摘要:

SECTION C Organic Chemistry Steroids. Part XI2 Westphalen-type Rearrangements of 5a-Hydroxy- 4,4-d imet hyll -steroids By J . G. LI. Jones and 6. A. Marples," Department of Chemistry, University of Technology, Loughborough The 6a-acetoxy-, 6$-acetoxy-, and 6-oxo-5a-hydroxy-4,4-dimethyl-steroids (9), (1 0), and (1 1) undergo Westphalen-type rearrangement to give the corresponding 5P-methyl- A9-compounds. The 6-deoxy-5a-hydroxy- 4,4-dimethyl-compound (1 2) gives the A5-compound. THE Jliestphalen rearrangement of 5ac-hydroxy-steroids [e.g. (1) + (3)] requires the presence of a 4p- or a 6p-electron-withdrawing s~bstituent.~ Such substit- uents exert important steric and electronic effects in controlling the course of dehydration. We have re- cently reported kinetic evidence which indicates that the methyl group migration is concerted with heterolysis of the C(5)-0 bond.4 This implies that part of the function of the 6p-substituent is to provide steric acceleration in the Westphalen rearrangement.We have now investigated the reactions of the 5a-hydroxy- 4,4-climetliyl-compounds (9), (lo), (11) ,5 and (12) under Westphalen condition~.~J We have thus made some changes in the electronic effects while retaining an important syut-1,3-diaxial interaction between the angular and 4p-methyl groups. Recently Jones and his co-workers 6a reported that the diol (6) was dehydrated by toluene-fi-sulphonic acid in benzene to give a mixture of the ~ C C - and 5p-6-ketones (13) and (14) and the ~-homo-s-nor-5ac- and SP-ketones (16) and (17). Similarly, dehydration of the trio1 (7) in methanolic sulphuric acid gave the 5p-6-ketone (15). Fbtizon has reported some similar results in the androstane series.6b Compounds (9), (lo), (11),5 and (12) 6a were prepared from the 4,4-dimethyl-As-compound (4) ,' cis-Hydr- oxylation of compound (4) gave the diol (6) 5 9 6 a which on Jones oxidation gave the ketol (ll).5 Reduction of the ketol with sodium borohydride gave the diol(8).Acetyl- ation of the diols (6) and (8) (the latter with some difficulty) gave the required diacetates (9) and (lo), respectively. Epoxidation of compound (4) with mono- (6) R1 = Ac, R2 = a-OH,H (7) R1 = H, R2 = a-OH,H (8) €3' = Ac, R2 = P-OM,H (9) R1 = Ac, R2 = a-OAc,H (10) R1 = Ac, R2 = p-OAc,H (11) R1 = Ac, R2 = 0 (12) K1 = H, R2 = H, (1) R = Me (5) (2) R = AC r;L ?+L perphthalic acid gave the a-epoxide (5) ,6a which RO @ Atop (13) R = Ac; 5% (14) R = Ac; 5j3 (15) R = H; 5g Part X, I.G. Guest and B. A. Marples, J . Chein. SOC. (C), T. Westphalen, Ber., 1915, 48, 1064. (a) J. W. Blunt, A. Fischer, M. P. Hartshorn, F. W, Jones, D. N. Kirk, and S. W. Yoong, Tetrahedron, 1965, 21, 1567; ( b ) A. Fischer, M. J. Hardman, M. P. Hartshorn, D. N. Kirk, and A. R. Thawley, ibid., 1967, 23, 169; (c) D. N. Kirk and &I. P. Hartshorn, ' Steroid Reaction Mechanisms,' Elsevier, Amster- dam, 2968, p. 257 et seq.; ( d ) J. M. Coxon and M. P. Hartshorn, Tetrahedvaa Letters, 1969, 105. 1970, 1626. reduction with lithium in ethylamine gave the 6-deoxy- compound (12) .6a The major products in the reactions of compounds (9), (lo), and (1 1) were the corresponding A9-compounds (18) ~ (19), and (20),8 respectively; these were identified from their lH n.m.r.data (Table). Also, hydrolysis of the diacetates (18) and (19) gave the corresponding diols, J. G. L1. Jones and B. A. Marples, Chem. Comm., 1970, 126. G. Just and K. St. C. Richardson, Canad. J . Chem., 1964, 42, 456. ( a ) T. G. Halsall, Sir E. R. H. Jones, E. L. Tan, and G. R. Chaudhry, J . Chewt. Soc. (C), 1966, 1374; (b) bl. FBtizon and 1'. Foy, Coll. Czech. Chem. Cowtm., 1970, 35, 440. R. B. Woodward, A. A. Patchett, D. H. R. Barton, D. A. J. Ives, and R. B. Kelly, J . Chem. SOL, 1957, 1131. * J. W. Blunt, M. P. Hartshorn, and D. N. Kirk, J . Chem. SOC. ( C ) , 1968, 635.2274 J. Chem. SOC. (C), 1970 against time was linear, indicating that the reaction under these conditions was first-order in steroid con- centration as are the normal Westphalen rearrange- m e n t ~ .~ The first-order rate constant was (2.9 & 0.1) x For comparison, the rearrangement of the 6~-acetoxy-5a-hydroxy-compound (1) was similarly studied; the first-order rate constant was (4-89 & 0.06) x lop3 sec.-l. This value agrees reasonably well with that (6.4 x determined by Kirk and Hartshorn and their co-~orkers.~b Since the rates of the reactions of compound (1) and its 3@-acetoxy-analogue (2) are in the ratio ca. 3 : l,3b the rates of the reactions of corn- pounds (10) and (2) are probably in the ratio ca. 1-8 : 1. At first sight, this may seem inconsistent with the angular methyl migration being concerted with the heterolysis of the C(5)-0 bond,4 since in compound (10) considerable relief of the syw-lJ3-diaxial interaction between the 4 p-methyl and the angular methyl groups should occur.Also, there would be some relief of the similar interaction between the 6P-acetoxy-group and the 4p-methyl group. However, models suggest such relief of strain will be counteracted to some extent by compression between the 4cc-methyl group and the 6a-hydrogen atom [see (29)]. sec.-l. which on oxidation gave the known As-diketone (21).8 In addition to the As-compound (18), compound (9) gave a small yield of a mixture of the A1Yl0-compound (22) (22) R = AC (23) R = H (18) R = w-OAC,H (19) R = P-OAc,H (20) R = 0 (24) R1 = P-OAc,H; R* = a-OAc,H (26) R1 = P-OH,H; R2 = P-OH,H (26) R1 = R2 = 0 and the backbone-rearranged compound (24).Hydroly- sis of the mixture and t.1.c. separated the diols (23) and (25). The lH n.m.r. spectrum of the former showed the presence of the C-1 vinylic proton ( T 4.5) ; on oxidation this compound gave the +-unsaturated ketone (27) (Amax. 231 nm.). The structure of the diol (25) was assigned tentatively from its lH n.m.r. spectrum, which showed important peaks a t T 8.92 (s, 4cc-Me and 5p-Me), 9.02) s, 4P-Me and low-field branch of C21-H3 doublet), and 9.16 (m, high-field branch of C21-H3 doublet, 26-H,, 27-H3, and 14P-Me). The diol was oxidised to the diketone (26),8 which showed an intense peak in the mass spectrum at m/e 313 corresponding to the loss of the side chain. This fragmentation is characteristic of A13J7-~~mp~~nd~.s An unusual by-product obtained from the oxidation of the diol (23) was isomeric with the ketone (27) (mass spectrum) and showed a carbonyl band at 1765 cm.-l (presumably lactone); we have not yet identified this material.The 6-deoxy-compound (12) gave the A5-compound TABLE Chemical shifts (T) (CCI, solutions) 4p-Me 4cr-Me 5,3-Me 18-H, 3-H 6-H OAc (4) *' Compd. A > (18) 9.06 8.93 8.74 9.20 5.3-5.6 5.02 (19) 9.03 9.10 5-72 9.21 5.42 4.7- 8.0, 5.2 8-08 (20) 9.04 9.08 8-72 9.26 5.4 7.99 The rearrangement of compound (10) in 0.01~- solutions in acetic acid which were 0 . 0 5 ~ in sulphuric acid and 0 . 5 ~ in acetic anhydride 3a9b was followed polarimetrically at 25.5" & 0.5". A plot of log (a - a,) * The 4-methyl groups would inductively stabilise the C-5 carbonium ion but this effect should be relatively unimportant.9 (a) G. Snatzke and M.-W. Fehlhaber, Annulen, 1964, 678, 188; (b) J. W. Blunt, M. P. Hartshorn, and D. N. Kirk, CIzern. Comnz., 1966, 2125. (29) These data do not however exclude the possible inter- mediacy of a discrete C-5 carbonium ion, and it is also possible, but perhaps less likely, that the same detailed mechanism does not apply for compounds (10) and (2). The rearrangement of the 6-ketone (11) offers some evidence in support of the concerted mechanism. In the absence of 4-methyl substituents, 5a-hydroxy-6-ketones are acetylated under Westphalen conditions.1° I t has been suggested that the carbonyl group destabilises the formation of the C-5 carbonium ion,1° allowing the inter- mediate acetyl sulphate to be attacked by a molecule of free a1cohol.ll Formation of a C-5 carboniuin ion from compound (11) should similarly be destabilised * but a concerted process would be subject to steric acceleration.The reaction of the 6-deoxy-compound (12) to give the A5-cornpound is similar to the reaction of the 5~-hydroxy- 6P-rnethyl-compound (28) .12 Both reactions indicate that the steric effect of the 4- or the 6-substituent alone is insufficient to ensure rearrangement. The rearrangements oi compounds (9), (lo), and (11) indicate that the combination of steric and electronic effects required for rearrangement need not be located in one particular group at position 4 or 6. Also a lo (a) 6. Ellis and V. Petrow, J . Chem Soc., 1939, 1075; (b) Y .I?. Shealy and R. M. Dodson, J. Org. Chenz., 1951, 16, 1427. 11 A. Fischer, M. J. Hardman, 11. P. Hartshorn, and G. 3 . Wright, I'efrahedroiz, 1969, 25, 5915. l 2 (a) L. F. Fieser and J. Rigaudy, J . A w w . Chenz. Soc., 1951, 73, 4660; (bl R. 6. Turner ibid., 1952, 74, 5362.Org. 2275 suggestion by Kirk and Hartshorn3c that the direction of the dipole induced by the 6-substituent is of prime importance now seems less tenable. We hope to study the rearrangements of 4-mono- methylated-5a-hydroxy-compounds. Production of C-5 carbonium ions from such compounds may be detected by the formation of A4-compounds. EXPERIMENTAL Solutions were dried over anhydrous sodium sulphate and solvents were removed i.la oacuo on a rotary evaporator. Kieselgel PF254 (Merck) (1 m.plates 0.5 mm. thick) was used for preparative t.1.c. and Camag or Woelm deactivated (grade 111) neutral alumina was used for column chroma- tography. 1.r. spectra were determined with Perliin-Elmer 237 and 257 spectrophotometers. U.V. spectra were determined with a Unicam SP 800 spectrophotometer. 1H N.m.r. spectra were determined a t 60 MHz with a Perkin-Elmer R10 spectrometer and mass spectra were recorded with A.E.I. MS9 and MS12 spectrometers. Rotations were measured for solutions in chloroform with a Bendix polari- meter 143C. 3Q-Acetoxy-4,4-divtzeth~,L5-hydroxy-5~-~~olestan-6-o~e (1 1) .5 -A solution of the diol (6) 5,6a (200 mg.) in acetone (15 ml.) a t 0" was treated with chromic acid solution l0.4 ml.; chromic oxide (6.25 g.) in 20% sulphuric acid (25 ml.)] and set aside for 4 min.The mixture was poured into water and the usual work-up gave the ketol (11) (180 mg.), m.p. 157- 159" (from methanol) Lull, 0" (lit.,5 m.p. 158-160", -1.1") (Found: C, 76.4; H, 10.5. Calc. for C31H5204: C, 76-2; H, 10.7%). 3j3-A cetoxy-4,4-dimethyl-5a-cholestane-5,6~-diol (8) .-A solution of the ketol (11) (150 mg.) in ethanol (20 rnl.) was treated with an excess of sodium borohydride (100 mg.), set aside for 1 hr., then acidified with acetic acid and diluted with water. The usual work-up gave the crude diol (8) (140 mg.), T (CC1,) 4.8-5.2 (m, C-3 H), 5.9-6.15 (m, C-6 H), 8.01 (s, AcO), 8.63 (s, 4p-Me), 8-68 (s, 19-H,), 9.0- 9.2 (d, 4a-Me, 2l-H,, 26-H,, 27-H,), and 9.32 (s, 18-H,). 3~,6[3-Diacetoxy-4,4-dimethyl-5u-cholestan-5-ol (10) .-A solution of the crude diol (8) (140 mg.) in pyridine and an excess of acetic anhydride was heated on a boiling water bath overnight.m'ater was added and the mixture was set aside for 30 min. Evaporation gave the diacetate (lo), m.p. 115-117O (from methanol), [a], -18" (c 0.6), 'i (CCI,) 4.8-5-2 (m, C-3 H and C-6 H), 7-98 (s, AcO), 8.04 (s, AcQ), 8.74 is, 4p-Me), 8.88 (s, 19-H,), 9.0-9-22 (d, 4a-Me, 2F-H,, 26-H,, 27-H,), and 9.33 (s, lS-H,) (Found: C, 74.5; €3, 10.9. Acetylation of the diol(6) 596 with acetic anhydride-pyridine overnight at room temperature gave a quantitative yield of the diacetate (9), m.p. 145-146" (from methanol), [E]~ +46O (c 0.4), T (CCl,) 4.45-4-85 and 4.85-5.3 (rn, C-3 H and C-6 H), 84br (s, 2 x AcO), 8.91 (s, 4a-Me), 8.98 (s, 19-H,), 9.07 (s, 4p-R!k), 9.14 (d, 2l-H,, 26-H,, 27-H,), and 9.37 (s, 18-H3) (Found: C, 74.2; H, 10.75.C,&&,O, requires C, 74.4; H, 10.6y0). Dehydration of Compounds (9), (lo), and (1 1).-A solution of the steroid in acetic acid (6 ml.) and acetic anhydride (1 ml.) was treated with sulphuric acid [O-1 ml. ; sulphuric acid (4 g.) in acetic acid (25 mol.)], set aside for the period specified, then poured into brine. The resultant mixture C&& requires C, 74.4; H, 10.6%). 3p, 6x-Diacetoxy-4,4-dimetlayl-5u-cholestan-5-ol (91.- was extracted with ether. The extracts were washed with water ( x 2) and evaporated t o leave the crude product. Compound (9) (80 mg.) after 1 hr. gave an oil (60 mg.). Preparative t.1.c. [benzene-ethyl acetate (40 : l)] gave 3p, 6a-diacetoxy-4,4,5-tvimethyZ- 19-nor-5P-cholest-9-ene (1 8) (24 mg.), an oil, [a], +4.4" (c 0.9); for 1H n.m.r.see Discus- sion section (Found: C, 76.7; H, 10.8. C,,H,,O, requires C, 77.0; H, 10.6%), a mixture of compounds (21) and (22) (1 1 mg.), and starting material (12 mg.). Compound (10) (90 mg.) after 30 min. gave an oil (80 mg.). Preparative t.1.c. [benzene-ethyl acetate (10 : l)] gave 313,6P-diacetoxy-4,4,5-trimethyl-19-nov-5~-cholest-9-ene (19) (45 mg.), an oil, [a], + 100" (c 0.9) ; for 1H n.m.r. see Discus- sion section (Found: C, 76.95; H, 10.7. C,,Hs40, re- quires C, 77.0; H, 10.6%). Compound (1 1) (100 mg.) after 2 hr. gave an oil (90 mg.). Preparative t.1.c. [benzene-ethyl acetate (10 : l)] gave 3~-acetoxy-4,4,5-trimethyl-19-nor-5~-cholest-9-en-6-one (20) (60 mg.), m.p.95-97', [a], -55' (c 0.4) (lit.,* m.p. Dehydmtion of Compound (12).-A solution of the diol (12) (400 mg.) in acetic acid (20 ml.) and acetic anhydride (4 ml.) was treated with sulphuric acid (0.5 ml. ; solution as in fore- going experiment) and set aside for 30 min. The usual work-up and preparative t .l.c. of the product [benzene-ethyl acetate (40 : l ) ] gave 3~-acetoxy-4,4-dimethylcholest-5-ene (4) (280 mg.), identical with an authentic sample. Separation of the DioZs (23) and (25).-A solution of the mixture of compounds (22) and (24) (30 mg.) in 1% methano- lic potassium hydroxide was heated under reflux for 6 hr., diluted with water, and extracted with ether. Preparative t .l.c. gave 3p, Ga-dihydroxy-4,4,5-trimethyl- 19-nor-5P-chol- est-l(l0)-ene (23) (14 mg.), an oil, z (CCl,) 4.5 (m, C-1 H), 5-4-58 and 5-9-6-1 (m, C-3 H and C-6 H), 8.85 (s, Sp-Me), 9-0-9.3 (m, 4a-Me, 4p-Me, 2l-H,, 26-H,, 27-H,), and 9.38 (s, 18-H,), m/e 430 (M+ low intensity) and 412.3705 (M - 18; calc.for CzgH4,0 : 412.3705), and 3p-6a-dihydroxy-4,4,5,14- tetramethyl- 18,19-bisnor-SP, 8a, 98,l Oa, 1 CP-cholest- 13 (1 7) - ene (25) (8 mg.), an oil; for 1H n.m.r. see Discussion section. Oxidation of the Diols (23) and (25).-Each compound was treated with chromic acid in acetone as already de- scribed. T.1.c. of the product from the diol (23) (14 mg.) gave 4,4,5-trimethyl-l9-nor-5p, lOE,-cholest-l-ene-3,6-dione (27), m.p. 134-136", v,, l700br cm.-l, h,. (ethanol) 231 nm. (E 9000), nz/e 426.3499 (M+, calc. for CzgH,,02 : 426*3498), and an unknown lactone vmau. 1765 cm.-l, mle 426.3502 (Mf, calc. for C2,H,,OZ: 426.3498). T.1.c. of the product from the diol (25) (8 mg.) gave 4,4,5,14-tetramethyl-18,19- bisnor-5P, 8a, 9p, 10a, 14p-cholest-13( 17)-ene-3,6-dione (26) ,8 an oil, m/e 426 (5.5%), 313 (M - 113, 45%), and 43 (100%). 4,4,5-T~inzethy1-19-nor-5~-cholest-9-ene-3,6-dione (21) .-A small sample of each of the diacetates (18) and (19) was hydrolysed by heating under reflux in a 1% solution of potassium hydroxide in methanol overnight. The diols thus obtained were oxidised with chromic acid in acetone; each gave the Ag-dione (21), m.p. 116-117° (frommethanol), (lit.,* m.p. 110-120", - 13,750°, [+I2,, + 14,600°, We thank the S.R.C. for a research studentship (to J. G. L1. J.) and an MS/12 mass spectrometer (to Professor G. W. Kirby). We also thank Professor W. Klyne for help in obtaining an 0.r.d. spectrum. [0/668 Received, A p ~ i l loth, 19701 95-96", [a], -53'). 0.r.d. [+]318 - 16,900°, [$I270 + 19,435", [+I246 [+I~E, +11,200")* f 13,945"

ISSN:0022-4952    

DOI:10.1039/J39700002273

出版商:RSC    

年代:1970

数据来源: RSC