J. CHEM. SOC. PERKIN TRANS. 1 1995 Simple synthetic approach to 6-oxa steroids. Synthesis of 6-oxa-5P-pregnane-3,20mdione Daniel Nicoletti, Albert0 A. Ghini, Adriana L. Brachet-Cota and Gerard0 Burton * Departamento de Quimica Organica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellh 2, Ciudad Universitaria, (1428)Buenos Aires, Argentina A two-step synthesis of 19-functionalized 6-oxapregnanes from a 5a,6P-dihydroxypregnane is described. Deoxygenation at C-19 afforded a 6-oxapregnane, which was converted into 6-oxa-5 P-pregnane-3,20-dione 7.An insight into the mechanism of formation of the key intermediate, a 5,6-secosteroid, via a hypoiodite type reaction is also given. The synthesis of heterocyclic steroids, is of special interest in view of their physiological properties and the claim that certain heterosteroids possess anabolic, antihormonal, anti- hypercholesterolaemic, vasodilatatory, anticancer, neuro-muscular-blocking, central nervous system depressant and antimicrobial activities.Several patents also describe the pharmacological utility of these compounds. In spite of their significant biological activity, there are few reported syntheses of oxa steroids. Suginome et ul. have reported the partial and total synthesis of various mono- and dioxa ~teroids.~ The key step in these partial syntheses was a p-scission of the alkoxyl radicals generated from steroidal alcohols or lactols derived from cyclic ketones, uiu irradiation of their hypoiodites, to give the corresponding secosteroidal iodoformates.The latter were then converted into the hetero- steroids. In particular, few methods are available for the preparation of 6-oxa steroids besides those mentioned above. A major route is based on the Torgov's carbocyclic total steroid synthesis for the preparation of 6-aza-, oxa- and thia-estrane~.~.~ Two other methods have been described starting from steroidal precursors with moderate overall The photochemical reaction of 3p-acetoxy-Sa,6p-dihydr-oxypregnan-20-one la with mercury(r1) oxide and iodine has la R=O 2a R=O lb R=H,OAc 2b R =H, OAC been described by us to afford in high yield the secosteroid 2a.' This compound has structural features that indicate it would be a suitable precursor for 19-functionalized 6-oxa steroids.Results and discussion Scheme 1 outlines the synthesis of the title compound 7 from diol lb. This diol can be easily prepared from pregnenolone acetate in ca. 70 yield. Treatment of diol lb with mercury(I1) oxide-iodine (HgO-I,) in carbon tetrachloride under photo- lytic conditions (3 h, 300 W tungsten lamp) as previously described by us,* afforded the key intermediate, secosteroid 2b. Reaction of the latter compound with sodium borohydride in ethanol gave in a single step the 5PH-6-oxa steroid 3, as the sole cyclization product in 50 yield from lb (see below). vOAc ACO-0' H I iv+ vo bsol;/OR 7 5 R=Ac vL 6 R=H Scheme 1 Reagents und conditions: i, HgO, I,, CCI,, ho; ii, NaBH,, EtOH; iii, DBU, CS,, CH,I, DMF; iv, Bu,SnH, xylene, reflux; v, LAH, diethyl ether; vi, PCC, BaCO,, molecular sieves (3 A), CH,Cl, Deoxygenation of the primary (neopentylic) hydroxy group attached at C-10 in compound 3, was attempted by different methods, ranging from the direct or indirect (via iodine) reductive removal of a tosyloxy or mesyloxy group' to the widely used radical deoxygenation procedures.".' In spite of the more complicated work-up procedure, the best yield was attained with the thermally initiated Barton reduction of the dithiocarbonate intermediate 4 with tributyltin hydride which is particularly suitable in the case of sterically hindered primary alcohols.Further deacetylation with lithium aluminium hydride and oxidation with pyridinium chlorochromate yielded 6-oxa-SP-pregnane-3,20-dione7in 18 yield from lb.After the usual work-up, 7 was purified by flash chromatography and its identity confirmed by 'H and I3C NMR spectroscopy. Formation of secosteroid 2b In a previous publication,' we proposed a mechanism for the cleavage reaction of steroidal 5a,6P-diols leading to 5,6-secosteroids like 2a and 2b. We now present experimental evidence for this mechanism. TLC analysis of the reaction mixture of diol lb with HgO-I, at different times, revealed the presence of two compounds that were formed transiently. When the reaction was carried out with bis(acetoxy)iodobenzene- 1090 iodine l3 in carbon tetrachloride or dichloromethane the major product was coincident by TLC with one of the transient species detected in the HgO-I, reaction.This product was identified by 'H and 13C NMR and mass spectroscopy as 3P,20P-bis(acetoxy)-5a-hydroxy-6P,19-epoxypregnane 8. The diagnostic signals in the 'H NMR spectrum were those assigned to the 19-H, (6 3.78 and 3.86, both doublets, J,,, 8.7 Hz) and 6-Ha (6 3.71, d, J 3.1 Hz). The 13C NMR and mass spectra also agreed with the proposed structure. When compound 8 was allowed to react under the photolytic conditions used before (HgO-I,, CCl,, hv) the secosteroid 2b was isolated after a shorter reaction time (2 h); this provided conclusive evidence that compound 8 was a true reaction intermediate. On the other hand, when the reaction of 8 with HgO-I, was stopped after only 1 h, another product was detected by TLC (coincident with the second transient species observed previously).After work-up and flash chromatogra- phy, we isolated this intermediate species which was identified by 'H and I3C NMR and mass spectroscopy as the seco-lactol9. Formation of 8 and 9 from lb can be explained by the sequence depicted in Scheme 2, where the initially formed vOAc 1 hv .34 -- AcO I OH 6. 8 + . . J. CHEM. SOC. PERKIN TRANS. 1 1995 Table 1 Calculated and observed vicinal coupling constants for relevant hydrogens in ring A of 5-HB-oxa steroid 3 Dihedral angle H,H (deg) 3JH-H(obs.)/Hz 3JH-,(calc.)/Hz 3a,4a 47.39 3.2 3.5 3a,4P -67.39 ca. 2.5 2.9 4a,5P -162.68 12.5 10.1 4p,5p -48.21 5.2 5.9 From PM3 calculations.decoupled and DEPT). The 'H NMR spectra presented a singlet for one angular methyl at 6 0.70 (13-H3C) and a doublet for the 20-H3C at 6 1.25 as well as singlets for the two acetoxy groups. The protons on C-19 appeared as an AB quartet at 6 3.51 and 4.02 (J,,, 11 Hz). The 5-H6 resonance was observed at 6 4.15 as a double doublet and the 3-Ha appeared as an unresolved multiplet at 6 5.19. The 13C NMR spectrum of 3 gave conclusive evidence on the structure of this compound. Only 20 resonances were observed (besides those of the acetyloxy groups). Five carbon resonances (two methylene and three methines) assigned to C-3, -5, -7, -1 9 and -20 were observed in the range 6 64.2 to 72.7, typical of oxygen bonded carbons.Two methyl carbon resonances appeared at 6 12.8 (C-18) and 19.9 (C-21). The assignment of the absolute configuration at C-5 in compound 3 was deduced from its 'H NMR spectrum, based on the coupling constants between 5-H and the hydrogens at position 4 and, of the latter hydrogens with 3-Ha (position 3 had a fixed configuration throughout the synthetic transform- ations). The primary evidence of an A/B cis fusion, was given by the resonance of 3-H, which appeared as a broad signal (W1,, 9.1 Hz) typical of an equatorial hydrogen. The axial hydrogen at position 4, identified by its large coupling constant with 5-H (also axial), was clearly visible at 6 2.30 as a double double doublet; the other couplings observed for the axial 4-H were the geminal coupling (13.8 Hz) and a 3.2 Hz coupling with 3-H which corresponded to an axial-equatorial J.This arrange- ment, only possible in an A/B cis steroid, had J values which agreed with those calculated using the Altona equation l5 forbsol; voActhe steroid in which the configuration was 5-HB (Table 1). AcOJif? bH1I2 9 2b Scheme 2 5a-hydroxy-6,19-epoxy steroid 8 reacts further by formation of the 5-oxyl radical and cleavage of the 5,6 bond. The carbon radical formed can be oxidized further by the HgO-I, system,14 yielding an oxyl-radical which upon work-up gives seco-lactol 9. The course of the reaction continues with the cleavage of the 6,7 bond and the formation of a methylene radical which is finally trapped by iodine affording secosteroid 2b.Stereochemistry of the reductive cyclization of secosteroid 2b The structure of the oxa steroid 3 and its stereochemistry at position 5 were confirmed by 'H and NMR (proton Final confirmation of the stereochemistry at C-5 was carried out on compound 5 based on the NOESY spectrum, as all the oxapregnanes synthesized had identical configuration at this position. This experiment gave us clear evidence of the cis-fusion of rings A and B, showing strong NOESbetween 5-H and the hydrogens of the 10-methyl group and between 4-Ha and 7-Ha (Fig. 1). The closure of secosteroid 2b to the usually less stable cis-juncture of the A/B rings in oxa steroid 3, prompted us to analyse by molecular modelling using the PM3 semiempirical method, the two possible ring A conformations of the inter- mediate 19-hydroxy secosteroid for each of the rotamers around the C(9tC(l0) bond (Table 2).$ Fig.2 shows the two most stable conformers found, which have ring A in a conformation analogous to that found in SP-steroids (i.e. 'CJ in agreement with the NMR data for 2b (i.e. 3-H resonance observed as a broad signal with W1,, 9 Hz). These conformers, have the rest of the steroid moiety (rings C, D and side chain) bound to C-10 in an axial orientation blocking attack of the hydride from the a face on C-5, thus reduction yields stereoselectively the 5a-alcohol (probably with participation of the 19-hydroxy group) which cyclizes to the oxa steroid 3 with the 5-HD configuration.t Diol lb dissolves only with difficulty in CCl, (especially if it has been recrystallized); the use of CH,Cl, allowed us to work in more $ Conversion of the 19-formate to the 19-hydroxy secosteroid takes concentrated solutions and did not alter the course of the reaction. place in the first stages of the reaction with sodium borohydride. J. CHEM.SOC. PERKIN TRANS. 1 1995 Table 2 Relative energies of the possible conformations of the 19-hydroxy analogue of secosteroid 2b, from PM3 calculations (AMPAC4.5) C( 19)-C( lOamp;C(9tH(9) Relative energy Ring A conformation (deg) (kcal mol-')" 177.33 0.00lc4'c4 34.30 0.84 -39.31 2.81 145.50 10.70 55.36 1.65 -82.49 4.41 1 ~al= 4.184 J 0 NOE Fig.1 Observed NOESon 6-oxa-5P-pregnane 5 Conclusions In conclusion, a simple method for the conversion of a 5a,6P- steroidal diol into 19-functionalized 6-oxa steroids with a cis A/B fusion, is described based on the stereospecific reductive cyclization of iodo secosteroid 2b. Deoxygenation at position 19 using the Barton procedure affords 10-Me oxa steroids. The synthesis of the 6-oxa analogue of 5P-pregnane-3,20-dione has been achieved by this procedure. Experimental Mps were taken on a Fisher-Johns apparatus and are uncor- rected. IR spectra were recorded in KBr pellets or thin films using KBr disks on a Nicolet Magna IR 550 FT-IR spectro- meter. 'H and I3C NMR spectra were measured at 200.13 and 50.32 MHz in a Bruker AC-200 NMR spectrometer in deuteriochloroform (using tetramethylsilane as internal stand- ard).J Values are given in Hz. Electron impact mass spectra (EI) were measured in a VG Trio 2 mass spectrometer at 70 eV by direct inlet. FAB mass spectra and electron impact high resolution mass spectra (HRMS) were obtained in a VG ZAB BEQQ mass spectrometer. Semiempirical calculations were performed with AMPAC 4.5 (Semichem, USA). All solvents used were reagent grade. Solvents were evaporated at ca. 45 "C under reduced pressure. 3P,20P-Diacetoxy-5a,6P-dihydroxypregnanelb was pre-pared from pregnenolone (3 P-hydroxypregn-5-en-20-one)ace-tate in 70 yield, as a single product, by reduction with sodium cyanoborohydride in methanol to the 20-alcohol followed by acetylation, epoxidation with rn-chloroperbenzoic acid and acid hydrolysis of the epoxide mixture with tetrahydrofuran and aqueous sulfuric acid.* 3p,20p-Bis(acetoxy)-19-forrnyloxy-7-iodo-6nor-5,7-seco-pregnan-5-one 2b To a solution of diol lb (0.400 g, 0.92 mmol) in freshly distilled carbon tetrachloride (66 cm3) were added mercury(I1) oxide (2.06 g, 9.51 mmol) and iodine (3.16 g, 12.5 mmol). The solution was then irradiated with a 300 W tungsten lamp (5000 lm) for 3.5 h while being vigorously stirred at room temperature. After filtration the solution was diluted with dichloromethane, 1091 I Fig. 2 Most stable conformers of the 19-hydroxy analogue of secosteroid 2b as predicted by PM3 calculations (see Table 2) washed with aqueous sodium thiosulfate and water, dried and then evaporated to dryness, yielding crude secosteroid 2b (0.5 17 g, 98).This product could not be crystallized,sect; an analytical sample was purified by preparative TLC (hexane-ethyl acetate 7: 3); v,,,(KBr)/cm-' 1728 (C4, esters), 1704 (C=O, ketone), 1438 (CH2-I), 1247 (C-0, acetate), 1163 (C-0, formate), 1028 and 1021; dH0.70 (3 H, s, 13-H3C), 1.15 (3 H, d,J 6, 20-H3C), 2.02 (3 H, s, acetate), 2.03 (3 H, s, acetate), 2.58 (1 H, br d, Jgem 15.0, 4-Ha), 3.13 (1 H, dd, J7a,8 2.7, Jgem10.9, 7-Ha), 3.39 (1 H, dd, J,,,, 1.9, Jgem10.9, 7-Hb), 3.63 (1 H, dd, J,,*3 4.3, J,,, 15.0, 4-HB), 4.31 (1 H, d, Jgem11.8, 19-Ha), 4.52(1 H, d, J,,, 11.8, 19- Hb),4.83(1H,m,20-H),5.41(1H,brs,3-H)and8.l1(1H,s, formate);amp; 13.2 (C-lE), 17.2 (C-7), 19.7 (C-21), 21.2 (acetate), 21.4 (acetate), 23.2 (C-I1 TI), 23.4 (C-151), 24.8 (C-167), 25.0 (C-1 TI), 28.8 (C-2), 37.6 (C-9), 38.9 (C-12), 40.0 (C-8), 41.6 (C- 13), 41.2 (C-4), 53.7 (C-lo), 54.7 (C-14), 54.8 (C-17), 64.7 (C-19), 72.5 (C-3), 72.5 (C-20), 160.7 (formate), 170.1 (acetate), 170.2 (acetate) and 212.2 (C-5); m/z (FAB, 3-nitrobenzyl alcohol) 577 (M + 1, 36), 517 (M + 1 -AcOH, 92), 457 (M + 1 -2AcOH, 54), 389 (M + 1 -HI, 52), 373 (55) and 303 (100) (Found M -HOAc, 516.1359.C23H33051 requires M, 516.1372; Found: M -HOAc -HI, 388.2248. Camp;32O, requires M, 388.2249). 3p,20p-Bis(acetoxy)-19-hydroxy-amp;ox a-5 p-pregnane 3 To a solution of the crude secosteroid 2b (0.5 g) in absolute ethanol (67 cm3) cooled to OOC, was added sodium borohy- dride (0.123 g, 3.21 mmol).The solution was stirred at 0 "C for 2 h and then at room temperature for another 2 h, acidified (pH 5-6) with hydrochloric acid (1 mol dm-3), and then neutralized with 10 aqueous sodium hydrogen carbonate. The solution was concentrated under reduced pressure to a volume of 25 cm3, diluted with water and extracted with diethyl ether. The extract was washed with water, dried and then evaporated to dryness. Chromatography on silica gel with ethyl acetate- hexane as eluent yielded 19-hydroxy oxasteroid 3 (0.190g, 52) 0 Attempts to recrystallize this compound were unsuccessful due to its instability.7 Assignments may be interchanged. homogeneous by TLC; v,,,(KBr)/cm-' 3443 (OH), 1734 (C=O), 1244 (C-0), 1151, 1070, 1047 and 1028; SH0.70 (3 H, s, 13-H3C), 1.15 (3 H, d, J6.0, 20-H3C); 2.01 (3 H, s, acetate), 2.05 (3 H, s, acetate), 2.30 (1 H, ddd, J4a,3 12.5, J,,,3.2, J4a,5 13.8, 4-Ha), 3.34(1 H, t, Jgem-J7aq8 11.5, 7-Ha), 3.51 (1 H, d, J.CHEM. SOC. PERKIN TRANS. 1 1995 successively with ethyl acetate and 10 aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with aqueous sodium hydrogen carbonate and water, dried and then evaporated to dryness, yielding diol6 (0.075 g, 95); SH0.77 (3 H, s, l3-H3C), Jq,,I1.O, 19-Ha),3.57(1H,dd,J7~,~5.2,Jg,,11.5,7-Ha),4.02(l H, d, Jgem11.0, 19-Hb), 4.15 (1 H, dd, J5,4' 5.2, J5,4a 12.5, 5-H'); 4.83 (1 H, m, 20-H) and 5.19 (1 H, br s, 3-H); 6, 12.8 (C-18), 19.9(C-21), 20.2 (C-1 l), 21.3 (acetate), 21.5 (acetate), 22.9 (C-1), 23.3 (C-l5), 24.1 (C-16), 25.7 (C-2), 27.8 (C-4), 34.7 (C-8), 38.4 (C-9), 39.1 (C-lo), 39.5 (C-12), 42.8 (C-13), 52.3 (C-14), 54.5 (C-l7), 64.2 (C-l9), 66.7 (C-7), 70.5 (C-5), 71.4 (C-3), 72.7 (C-20), 170.4 (acetate) and 170.5 (acetate); m/z (FAB, 1-sulfanylglycerol) 423 (M + 1,15), 363 (M + 1 -AcOH, 49), 36 1 (40), 345 (20), 33 1 (22), 303 (19), 285 (1 8), 27 1 (15), 267 (1 5) and 91 (100).Acetylation with Ac,O-pyridine gave the 19- acetate, mp 162-163 "C (from acetone-hexane) (Found: C, 67.2; H, 8.7. C26H4007 requires C, 67.2; H, 8.7). 3p,ZOp-Bis(acetoxy)-6-oxa-5 p-pregnane 5 6-Oxapregnane 3 (0.3 g, 0.71 mmol) and 1,8-diazabicyclo- C5.4.01undec-7-ene (0.434 g, 2.84 mmol) were dissolved in dry N,N-dimethylformamide (3.6 cm3). Carbon disulfide (4.0 cm3) was added and the reaction mixture was stirred for 45 min at room temperature.After addition of methyl iodide (7.8 cm3) stirring was continued for a further 45 min at room temperature and the reaction mixture was then evaporated. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried and then evaporated to dryness. Chromatography on silica gel with ethyl acetate-hexane as eluent yielded 3p, 20 P-bis(acetoxy)- 19-(methylsulfanylthiocarbonyloxy)-6-oxa-5p-pregnane 4 (0.256 g, 70); SH0.67 (3 H, s, 13-H3C), 1.15 (3 H, d, J6.0, 20-H3C), 2.00 (3 H, s, acetate), 2.04 (3 H, s, acetate), 2.35 (I H, ddd, J4a.3 3.0, J4a,5 12.1, J,,, 14.7, 4-Ha), 2.58 (3 H, S, SCH,), 3.33 (1 H, t, Jgem-J7a,8 11.4, 7-Ha), 3.60(1 H,dd,J,P,8 4.9, J,,, 11.4, 7-HD),4.14(1 H,dd, J5,4D4.8, J5,4a 12.1, 5-HP), 4.78 (1 H, d, J,,, 10.9, 19-Ha), 4.86 (1 H, d, J,,, 19-Hb), 4.83 (1 H, m, 20-H) and 5.21 (1 H, br s, 3-H).Tributyltin hydride (1.082 g, 3.35 mmol) in xylene (1 6 cm3) was added during 2 h to the dithiocarbonate 4 (0.240 g, 0.47 mmol) in xylene (16 cm3) at 150 "C under nitrogen. After heating for a further 14 h, the solvent was evaporated and the residue was partitioned between hexane (100 cm3) and aceto- nitrile (100 cm3). The acetonitrile layer was separated and washed with hexane (3 x 50 cm3) and evaporated to dryness. Chromatography on silica gel with ethyl acetate-hexane as eluent yielded oxapregnane 5 (0.121 g, 63.5); mp 114115 "C (from ethanol-water) (Found: C, 70.6; H, 9.4.C24H3805 requires C, 70.9; H, 9.4); v,,,(KBr)/cm-' 1734 (C=O), 1254 and 1238 (C-0), 1191,1162,1089,1078 and 1034; BH 0.65 (3 H, s, 13-H3C), l.l'1(3H,s, lo-H,C), 1.15(3H,d,J6,20-H3C),2.01 (3 H, s, acetate), 2.04 (3 H, s, acetate), 2.32 (I H, ddd, J4a.33.1, J4a,5 12.4,J,,, 13.5, 4-Ha), 3.30 (1 H, t, Jgem-JTa,8 11.2,7-H"), 3.56(1H,dd,J7p,~5.0,Jg,,11.2,7-HB),3.69(1H,dd,J5,4B4.9, 1.1 1 (3 H, s, 10-H3C); 1.14 (3 H, d, J 6, 20-H3C), 2.32 (1 H, ddd, J4a,3 3.1, J4a,5 12.2, Jgem 13.4, 4-Ha), 3.31 (1 H, t, J,,, -J7a,8 11.4, 7-Ha), 3.56(1 H,dd, J7P,8 5.l,Jgem 11.4, 7-HP), 3.72(1 H, m,20-H)3.79(1 H,dd, J5,4B4.8, 12.2, 5-HB)and4.26(1 H, J5,4a br s, 3-H).Pyridinium chlorochromate (0.38 g, 1.76 mmol), barium carbonate (0.22 g, 1.13 mmol) and 3 8, molecular sieves (0.15 g) in dry dichloromethane (2.0 cm3) were vigorously stirred at room temperature for 20 min and then the diol6 (0.068 g, 0.21 mmol) in dry dichloromethane (3.0 cm3) was added. After a further 4 h, the reaction mixture was diluted with diethyl ether, percolated through Florisil, eluting with diethyl ether and dichloromethane and then evaporated to dryness. Chromato- graphy on silica gel with ethyl acetate-hexane as the eluent yielded diketone 7 (0.054 g, 80); mp 153-154 "C (from diisopropyl ether) (Found: C, 75.2; H, 9.8.C20H3003 requires C, 75.4; H, 9.5); v,,,(KBr)/cm-' 1716 and 1709 (GO) and 1077 (C-0-C); 6, 0.67 (3 H, S, 13-H,C), 1.16 (3 H, S, 10-H,C); 2.13 (3 H, s, 20-H3C), 2.41 (1 H, ddd, 4J4e,2s 1.9, J4B,5 5.6, Jgem14.7, 4-HP), 3.05 (1 H, dd, Jaa,5 11.4, J,,, 14.7, 4-Ha), 3.35 (1 H, t, J,,, -J7a,8 11.5, 7-Ha), 3.67 (1 H, dd, J7P,8 5.1, J,,, 11.5,7-HP)and3.71 (1 H,dd, J5,4D5.6, J5,4a11.4,5-HB);6, 13.5 (C-l8), 20.4 (C-11), 21.8 (C-19), 23.3 (C-l5), 23.6 (C-16), 31.5 (C-21), 31.9 (C-l), 34.6 (C-8), 35.2 (C-lo), 36.4 (C-2), 38.8 (C-12), 39.5 (C-9), 40.7 (C-4), 44.4 (C-13), 52.6 (C-14), 63.1 (C-17), 64.8 (C-7), 79.7 (C-5), 208.9 (C-20) and 209.8 (C-3); m/z (EI) 318 (M+,34),300(M -H20,76), 261 (13), 248 (lo), 233 (12), 215 (8), 55 (49) and 43 (100).3~,20~-Bis(acetoxy)-5a-hydroxy-6p,l9-epoxypregnane8 A solution of diol lb (0.100 g, 0.23 mmol) in freshly distilled carbon tetrachloride (21 cm3) containing bis(acetoxy)iodo- benzene (0.084 g, 0.25 mmol) and iodine (0.063 g, 0.25 mmol) was irradiated with a 300 W tungsten lamp for 85 min at room temperature. The reaction mixture was then poured into water and extracted with diethyl ether. The organic layer was washed successively with sodium thiosulfate and water, dried and then evaporated to dryness. Chromatography on silica gel with ethyl acetate-hexane as eluent yielded hydroxy ether 8 (0.070 g, 70); mp 201-203 "C (from acetone) (Found: C, 69.2; H, 9.07. C25H3806 requires C, 69.09; H, 8.81); v,,,(KBr)/cm-' 3423 (OH), 1728 (GO), 1240 (C-0, acetate), 1078,1039 and 1023;SH 0.67 (3 H, s, 13-H3C), 1.14 (3 H, d, J 6, 20-H3C), 2.01 (3 H, s, acetate), 2.04 (3 H, s, acetate), 3.71 (1 H, d, J6a,73.1, 6-Hu), 3.78 (1 H,d, Jg,,8.7, 19-Ha),3.86(1 H,d, Jqem8.7, 19-Hb),4.87(1 H, m, 20-H)and4.99(1 H,m, 3-H);SC12.8(C-18), 19.8(C-21), 21.3 (acetate), 21.4 (acetate), 22.1 (C-1 l), 23.5 (C-16 y), 23.6(C-15 I), 25.4 (C-7), 27.1 (C-2), 31.0 (C-1), 33.0 (C-8), 38.6 (C-127), 39.2 (C-47), 42.9 (C-l3), 44.1 (C-10) 44.4 (C-9), 54.0 (C-14), 54.9 (C-l7), 68.8 (C-19), 69.8 (C-3), 72.8 (C-20), 76.9 (C-5), 81.3 J5,,a12.4,5-HP),4.83(lH,m,20-H)and5.20(lH,brs,3-H);6,(C-6), 170.1 (acetate) and 170.4 (acetate); m/z (FAB 1-12.7 (C-18), 20.0 (C-19), 20.5 (C-11), 21.4 (acetate), 21.5 (acetate), 22.8 (C-21), 23.4 (C-15), 24.5 (C-16), 25.8 (C-2), 29.3 (C-1), 28.0 (C-4), 34.7 (C-8), 35.5 (C-lo), 38.8 (C-9), 39.3 (C-12), 42.8 (C-13), 51.7 (C-14), 54.7 (C-17), 64.8 (C-7), 71.1 (C-3), 72.8 (C-20), 76.5 (C-5), 170.4 (acetate) and 170.5 (acetate); mjz (EI) 346 (M' -AcOH, loo), 331 (17), 271 (8.6), 111 (30) and 43 (68).6-Oxa-Sp-pregnane-3,20-dione 7 The diacetate 5 (0.1 g, 0.25 mmol) in dry diethyl ether (9.5 cm3) was stirred with lithium aluminium hydride (0.1 g, 2.6 mmol) for 6 h under nitrogen. The reaction mixture was treated sulfanylglycerol) 433 (M -1, 9.573, 375 (27), 373 (M -1 -AcOH, 35), 3 16 (19), 3 15 (83), 3 13 (22), 297 (43), 267 (19.5) and 121 (100). 3p,20p-Bis(acetoxy)-6a-hydroxy-6p,19-epoxy-5,6-seco-pregnan-5-one 9 To a solution of hydroxy ether 8 (0.174 g, 0.41 mmol) in freshly distilled carbon tetrachloride (28 cm3) were added HgO (0.890 g, 4.I 1 mmol) and I, (1.33 g, 5.26 mmol). The solution was then irradiated with a 300 W tungsten lamp for 1 h while being vigorously stirred at room temperature. After filtration, the solution was diluted with dichloromethane, washed with J. CHEM. soc. PERKIN TRANS. I 1995 aqueous sodium thiosulfate and water, dried and then evap- orated to dryness. Chromatography on silica gel with ethyl acetate-hexane as eluent yielded lactol 9 (0.021 g, 1l), an analytical sample was purified by preparative TLC (hexane- ethyl acetate 1 :1) (Found: M -AcOH -H20, 372.2297. C23H3204 requires M, 372.2301; Found: M -AcOH -HCOH, 360.2295.C22H320, requires M 360.2301); vmax-(film)/cm-' 3435 (OH), 1728 (Ck-0, acetate), 1668 (C=O, ketone), 1246 (C-0, acetate) and 1026 (C-0-C); amp;,0.62 (3 H, S, 13-H3C), 1.14 (3 H, d, J 6, 20-H3C), 1.99 (3 H, S, acetate), 2.04 (3 H, s, acetate), 2.43 (1 H, dd, J4a,38.7, Jgem 16.8, 4-Ha), 2.69 (1 H, dd, J4b.3 5.6, J,,, 16.8, 4-Hb), 3.59 (I H, d, Jgem13.0, 19-Ha), 3.83 (1 H, d, Jgem13.0, 19-Hb), 4.83 (lH,m,20-H),5.05(1 H,m,3-H)and5.14(1H,dd,J6,,,5.1, J6.7b 9.2, 6-H); 6, 12.1 (C-18), 19.7 (C-21), 20.9 (C-ll), 21.1 (acetate), 21.4 (acetate), 24.1 (C-l5), 24.7 (C-16), 25.5 (C-1 TI), 25.8 (C-27), 32.7 (C-8), 38.4 (C-12), 39.1 (C-7), 41.6 (C-13), 45.0 (C-4) 50.4 (C-9), 54.3 (C-14), 54.9 (C-17), 56.4 (C-lo), 62.5 (C-19), 69.8 (C-3), 72.5 (C-20), 95.6 (C-6), 170.1 (acetate), 170.4 (acetate) and 21 1.O (C-5); m/z (EI) 372 (M' -AcOH -HZO, 8.6), 360 (M -AcOH -HCOH, 25), 342 (9,161 (21), 126 (26), 125 (29), 109 (40) and 43 (100).Acknowledgements We thank the Universidad de Buenos Aires and CONICET (Argentina) for financial support of this work. A. A. G. is grateful to CONICET for a fellowship. References 1 S. R. Ramadas and J. Radhakrishnan, J. Sci. Ind. Rex, 1972,31,14.5. 2 See for example: A. D. Cross, F. A. Kincl and A. Bowers, USP 3 1.50 140/1964 (Chem. Abstr., 1964,61, 16131f). 3 H. Suginome and T. Kondoh, J. Chem. Soc., Perkin Trans. I, 1992, 31 19 and references cited therein. 4 H. 0.Huisman, Angew. Chem., Int. Ed. Engl., 1971,10,4.50. 5 S. N. Ananchenko and I. V. Torgov, Tetrahedron Lett., 1963, 1553. 6 W. N. Speckamp and H. Kesselaar, Tetrahedron Lett., 1974,3405. 7 T. L. Jacobs and R. B. Brownfield, J. Am. Chem. SOC.,1960, 82, 4033. 8 A. L. Brachet-Cota and G. Burton, Z. Naturforsch., Teil. B, 1988,43, 491. 9 Y. Fujimoto and T. Tatsuno, Tetrahedron Lett., 1976, 3325. 10 W. Hartwig, Tetrahedron, 1983, 39, 2609 and references cited therein. 11 D. H. R. Barton, D. 0.Jang and J. Cs. Jaszberenyi, J. Org. Chem., 1993,58,6338. 12 D. H. R. Barton, W. B. Motherwell and A. Stange, Synthesis, 1981, 743. 13 P. de Armas, J. J. Concepcion, C. G. Francisco, R. Hernandez, J. A. Salazar and E. Suarez, J. Chem. SOC.,Perkin Trans. I, 1989, 405. 14 H. Suginome and S. Yamada, J. Org. Chem., 1984,49,3753. 15 C. A. G. Haasnoot, F. A. A. M. de Leeuw and C. Altona, Tetrahedron, 1980,36, 2783. Paper 4/0767 1K Received 16th December 1994 Accepted 9th January 1995
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