Totally synthetic steroid heterocycles. Part 3. Stereochemical course of oxidation of sulphur in 16-thia-8,14-didehydro-D-homoestrone 3-methyl ether and its derivatives

摘要

1254 J.C.S. Perkin I Totally Synthetic Steroid Heterocycles. Part 3.l Stereochemical Course of Oxidation of Sulphur in 16-Thia-8,14-didehydro-~-homoestrone 3-Methyl Ether and its Derivatives By Tadao Terasawa and Toshihiko Okada, Shionogi Research Laboratory, Shionogi and Co. Ltd., Fukushima- ku, Osaka 553, Japan The stereochemistry of oxidation at sulphur of the steroidal systems 16-thia-8,14-didehydro-~-homoestrones (1a-e) was studied with the oxidants sodium metaperiodate and m-chloroperbenzoic acid. The configurational assignments of the a-and @-oxides obtained are based on i.r. (intramolecular hydrogen bonding) and n.rn.r. data. The direction and degree of stereoselectivity in the oxidation contrasts with that observed for thians. A marked directive effect is observed for peracid oxidation of the a-hydroxy-sulphide (1b), leading to the a-cxide (2b) in a highly stereoselective manner.INPart 1,2 we described the synthesis of the tetracyclic tempting further stepwise reduction of the double bond intermediates (1) of 16-thia-~-homoestrogens. In at-system, we observed that these compounds are very Part 2, T. Teresawa and T. Okada, preceding paper. T. Terasawa and T. Okada, J.C.S. Perkin I, 1978, 576. 1978 1255 resistant to catalytic hydrogenation under the usual acid, oxidation led directly to the sulphones (4) in almost conditions, probably due to a poisoning effect of sulphur 70 yield. The sulphones were obtained quantitatively (2 1 c1-oxide (3) p-oxide a; R', R~= d; R'= OH, R2= Ho b;R'= H,R2= 0H e; R'=OAc, R2= H c ;R' =H, R~=OA c SCHEME atom. To overcome this difficulty, we initially con-from the corresponding sulphoxides (2) and (3).The sidered use of the sulphoxides (2) and (3) and sulphones sulphoxide isomers were separated by preparative t.1.c. (4) as substrates. We now report oxidations of the Conjigurational Assignments .-The assignment of con-steroidal sulphides (la-e). The stereochemical aspects figuration at sulphur of the sulphoxides obtained was TABLE1 Spectral data of sulphoxides and sulphones M.D. 17 3- 175 178-1 80 182-186 204-213 200-205 203-212 2 00-2 06 210-215 187-191 184-187 172-1 73 Amax. (EtOH)/nm (4348 351 341.5 343 337.5 (30 900) 340 (30 800)343 344.5 (30 400) 338.5 (28 600) 341 (30 500)345 (27 600) (27 300) (27 300) (31 300) (31 200) (28 700) v,,./crn-' OH 3 378 3 617 3 309 3 617 3 613 3 344 (CHCl,) co 1713 1713 1 744 1730 1737 1747 1747 1728 1 S+O 1034 1036 1021 1057 1040 1041 1038 1013 1038 1018 1032 1013 1028 1020 1028 1018 1312 1 138 1123 1028 1012 .13-Me 1.29(s) 1.53 (s)(0.16)1.00 (s)(0.01)1.03 (s) 1.25 (s)(0.26)1.33 (s)(0.26)1.04 (s)(0.02)1.10 (s) 1.24 (s) 1.31 (s)(0.21)1.49 (s)(0.12) (-0.08) (-0.04) (0) (0.22) h 6 (CDC1,) 15-H 6.72 (s) 6.66 (s) 6.42 (s) 6.40 (4J 2)6.47(s) 6.52 (s) 6.27 (s) 6.31 (d, J 1.5) 17a-H (J/Nz) 5.11 (t, J 3.5) 5.16 J 5.5,2) 5.63 (q, J 9, 6.5) 237-240 335.5 (28 500) 1295 1 136 1118 1.18 (s)(0.19) 21 3-215 336.5 (28 800) 1291 1139 1120 1.16 (s)(0.14) a All new compounds gave satisfactory elemental analyses.Dilute solution. Values in parentheses refer to substituent effects based on the parent sulphides. are of particular interest in the absence of comparable made on the basis of the spectral data summarized in results. Table 1. For example, in the n.m.r. comparison of the For this purpose, oxidation of sulphides was carried acetoxy-sulphoxides (2e) and (3e), the signal for the axial out using sodium metaperiodate and m-chloroperben- 17aa-proton of the former appears at lower field (0.74 zoic acid. When the sulphides (1) were carefully oxi- p.p.m.) than for the latter. Also, the 13-Me protons of dized with an equimolar amount or a slight excess of the a-oxide (2e) resonate at higher field (0.21 p.p.m.) than oxidants, there resulted isomeric mixtures of the sul- those of the p-oxide (3e).These results are consistent phoxides (2) and (3). With two mol. equiv. of the per- with the assigned configuration based on the known acetylene-type anisotropic effect of the sulphur-oxygen bond,3 suggesting cis- and trans-relationships between l7aa-H and the sulphur-oxygen bond in sulphoxides (2e) and (3e), respectively. The same conclusions were drawn J.C.S. Perkin I both oxidations of sulphoxides (la or d) contrasts with the above results for thians. Examination of our data also reveals that the isomer ratio is unaffected by the nature of the 17a-substituent, as suggested by a com- from an n.m.r. study using the shift reagent, E~(dpm),.~ parison of the cases (lc and e).Thus, we cannot The stereochemistry of the sulphoxide alcohols (2d) and (3d) was confirmed by chemical correlation with the cor- responding acetates (2e) and (3e). The configurations of the sulphoxides (2b) and (3b) also (2c) and (3c)l could be determined by physical comparison with (2d) and (3d) also (2e) and (3e)l. The i.r. spectrum of a dilute solution of the @-oxide (3b) in chloroform exhibits a free OH (3 617 cm-l) and associated OH band (3309 cm-l), while that of the a-oxide (2b) shows only one intramolecu- larly bonded OH band (3378 cm-l) indicating that the sulphur-oxygen bond is cis to the a-oriented OH group. Other data recorded in Table 1also supported the assigned structures. In particular, the n.m.r. signals for 13-Me of the a-oxides commonly occur at higher field (0.24.3 p.p.m.) than those of the corresponding @-oxides.Also, the signals for 15-H appear at lower field (0.2-4.3 p.p.m.) in the a-oxides compared with the p-oxides. These results are also consistent with the general anisotropic effect of the sulphur-oxygen bond. Furthermore, there is a substituent effect by the a-and @-oxides on the chem- ical shift of the 13-Me protons (ca. 0 and 0.24 p.p.m., respectively). On this basis, the configurations of the oxo-sulphoxides (2a) and (3a) were deduced. Oxidations.-The stereochemical results of oxidation to sulphoxides are summarized in Table 2. Since all TABLE2 Stereocheniical outcome of sulphur oxidation Product ratio Isolated yield ()(2) (3) r-* 7 Compound (1) Method a-S+O : p-S+O (2) (3) offer, at the moment, a satisfactory explanation for the stereochemical results.Of particular interest is the remarkable stereoselectivity of peracid oxidation of the a-hydroxy-sulphide (1b) leading to a marked predomin- ance of the a-oxide. This result is probably attributable to a directive effect by the hydroxy-group, as shown in the Figure. Participation of a neighbouring hydroxy- I......., 0 Suggested transition state for peracid oxidation of sulphide (lb) group in influencing the stereoselectivity of peracid oxidation is well known.6 This orientation effect is no longer apparent in peracid oxidation of the acetoxy- sulphide (1c). Finally, we examined whether the parent sulphides can be easily restored from the corresponding sulphoxides and sulphones.The sulphoxides (2b and d) were treated with sodium borohydride by stirring at room temperature in aqueous alcohol in the presence of cobalt chloride to give smoothly the sulphides (lb and d), respectively, in 65-75 yield.' However, all our attempts to deoxy- genate the sulphones proved unpromising. Lithium aluminium hydride reduction of sulphone (4e) in tetra- hydrofuran, even at low temperatures, effected elimin- ation and hydrogenolysis of the l7a-oxygen function, while the sulphonyl group remained unaffected. EXPERIMENTAL For general directions see ref. 2. Oxidation to Sulphoxides .-General methods. (A) SoJium metaperiodate. A solution of sodium metaperiodate (0.4 mmol) in water (2 ml) was added to an ice-cold solution of the sulphide (0.3 mmol) in methanol (15 ml) (for the alco- hols) or 1 : 1 or 2 : 1 methanol-acetone (15 ml) (for the ke- tone and acetates). The mixture was stirred at room tem-perature for 20 h.(B)m-Chloroperbenzoic acid. A solution of m-chloroper- benzoic acid (0.3mmol) in dichloromethane (2ml) was added dropwise at 0" to a stirred solution of the sulphide (0.3mmol) For recent examples for hydroxy-olefins, see (a) M. Mous-seron-Canet and J.-C. Guilleux, BUZZ. SOC.chim. France, 1966, 3853; (6) M. Mousseron-Canet, B. Labeeuw, and J.-C. Lanet, Compt. rend., 1966, 262, 1438; (c) E. Glotter, S. Greenfield, and D. Lavie, Tetrahedron Letters, 1967, 5261; (d) D. H. R. Barton and Y.Houmier, T.C.S. Perkin I. 1972, 919; For a similar ex-ample for hydroxy-sulphides, see (e) C. A. Kingsbury, J. Org. Chem., 1972, 37, 102. D. W. Chasar, J. Org. Chem., 1971, 36, 613. (a) A B (b) A B (4 A B (d) A B (4 A B a See Experimental section. 1 : 1.8 26.5 31.9 1 : 2.0 23.8 32.5 1 : 1.5 24.3 67.4 9.2: 1 73.5 6.3 1 : 2.2 27.5 64.8 1.1 : 1 45.4 36.2 1.5: 1 73.4 20.8 2.2: 1 58.4 14.0 1: 1.2 29.9 35.9 1.2: 1 54.2 40.3 Estimated from the n.m.r. spectrum of the crude mixture. pairs of isomeric sulphoxides isolated are found not to be isomerized under the conditions employed, the isomer distribution is believed not to be governed by thermo- dynamic control. Johnson and McCants suggested that in 4-substituted thians periodate oxidation is governed by product development control, whereas per- acid oxidation is determined by steric approach control.The identical direction and degree of stereoselectivity for K. W. Buck, A. B. Foster, W. D. Pardoe, M. H. Qadir, and J. M. Webber, Chem. Comm., 1966, 759. R. R. Fraser and Y. Y.Wigfield, Chem. Comm., 1970, 1471. C. R. Johnson and D. McCants, jun., J. Amer. Chem. Soc., 1965, 87, 1109. in dichloromethane (3 ml). The solution was stirred at room temperature for 1-2 h. Isolation of SuZphoxides.-The reaction mixture was poured into water and extracted with dichloromethane. After the usual work-up, the residue obtained was purified by preparative t.1.c. (1 : 1 or 2 : 1 chloroform-acetone for the alcohols and the acetates; 2 : 1 benzene-ethyl acetate for the ketone) to separate the epimeric sulphoxides. Product ratios and yields of the isolated sulphoxides are listed in Table 2. The sulphoxide alcohols were acetylated with acetic anhydride and pyridine in the usual manner. All the sulphoxides were crystallized from dichloromethane-ether or acetone. Pre9aration of Sulfihones.-As for oxidation to sulphox- ides, sulphide or sulphoxide was oxidized with a slight excess of m-chloroperbenzoic acid in dichloromethane. The sul- phones thus obtained were directly, or after purification by preparative t.l.c., crystallized from dichloromethane-ether. Physical data of the sulphoxides and sulphones are summarized in Table 1. 7/2040 Received, 21st November, 19771