triene by a dienol-benzene pathway. Under the same conditions3~-hydroxy-4~,5~-epoxyandrostane-6,17-dione gave 1 -rnethyloestra-l,3,5( lO)-triene-6.17-dione, whilst 3p.178-diacetoxy-4a.5a-epoxyandrostan-l1 -one gave a low yield of 17~-acetoxy-4-methyloestra-1,3,5(10) -trien-1 1 -one,revealing that the influence of the carbonyl groups at C-6 and C-11 on this reaction is similar to that on the dienone-phenol rearrangement.THE formation of aromatic steroids by reactions whichare related to the dienol-benzene rearrangement is moregeneral than has hitherto been realized.lS2 We haverecently shown that treatment of 5a-hydroxy-2a,3a-epoxyandrostanes with hydrogen bromide in glacialacetic acid leads to either 1- or 4-methyloestra-l,3,5(10)-trienes, depending upon the presence or absence of a C-6carbonyl f~nction.~ We now report the aromatizationof some 4,5-epo~y-3-hydroxy-steroids.~1 - and 4-Methyl- 19-norcholesta-l,3,5 (10)-trienes wereamongst the products obtained when the 4,5-epoxy-3-+-tolylsulphonyloxycholestanes were heated with ~ollidine.~Testosterone was converted into a mixture of the4 a, 5 a-epoxy- and 4 p, 5 g-epoxy-s teroids with alkalinehydrogen peroxide.6 The 4a,5a-epoxide was acetylatedand reduced with sodium borohydride to afford 17p-acetoxy-4a,5a-epoxyandrostan-3~-ol (1 ; R1 = H, R2 =H2).The 3@,17@-diacetate (1; R1 = Ac, R2 = H,) wasidentical with material prepared by epoxidation ofJ. R. HansonandT. D. Organ, J . Chem. Soc. (C), 1971, 1313.J. Libman and Y . Mazur, Chem. Comm., 1971, 729.J. R. Hanson, Chem. Comm., 1971, 1119; J. R. Hanson4 Preliminary communication, J . R. Hanson, Chem. Comm.,5 J. M. Coxon, R. P. Garland, M. P. Hartshorn, and G. A.H. B. Henbest and W. R. Jackson, J . Chem. SOC. (C), 1967,and H. J. Shapter, J.C.S. Perkin I, 1972, 1445.1971, 1343.Lane, Tetrahedron, 1970, 26, 1633.2469.3 p,17 p-diacet oxyandrost-Cene .8 Testosterone acetatewas reduced with sodium borohydride and the productwas epoxidized with m-chloroperbenzoic acid to afford17@-acetoxy-4@,5~-epoxyandrostan-3~-ol (2 ; R1 = H,,R2 = a-H, p-OAc).STreatment of 17 p-acetoxy-4a,5a-epoxyandrost an-3 g-01(1; R1 = H, R2 = H2), the corresponding 3p,17p-diacetate (1; R1 = Ac, R2 = H2), and 17P-acetoxy-4@,5p-epoxyandrostan-3p-ol (2 ; R1 = H,, R2 = a-H,(3-OAc) with hydrobromic acid in glacial acetic acidgave (3 ;R = H,) as the major aromatic steroid product, togetherwith smaller amounts of testosterone acetate.17p-Acetoxy-l-methyloestra-l,3,5( 10)-triene was also isolatedfrom the aromatization of compound (2; R1 = H,,R2 = a-H, 8-OAc) in low yield.A number of pathways may be envisaged for thisreaction. One, a modification of the Westphalen re-arrangement, involves a migration of the C-19 groupfirst to C-5 and then to C-4.Another, related to thedienol-benzene rearrangement ,lo involves a spirocyclicH. Wehrli, C. Lehmann, P. Keller, J. J. Bonet, K. Schaffner,and 0. Jeger, Helv. Chim. Acta, 1966, 49, 2218. * S. Julia and C. Moutonnier, Bull. Soc. chim. Frame, 1964,321. * P. Keller, Frl. Eggart, H. Wehrli, K. Schaffner, and 0.Jeger, Helv. Chim. Acta, 1967, 50, 2269.lo For a review, see D. N. Kirk and M. P. Hartshorn, ' SteroidReaction Mechanisms,' Elsevier, London, 1968.17 p-acetoxy-4-meth yloest ra- 1,3,5 ( 10) - trien1890 J.C.S. Perkin Iintermediate in which the 9,lO-bond migrates first to C-5and then to C-4 (cj. ref. 1). 17p-Acetoxy-3a-deuterio-4@,5 p-epoxyandrostan-3p-01 was prepared by reductionof testosterone acetate with sodium borodeuterideUAc R2'0(1 IOAc(210followed by epoxidation.On rearrangement this gave1 -deuterio-4-methyloestra-l,3,5 (10) -trien-17 p- yl acetate.This showed an n.m.r. spectrum identical with that ofthe aromatization product from 17p-acetoxy-3a-deuterio-3p-hydroxyandrosta-lJ4-diene. In particular, multi-plets at z 3.07 (1H) and 3.19 (2H) for the undeuteriatedcompounds were replaced by a singlet a t z 3.19 (2H) forthe deuteriated compound. Had the modified West-phalen pathway been involved , then the hydroxy-epoxide would have given a 3-deuterio-4-methyl aromaticcompound with a different aromatic C-H resonancepattern.Carbonyl groups a t C-6 l1 and C-11 l2 modify thecourse of the dienone-phenol rearrangement.We havestudied their influence on this reaction. 4pJ5p-Epoxy-3p-hydroxyandrostane-6,17-dione (2 ; R1 = R - 0) l3was treated with hydrogen bromide in glacial acetic acid.The aromatic product was l-methyloestra-l,3,5( 10)-triene-6,17-dione (4). The 4-methyl isomer was notdetected by t.1.c. The reaction also furnished androst-4-ene-3,6,17-trione. Thus the pathway to aromatizationhas been profoundly modified by a C-6 carbonyl group.As in the dienone-phenol rearrangement, the C-6carbonyl group destabilizes an adjacent C-5 carboniumion and thereby prevents the formation of a spirocycliccarbonium ion.Partial reduction and acetylation of androst-4-ene-3 , l l ,l7-trione afforded 3~,17p-diacetoxyandrost-4-en-l1-one ,14 which was epoxidized with m-chloroperbenzoicacid to give 3~,17~-diacetoxy-4aJ5a-epoxyandrostan-l 1-one (1 ; R1 = Ac, R2 = 0).This gave a low yield of17~-acetoxy-4-methyloestra-l,3,5(10)-trien-1l-one (3 ;R = 0) on treatment with hydrogen bromide in glacialacetic acid. The alternative l-methyl structure wasexcluded since the n.m.r. spectra of compounds (3;R = H2) and (3; R = 0) showed the Ar-C-CH,11 D. Burn, V. Petrow, and G. Weston, J . Ckem. SOC., 1962, 29.12 D. N. Kirk and V. Petrow, J . Chem. Soc., 1960, 4664.resonances at 7 7.79 and 7.81, unaffected by the intro-duction of a carbonyl group at C-11 . As in the dienone-phenol rearrangement, the C-11 carbonyl group de-stabilizes the formation of the spirocyclic cation butcompletely inhibiting this pathway to aromatization.EXPERIMENTALGeneral experimental details have been describedprevi0us1y.l~17~-Acetoxy-4/3,5~-epoxyandrostan-3~-ol was preparedby reduction of testosterone acetate with sodium boro-hydride followed by epoxidation with m-chloroperbenzoicacid. It crystallized from acetone-light petroleum asneedles, m.p.127-128', alDz0 -17' (c 0.25) (lit.,9 m.p.128-130deg;, a, -22') (Found: C, 72.5; H, 9.4. Calc. forC21H3204: C, 72-4; H, 9.3y0), vmX 3600 and 1720 cm-l,T 9.18 (3H, s), 8.96 (3H, s), 7.96 (3H, s), 6-87 (lH, d, J5 Hz), 5.92 (lH, m), and 5-36 (lH, t, J 8 Hz).17~-Acetoxy-4a,5a-ePoxyandrostan-3~-01 (1 ; R1 = H,R2 = H,) .-17~-Acetoxy-4a,5a-epoxyandrostan-3-one m.p.167-168" (lit.,' 164-165') (400 mg) in methanol (10 ml)was treated with sodium borohydride (250 nig) a t roomtemperature for 2 h.A few drops of acetic acid wereadded and the solution was poured into water. Theproduct was recovered in ether and chromatographed onalumina. Elution with 30 ether-light petroleum gave17~-acetoxy-4a,5a-e~oxyandrostan-3~-oZ (250 mg), whichcrystallized from light petroleum as needles, m.p. 126-127", aIDz0 +6S0 (c 0.25) (Found: C, 72.6; H, 9.15.C21H3204 requires C, 72.4; H, 9~3)~ v,, 3600 and 1725cm-l, 7 9.20 (3H, s), 8.90 (3H, s), 7.90 (3H, s), 7.12 (lH,s), 6.04 (lH, m), and 5.43 (lH, t, J 7 Hz).The diacetate, prepared with acetic anhydride in pyridinecrystallized from light petroleum as needles, m.p. 1 7 A175O, alDz0 +39" (G 0.24) (lit.,8 m.p.174", a, +40deg;) (Found:C, 70.6; H, 8.9. Calc. for C23H3405: C, 70.7; H, 8.8yo),vmX. 1735br cm-l, z 9-20 (3H, s), 8-88 (3H, s), 7.99 (6H, s ) ,7.15 (lH, s), 5.43 (lH, t, J 7 Hz), and 5.08 (lH, t, J 8 Hz).313,17p-Diacetoxyandrost-4-ene gave the same compoundon treatment with m-chloroperbenzoic acid.83p, 17~-Diacetoxyandrost-4-en-11-one crystallized fromacetone-light petroleum as prisms, m.p. 173-174',+29" (e 0-25) (lit.,14 177-178') (Found: C, 71.6; H, 8-2.Calc. for C23H3205: C, 71.1; H, 8.3), vmX. 1735, 1705,and 1680sh cm-l, z 9-25 (3H, s), 8-71 (3H, s), 7.98 (6H, s),5.25 (lH, t, J 8 Hz), 4.84 (lH, m), and 4.75 (lH, m).3p, 17P-Diacetoxy-4aJ 5a-epoxyandrostan- 1 l-one (1 ; R1 =Ac, R2 = 0) .-3/3, 17~-Diacetoxyandrost-4-en-1l-one l4 (520mg) in dry benzene (10 ml) was treated with m-chloro-perbenzoic acid (800 mg) a t room temperature overnight.The solution was diluted with ethyl acetate, washedthoroughly with aqueous ferrous sulphate, dil.hydrochloricacid, aqueous sodium hydrogen carbonate, and water,dried, and evaporated. The product was chromatographedon alumina. Elution with 50 ether-light petroleum gave3p, 17@-diacetoxy-4a, 5a-epoxyandrostan-l l-one (260 mg)which crystallized from acetone-light petroleum as prisms,m.p. 157-158", alDZ0 +56" (c 0.25) (Found: C, 68.8; H,8.2. C,,H,,O, requires C, 68-3; H, 8-0), v,, 1735 and1705 cm-l, T 9-15 (3H, s), 8-68 (3H, s), 8.00 (3H, s ) , 7.95(3H, s), 7.13 (lH, s), 5.22 (lH, m), and 5.10 (lH, t, J 8 Hz).13 D. Baldwin and J.R. Hanson, unpublished work.14 C . E. Morreal, Steroids, 1966, 8, 671.l5 J. R. Hanson and T. D. Organ, J . Chern. SOC. ( C ) , 1970, 5131972Aromatization Reactions.-(a) 17P-Acetoxy-4PJ 5P-epoxy-androstan-3P-01 (660 mg) was dissolved in a mixture of48 hydrobromic acid (1.2 ml) and glacial acetic acid(4.8 ml) and heated under reflux for 15 min. The solutionwas neutralized with sodium hydrogen carbonate and theproduct (450 mg) was recovered in ether and chromato-graphed on alumina. Elution with 5 ether-lightpetroleum gave 1 7P-bromo-4-methyloestra- 1,3,5 ( 10) -triene(40 mg), which did not crystallize. It was identified by itsn.m.r. and mass spectra. Elution with 8 ether-lightpetroleum gave 17P-acetoxy-kmethyloestra- 1,3,5 (10)-triene(120 mg), m.p.185" (1it.,l6 188"), identified by its i.r.spectrum. Elution with 25 ether-light petroleum gavetestosterone acetate (70 mg), m.p. 140-142" (lit.,17 139-141deg;), identified by its i.r. spectrum.(b) Similarly 17~-acetoxy-4aJ5a-epoxyandrostan-3~-ol(1 50 mg) gave 17P-acetoxy-4-methyloestra-1, 3,5 (1 0)-triene(60 mg) and testosterone acetate (35 mg). 3PJ17P-Di-acetoxy-4a,5a-epoxyandrostane (1 20 mg) gave 17P-acetoxy-4-methyloestra-l,3,5(10)-triene (36 mg) and testosteroneacetate (10 mg).(c) 3P-Hydroxy-4PJ5P-epoxyandrostane-6, 17-dione l3 (500nig) was dissolved in a mixture of 48 hydrobromic acid(0.5 ml) and glacial acetic acid (2 ml) and heated underreflux for 15 min. The solution was poured into waterand the product (400 mg) was recovered in chloroform andchromatographed on alumina.Elution with 40 ether-light petroleum gave 1-methyloestra-1,3,5( lO)-triene-6,17-dione (50 mg), which crystallized from light petroleum asneedles, m.p. 159-161deg;, aID2O +128" (c 0.2) {lit.,3 m.p.156-158", aID2O +132" (G O - S ) ) , identified by its i.r. andn.m.r. spectra. Elution with ether gave androst-4-ene-3,6,17-trione (1 10 mg), which crystallized from ethylacetate-light petroleum as needles, m.p. 221-223", aID2O + 28" (c 0.2) {1it.,l8 m.p. 216-217", aID2O $42" (in Me2CO)(Found: C, 75.95; H, 7-7. Calc. for C,,H,,03: C, 76.0;H, 8.05), vmx, 1740, 1690, 1670, and 1605 cm-l, 7 9.07(3H, s), 8.80 (3H, s), and 3.82 (lH, s). This was identifiedby comparison with an authentic sample prepared v i a3P-hydroxy-5~, Ga-epoxyandrostan- 17-one and 5a-hydroxy-androstane-3,6, 17-trione.ls(d) 3P, 17~-Diacetoxy-4aJ5a-epoxyandrostan-l 1-one (200mg) was dissolved in a mixture of 48 hydrobromic acid(1 i d ) and glacial acetic acid (4 ml) and heated underl6 J.Schmitt, J. J. Panouse, P. J. Cornu, A. Hallott, H.Pluchet, and P. Comoy, Bull. SOC. china. Fvance, 1965, 1934.reflux for 30 min. The solution was poured into aqueoussodium hydrogen carbonate and the product was recoveredin ethyl acetate and chromatographed on alumina. Elutionwith 10 ether-light petroleum gave 17p-acetoxy-4-methyZ-oestra-lJ3,5(10)-trien-ll-ofie (3; R = 0) (20 mg), whichcrystallized from light petroleum as prisms, m.p. 183--184O,aID2O +114" (c 0.04) (Found: C, 77.5; H, 7-9.C,1H2603requires C, 77.3; H, 8.0), vmX. 1730, 1705, and 1600 cm-1,7 8.93 (3H, s), 7.96 (3H, s), 7-79 (3H, s), 5-30 (2H, m), and2-80 (3H, m).Deuteriation Experiments.-(a) 1 7P-Acetoxy-4P, 5P-epoxy-androstan-3-one (250 mg) in methan2H01 (2 ml) wastreated with sodium borodeuteride (100 mg) for 1 h. Thesolution was acidified with a few drops of acetic 2Hacidand diluted with deuterium oxide, and the product wasrecovered in ether to give 17P-a~etoxy-4P,SP-epoxy3a-~H-androstan-3P-o1(150 mg). The deuteriated steroid (125 mg)was dissolved in a mixture of 48 hydrobromic acid (1 nil)and glacial acetic acid (4 ml) and heated under reflux for15 min. The product was neutralized with aqueous sodiumhydrogen carbonate and recovered in ether. Chromato-graphy on alumina afforded 17P-a~etoxy-4-methyll-~H-oestra-l,3,5(10)-triene, m.p. 185-187", vmx. 1725 and850 cm-l (undeuteriated material 1725, 790, and 745 cm-I),T (CC1,) 9-17 (3H, s), 8.00 (3H, s), 7.81 (3H, s), 5.41 (lH, t,J 8 Hz), and 3.19 (2H, s) undeuteriated material 3.19 (2H,m) and 3-07 (lH, m).(b) 17P-Acetoxyandrosta-1,4-dien-3-one (250 mg) inmethan2H01 (2 ml) was treated with sodium borodeuteride(100 mg) for 1 h. The solution was treated with acetic2Hacid and poured into deuterium oxide and the steroidwas recovered in ether. The crude product was heatedunder reflux in a mixture of 48 hydrobromic acid (1 ml)and glacial acetic acid (4 ml) for 15 min. The solution wasneutralized with aqueous sodium hydrogen carbonate andthe steroid was recovered in ether and chromatographed onalumina. Elution with 10 ether-light petroleum gave17~-acetoxy-4-methyl1-2Hoestra-1,3,5(1O)-triene (35 mg) ,m.p. 186-187", i.r. and n.m.r. identical with those of thesample prepared in (a).We thank Schering Chemicals Ltd. for financial assistance.2/406 Received, 22nd February, 19721l7 L. Ruzicka and A. Wettstein, Helv. China. Ada, 1935, 18,l8 A. Butenandt and B. Riegel, B e y . , 1936, 69, 1163.1264