摘要:

1976 821Synthetic Uses of Steroidal Ring B Diene Protection : 22,23-Dihydro-ergosterolBy Derek H. R. Barton,, A. A. Leslie Gunatilaka, Tsutomu Nakanishi, Henri Patin, David A. Widdowson,Protection of the ring B diene system of ergosterol by (i) a two-step addition of the elements of water across the 5.6-double bond, (ii) formation of the 4-phenyl-l,2,4-triazoline-3,5-dione adduct, or (iii) formation of the iron tri-carbonyl adduct by treatment with p-methoxybenzylideneacetonetricarbonyliron, allowed selective reduction of the22.23-double bond by catalytic or, as appropriate, ionic hydrogenation. Regeneration of the 5.7-diene system ineach case gave a high yield of 22,23-dihydroergosterol.and Brian R. Worth, Department of Chemistry, Imperial College, London SW7 2AYSYNTHETIC manipulation of ergosterol (1; R = H) otherthan at the 5,7-diene system requires an efficient methodfor the protection of this function. The Diels-AlderI II I)5- NPh0(2)IRO 1 \ (31'.*RO @ ' (31adduct with maleic anhydride and the 5,8-epidioxideare not useful.In contrast, the effective use of thehere further exploitation of this approach and thedevelopment of two alternative methods which comple-ment the first.Our synthetic objective was 22,23-dihydroergosterol(3; R = H), which occurs in a number of fungi andwhich we have recently isolated from a mutant yeastenzymatically blocked at the 22,23-dehydrogena~e.~22,23-Dihydroergosterol (of uncertain purity) has beensynthesised via hydrogenation of the maleic anhydrideadduct of ergosterol.' The overall process is, however,very inefficient. Our initial approach was to use theazo-adduct (2).Electrophilic attack on this systemgenerally occurs selectively at the 22,23-double bond,6but catalytic hydrogenation shows a preference for 6,7-attack and a simple synthesis by this means was thusprecluded. Instead, use was made of the selectiveelectrophilic attack on the side chain to introducereducible groups at C-22 and C-23. Conventionalchemical reductions of the difunctionalised side chainhowever predominantly regenerated the A22-system anda variant on ionic hydrogenation8 (Schemes 1 and 2)was developed for the successful method.As a simplified model system, methyl oleate wastreated with benzenesulphenyl chloride and mercury(I1)acetate in dichloromethane at room temperature(Scheme 1).The product was an isomeric mixture ofOAc SPh .--L { - C H - - C H - } I Iii / ( 4 )I Ph <Ph... I s+/ \ { - CH-CH--J { -CH -CH,- } - CHj [ CH2 ],6.COZMe( 5 1 (61 ( 7 ISCHEME 1 Reagents : i, Hg(0Ac) ,-PhSCl; ii, CF,CO,H-PhCH,*SiHMe, ; iii, Raney Ni4-phenyl-l,2,4-triazoline-3,5-dione adduct (2) for pro-tection of the diene has been e~tablished.~ We report(a) D. N. Jones, P. F. Greenhalgh, and I. Thomas, Tetya-hedron, 1968, 24, 297; (b) K. D. Bingham, G. D. Meakins, andJ. Wicha, J . Chem. SOG. (C), 1969, 671.D. H. R. Barton, R. K. Haynes, G. Leclerc, P. D. Magnus,and I. D. Menzies, J.C.S. Perkin I, 1975, 2055.R. C. Cookson, S. S. H. Gilani, and I.D. R. Stevens,J . Chem. Soc. (C), 1967, 1905. * D. H. R. Barton, T. Shioiri, and D. A. Widdowson, J . Chem.SOG. (C), 1971, 1968.(a) N. J. McCorkindaIe, S. A. Hutchinson, B. A. Pursey,TnT. T. Scott, and R. Wheeler, Phytochemistry, 1969, 8, 861;(b) P. Singh and S. Rangaswami, Current Sci., 1966, 35, 615;(G) A. Santos Ruiz, Anales veal acad. farm., 1943, 3, 201.9,IO-phenylt hioacet oxy-derivatives of methyl stearat e(4) (70%). This was treated with benzyldimethylsilanein trifluoroacetic acid solution to give the mixed methyl9- and 10-phenylthiostearates (6) (62%). Other work lo6 D. H. R. Barton, J. E. T. Corrie, D. A. Widdowson, M. Bard,and R. A. Woods, J.C.S. Perkin I, 1974, 1326.7 (a) A. Windaus and R. Langer, Annalan, 1934, 508, 106;(b) H.H. Inhoffen, ibid., p. 81; ( c ) J. Brynjolffssen, D. Hands,J. M. Midgley, and W. B. Whalley, following paper.8 D. N. Kursanov, 2. N. Parnes, and N. M. Loim, Synthesis,1974, 633, and references there cited.T. Mukaiyama, T. Endo, S. Ikengaa, and K. Osonoi,J . Org. Chem., 1968. 33, 2242.lo D. H. R. Barton, J . E. T. Corrie, and D. A. Widdowson,unpublished results822 J.C.S. Perkin Idienes,ll free of 4,6- and 6,8(14)-diene analogues.12Direct hydration of a 5,7-diene to the Sa-hydroxy-derivative is not possible but it was found l3 that, at-78 "C, chromyl chloride reacted with ergosterylacetate to give, in 95% yield, the 6a-chloro-5a-hydroxy-derivative (12), m.p. 192-193". We immediately re-duced this compound with lithium aluminium hydride togive, after reacetylation the 5cr-hydroxy-derivative (13)(80y0), m.p.231-233", [a], 0". Hydrogenation ofcompound (13) over freshly prefiared Adams catalyst inethyl acetate led to saturation of the side chain withoutmigration of the 7,8-double bond l4 (see spectral data inExperimental section). The 22,23-dihydro-product (14),m.p. 227-230", [aID +15.2", was dehydrated withfreshly purified thionyl chloride in pyridine at roomtemperature to give 22,23-dihydroergosterol acetateAlthough this approach gave an improved overallyield, it was still considered that a more efficient processwas desirable. The problem with azo-adduct protectionof the 5,7-diene lay in the normal, if sterically con-strained, reactivity of the 6,7-double bond generated.If the total x-system of the diene were complexed, as inthe tricarbonyliron complexes,l5 then the problemwould be avoided.Accordingly, ergosterol benzoatewas converted into the tricarbonyliron complex (15) in70% yield, by treatment with pentacarbonyliron inrefluxing di-n-butyl ether (144 "C). When formed inthis way, the product always contained 3-5y0 of un-changed ergosterol benzoate. This couId be removed(80%), m.p. 146--148", [a], -82".has shown that this process should occur with apparentretention of configuration by involvement of an epi-sulphonium intermediate [as (5)] which is opened by ahydride ion delivered from the silane. FinaI desulphuris-ation with Raney nickel gave methyl stearate.- OAC-SPh :PhIc+ 'H H(8) [ 91 /- H-SPh I 1IH(10 1 1111 ASCHEME 2 Reagents : i, Hg(0Ac) ,PhSCI : ii, CF,CO,H-PhCH,*SiHMe,; iii, Raney NiIn the steroid series (Scheme 2) the azo-adduct (2;R = Ac) was treated with a five-fold excess of benzene-sulphenyl chloride and mercury(I1) acetate in dichloro-methane to give the mixed 22,23-acetoxy-phenylthio-adducts (8) in Myo yield.Without separation (ana-lytical t .l.c. indicated 3 components) these were reducedat 0 "C in trifluoroacetic acid with benzyldimethylsilaneto give the 22- (and/or 23-)phenylthio-adducts (10) (76%)aia the presumed episdphonium intermediate (9). Thestarting ergosterol acetate azo-adduct (2; R = Ac) wasalso reformed in 16% yield. No conditions were foundwhereby the formation of this could be completelysuppressed.Desulphurisation of the thioether (6) withRaney nickel in refluxing tetrahydrofuran-ethanol gavethe azo-adduct of 22,23-dihydroergosterol (1 1) in 33%yield (based on recovered starting material). Thisproduct contained traces of the 22,23-olefin which couldbe removed by treatment with m-chloroperbenzoic acid.6The 22,23-epoxide formed was readily separated fromthe required dihydro-adduct (7) (see Experimentalsection). Finally, reduction of the adduct with lithiumaluminium hydride gave 22,23-dihydroergosterol (85%),m.p. and mixed m.p. 128-130", [a]= -121". Thismaterial was also spectroscopically identical with thatobtained from the pol 5 mutant of Saccharornycescerevisiae.Although successful, this approach was cumbersomeand a more direct synthesis was sought (Scheme 3).Inanother connection, it had been observed that Sa-hydroxy-A7-steroids were readily dehydrated to 5,7-l1 D. H. R. Barton and A. G. ILI. Barrett, unpublished results.la D. Freeman, A. Acher, and Y. Mazur, Tetrahedron Letters,1976, 261.I2.. I t . I l l ... J-Jy AcO I HOI141SCHEME 3 Reagents: i, CrO,Cl,; ii, LiAlH,; iii, Ac,O-C,H,N; iv, Ha-PtO,; v, SOCl,-C,H,Nby formation of the azo-adduct (2; R = PhCO) with4-phenyl-1,2,4-tria~oline-3,5-dione.~ In order to circum-l3 D. H. R. Barton and R. K. Haynes, J.C.S. Pevkin I , 1975,2066.l4 D. H. R. Barton and J . D. Cox, J. Chem. SOC., 1948, 1364.l5 H. Alper and J, T. Edward, J . Organometallic Chem., 1968,14, 4111976 823vent the problem of high reaction temperature andn-complete reaction, use was made of the arylmethylene-acetone-tricarbonyliron complexes which have beenI I111 -lii 115) + IIk I161SCHEME 4 Reagents : i, Fe,(CO) D-MeOC6H4-CH:CH*COMe ;ii, H,-Pt0,-PhCH,*SiHMe, ; iii, FeCls,6H,0 ; iv KOHshown to be efficient tricarbonyliron transfer agents.lsBenzylideneacetonetricarbonyliron reacted with ergo-steryl acetate at 90 "C to give a 69% yield of the complex(15; R = Ac) (see Table).The more electron-richFormation of tricarbonyliron complexes of ergosterolderivativesNo.12346678ErgosterolderivativeBenzoateAcetateAcetateBenzoateBenzoateAcetateBenzoateBenzoateConditions Yield144; 20 7090; 24 6990; 16 6490; 20 6590; 16 6060; 48 6660; 48 5965; 120 80(T/"C; tlh) (%I0 Purified product.bza = benzylideneacetone; mba =methoxybenzylideneacetone.p -me t hox yb enz yli deneace t one t ricarb on yliron reacted at90 "C during 16 h or at 60 "C during 48 h to give a 60%vield. It was subsequently found that the aryl-methyleneacetone could be used catalytically for thereaction between ergosteryl benzoate and nonacarbonyl-di-iron. By the use of reagents in excess after 120 h at55 "C the yield of the purified tricarbonyliron complex ofergosteryl benzoate was raised to 80%. The results ofthe evaluation of this method are given in the Table.Hydrogenation of the complex (15) over Adamscatalyst, palladium-charcoal, Raney nickel, or chloro-tristriphenylphosphinerhodium was in each case veryslow or non-existent. The addition of acid catalystscaused concomitant decomposition of the diene complex.The addition of a catalytic amount of benzyldimethyl-silanel' to a hydrogenation over Adams catalyst in16 J.A. S. Howell, B. F. G. Johnson, P. L. Josty, and J. Lewis,J . Organometallic Chem., 1972, 39, 329.G. F. Emerson and R. Pettit, J . Amer. Chew. Soc., 1962,84, 4691.ethyl acetate gave smooth reduction of the 22,23-doublebond (in 94% yield) together with some saturation of thephenyl ring of the benzoate (indicated by the massspectrum). The diene was regenerated by oxidativecleavage of the complex (16) with iron(m) chloridehexahydrate.l* Saponification of the esters (benzoate +cyclohexanecarboxylate) without purification , gave the22,23-dihydroergost erol (92 yo), m.p . 129-1 3 1 O, [aID- 131 O, spectroscopically identical with the previoussamples. This material was converted into the 3p-acetate (3; R = Ac) and the benzoate (3; R = PhCO).The latter was converted into the azo-adduct (2; R =PhCO), m.p. 201203O. These were all identical withthe corresponding derivatives of the natural material.EXPERIMENTALM.p.s were determined on a Kofler hot-stage apparatus.Unless otherwise stated, [a], values were recorded forsolutions in chloroform and i.r. spectra for solutions incarbon tetrachloride or Nujol mulls. N.m.r. spectra wererecorded with CDCl, as solvent and tetramethylsilane asinternal standard.U.V. spectra were recorded for solutionsin absolute ethanol.Unless otherwise stated, light petroleum refers to thefraction of b.p. 40-60" and solvent mixtures used aredescribed in ratios of volumes. T.1.c. and p.1.c. werecarried out on Merck Kieselgel GF,,, plates (0.2 and 1 mrnlayers, respectively).The Mixture of Methyl 9,lO-Acetoxy-phenylthio-stearates(4) .-Benzenesulphenyl chloride (1.17 g , 8.34 mmol) in drydichloromethane (10 ml) was added gradually a t roomtemperature during 30 min to a stirred mixture of methyloleate (2.25 g, ca. 7.57 mmol) and mercury(I1) acetate(1.30 g , 4.08 mmol) in dry dichloromethane (10 ml). After3.5 h, t.1.c. showed that most of the starting material wasconsumed. Mercury(I1) chloride was removed by filtration,the filtrate was evaporated, and the residue was chromato-graphed over alumina (grade 111 ; 80 g) .Elution with lightpetroleum (ca. 250 ml) gave a small amount of startingmaterial. Further elution with light petroleum (1.6 1) andthen light petroleum-ether (10 : 1; ca. 176 ml) yielded theisomeric methyl 9,lO-acetoxy-phenylthio-stearates (4) as anoil (2.47 g, 70%), v,, (film) 1730, 1582, and 1236 cm-l,z 9.12 (3 H, CH,), 8.75 (ca. 26 H, CH,), 7.98 (3 H, s, Ac),7.70 (2 H, CH,*CO,Me), 6.77 (1 H, m, HC-SPh), 6.35 (3 H,s, CO,Me), 4.95 (1 H, m, HC*OAc), and 2.65 (5 H, m, ArH).Methyl 9- and 1 O-P~enylthio-st ear ate^ (6) .-The mixture ofmethyl 9, IO-acetoxy-phenylthio-stearates (4) (49.5 mg) inbenzyldimethylsilane (0.13 ml, cn. 120 mg) and trifiuoro-acetic acid (2 ml) was stirred at room temperature for20 h.19 T.1.c.[light petroleum-ether (20 : I)] showed thatthe desired compound (RF 0.33) was generated almostexclusively. After the reaction was complete (t.l.c.), thesolution was poured into saturated aqueous sodiumhydrogen carbonate and extracted with ether. The extractwas washed with N-sodium hydroxide and water, dried(MgSO,), and evaporated. P.1.c. [light petroleum (b.p.60-80°)-ether (20: l)] gave the methyl 9- and 10-phenyl-thiostearates (6) (27 mg, 62%), as an oil, vmx. 1730 and1 170 CIII-~, z 9.13 (3 H, CH,), 8.75 (ca. 28 H, CH,), 7.72G. F. Emerson and R. Pettit, J . Org. Chem., 1964, 29,3620.l9 C. T. West, S. J. Donnelly, D. A. Kooistra, and M. P. Doyle,J . Org.Chem., 1973, 38, 2676J.C.S. Perkin I(2 H, m, CH,CO,Me), 6.95 (1 H, m, NC-SPh), 6.37 (3 H, s,CO,Me), and 2.70 ( 5 H, m, ArH), 7nie 406 (M, 14y0), 378,297, 296, 110 (loo%), and 109.Methyl Stearute (7) .-The methyl 9- and 10-phenylthio-stearates (6) (80 mg) in 90% ethanol was refluxed withRaney nickel (1.5 g) for 3 h. T.1.c. Fight petroleum-ether(20 : 1)) showed that the starting material was convertedinto one product. The bulk of the nickel was removed bydecantation and centrifugation and then washed severaltimes with ethanol. Dimethylglyoxime was added to thecombined ethanolic solutions, which were then evaporated.The residue was separated by p.1.c. [light petroleum-ether(20 : 1)] to give methyl stearate (7) as a solid, spectro-scopically and chromatographically identical with authenticmaterial.4-Phenyl- 1,2,4-triazoline-3,5-dione Adduct ( 8 ) of the Mixtureof 22-Acetoxy-23-phenylthio- and 23-Acetoxy-22-phenylthio-ergosta-5,7-dien-SP-yl Acetates.-To a stirred mixture of the4-phenyl- lf2,4-triazoline-3, 5-dione adduct of ergosterylacetate4 (111) (860 mg, ca.1.4 mmol) and mercury(I1)acetate (2.16 g, ca. 6.75 mmol) in dry dichloromethane (3 ml),benzenesulphenyl chloride (1.96 g, ca. 13.5 mmol) in drydichloromethane (4 ml) was added slowly at room tem-perature during 40 min. The mixture was stirred at roomtemperature for a further 20 h. T.1.c. showed the presenceof the polar isomeric mixture of the desired compounds asthree spots overlapping each other, 1 1 ~ 0.51, 0.45, and 0.38[benzene-ether (5 : l)] or two spots overlapping each other,RF 0.39, 0.33 [ether-light petroleum (3 : 2)] in additionto the small amount of the starting material, RF 0.62[benzene-ether (5 : l)] or 0.61 [ether-light petroleum (3 : 2)J.After the removal of mercury(I1) salts, p.1.c.[ether-lightpetroleum (3 : 2)] gave the mixture of the adducts (8)(650 mg, 60%) as a solid (from aqueous ethanol), vmx.1 749, 1 733, 1 702, 1 510, and 1 245 cm-l, T 7.95br (6 H, s,OAc), 6.77 [l H, m, 23-(or 22-)HI, 4.65 [l H, m, 22-(or23-)HI, 3.80 and 3.60 (2 H, ABq, J 8 Hz, H-6 and -7),and 2.67 (10 H, m, ArH), nz/e 781 (M+), 779, 546 (loo%),486, 437, 436, 377, 376, 361, 110, and 109 (Found: C,70.55; H, 7.45; N, 5.25. C,,H,,O,N,S requires C, 70.65;H, 7.6; N, 5.35%).From the less polar band, startingmaterial (105 mg, 12% ; identified by n.m.r.) was obtained.Reduction of the A cetoxy-phenylthio-adducts (8) .-To themixed isomers (8) (650 mg) in benzyldimethylsilane (5 ml,ca. 4.75 g), trifluoroacetic acid (30 mi) was added dropwisewith stirring at 0 "C during 1 h. The mixture was stirredat 0 "C for a further 2 h, then poured into saturated aqueoussodium hydrogen carbonate a t 0 "C and extracted withether. The ether layer was washed with sodium hydrogencarbonate solution until neutral and then water and dried(MgSO,). T.1.c. [light petroleum-ether (1 : l)] showed thepresence of two products (Rp 0.5 and 0.42). After evapor-ation of the ether, the product was chromatographed overaluminium oxide (grade 111; 30 g) in order to remove theexcess of benzyldimethylsilane. Elution with lightpetroleum (200 ml) gave unchanged benzyldimethylsilane.Elution with ether gave the product mixture, which wasseparated by p.1.c.[light petroleum-ether (1 : l), twicedeveloped]. From the less polar band ( B p 0.69), theregenerated 4-phenyl-1,2,4-triazoline-3,5-dione adduct ofergosteryl acetate (1 ; R = Ac) (100 mg, 16%) was obtained.From the more polar band, the 4-phenyl-l,2,4-triazoline-3,5-dione adduct of the isomeric mixture (10) of 22- and23-phenylthioergosta-5,7-dien-3p-yl acetates (10) (480 mg,76O/,\ was isolated. Recrvstallisation from aqueous ethanolgave fine needles, m.p. 130.5-132.6", vmx. 1749, 1735,1 705, 1 511, and 1 247 cm-l, T 8.00 (3 H, s, OAc), 6.78[I H, m, 22-(23-)HI, 4.55 (1 H, m, H-3), 3.80and 3.80 (2 H,ABq, J 8 Hz, H-6 and -7), and 2.68 (10 H, m, ArH), nzle723 (iM+), 721, 488, 379, 378, 363, 119 (loo%), 110, and109 (Found: C, 3.0; H, 7.85; N, 5.6.Calc. for C4aH,7N,0,:C, 3.0; HI 7.95; N, 5.8%).4-Phenyl-1,2,4-triazoline-3,5-dione Adduct (1 1) of 22,23-Dihydroergosteryl A cetate.-Raney nickel (2 g) in tetra-hydrofuran (25 ml) and ethanol (12 m1) and the isomericphenylthio-adducts (10) (220 mg) were refluxed for 1 11(t.1.c. control). T.1.c. [light petroleum-ether (1 : l)] showedthree spots (RF cu. 0.5, 0.42, and 0.34). The nickel wasremoved by decantation and centrifugation and washedwith absolute ethanol several times. The residual nickelcontained in the combined solutions was removed byfiltration.The solvents were evaporated off and theresidue was separated into the three components by p.1.c.[light petroleum-ether (1 : l), twice developed]. From thesecond band, the starting material (10) was recovered(90 mg, 40.9%). From the less polar band, the adduct (1 1)(50 mg, 26.7 yo) was obtained. Recrystallisation fromaqueous methanol and then acetone-methanol gave plates,m.p. 179-181", [a],21 -95.2" (c 0.69), vmK (CHCI,) 1742,1 726, and 1694 cm-l, n.m.r. data as below, wzle 616 (M+),613, and 380 (100%) (Found: C, 74.2; H, 8.55; N, 6.7%).Though physical data supported the structure of ( l l ) , theappearance of an Mf - 2 peak in the mass spectrumsuggested the presence of a small amount of a didehydro-compound. The product (11) was therefore purified asfollows.To the crude material (50 mg) from p.l.c., in dry dichloro-methane (3 ml), m-chloroperbenzoic acid (15 mg) wasadded a t 0 "C, and the solution was kept at 0 "C for 43 h.6It was then diluted with cold dichloromethane and filteredthrough an alumina (grade 111; 3 g) column to removeacidic material.P.1.c. [light petroleum-ether (1 : 1)* twicedeveloped] of the resulting mixture gave the pure 4-phenyl-1,2,4-triazoline-3,5-dione adduct (1 1) (28 mg, 56%), m.p.(plates from acetone-methanol) 188-190", [a],18 - 96.5"(c 0.29), T 7.97 (3 H, s, OAc), 4.52 (1 H, m, H-3), 3.76 and3.57 (2 H, ABq, J 8 Hz, H-6 and -7), and 2.62 (5 H, 111,ArH), in]e 615 (M4), 440, 438, 380 (loo%), 378, and 365(Found: C, 74.15; H, 8.85; N, 7.0.C,,H,,N,04 requiresC, 74.1; H, 8.7; N, 6.8%).22,23-DihydroergosteroI (3 ; R = H) .-To the acetate(11) (20 mg) in dry tetrahydrofuran (8 ml), lithium alu-minium hydride (62 mg) was added with stirring, and themixture was refluxed for 18 h under nitrogen., A fewdrops of water were added to the stirred mixture a t 0 O Cand the solution was dried (MgSO,) and evaporated. Theresidue was fractionated by t.1.c. [benzene-ether (1 : l)] togive 22,23-dihydroergosterol (3; R = H) (11 mg, 85%),m.p. (needles from chloroform-methanol) 128-130", [aIDl9-121" (c O . l ) , Amax. 262 ( E 8 000), 272 (11 200), 282 (11 SOO),and 294 nm (6 800) (lit.,7 m.p. 152-153", [a],l9 -109";lit.,6 m.p. 148-150", [a], -128.7" (c 0.41), hmK 262 ( E8 900), 272 (12 SOO), 282 (13 600), and 294nm (7 700)), mle398 (M+) (mass spectrum identical with that of the authenticspecimen 6 ) .The m.p. of the original specimen from yeastwas 128-130"; the m.p. we gave earlier is incorrect.3~-Acetoxy-6a-chloroergosta-7,22-dien-5a-ol(12) .-Chromylchloride (310 mg) in dry methylene chloride (4 ml) wasadded, over 2-3 min a t - 78 "C, to a deoxygenated solutionof ergosteryl acetate (438 mg) in redistilled toluene (85 ml1976under nitrogen. The mixture was stirred a t -78 "C (5min) and a saturated solution of sodium borohydride inethanol (1 ml) was added. After 15 min (-78 "C) themixture was poured into N-hydrochloric acid (150 ml) andbenzene (100 ml). The organic layer was separated,washed successively with water (100 ml) and brine solution(3 x 50 ml), dried (MgSO,), and filtered through a plug ofanhydrous sodium sulphate.Evaporation of the filtrategave the crude chlorohydrin (12) (465 mg, 95%). Re-crystallisatioii from ethyl acetate gave material (12)(320 mg, 65%), m.p. 192-193" (lit.,13 192-194"), identicalwith an authentic sample.3a-A cetoxyergosta-7,22-dien-5cc-ol ( 13) .-The crude chloro-hydrin (12) (980 mg) in dry tetrahydrofuran (100 ml) wasadded slowly to a stirred suspension of lithium aluminiumhydride (120 mg) in dry tetrahydrofuran (50 ml) a t roomtemperature under nitrogen. The mixture was refluxed(3 h) and cooled to 0 "C, and the excess of hydride destroyedwith saturated sodium sulphate solution. Filtrationthrough a plug of anhydrous sodium sulphate and evapor-ation of the filtrate gave a solid, which was treated withacetic anhydride (5 ml) and pyridine (10 ml) at 0 "C (18 h).Removal of the solvents under reduced pressure affordedthe acetate (13) (735 mg, 80%), m.p.231-233' (fromacetone) (lit.,20 230-232'1, [a]D23 &O' (c 2.0) (lit.,20 f0").3~-Acetoxyergost-7-en-5a-o1 (14) .-The diene (13) (200 mg)was shaken (4 h) with freshly prepared Adams catalyst(20 mg) in redistilled ethyl acetate (75 ml) under hydrogen(ca. 1 atm). The catalyst was removed by filtration, freshcatalyst was added, and the procedure was repeated.Filtration through a plug of anhydrous sodium sulphateand evaporation of the filtrate gave the acetate (14) (189 mg,94%), m.p.227-230' (from acetone), f15.2' (c 2.0),T 4.95 (2 H, m, 3a- and 7-H), 8.00 (3 H, s, ~P-OAC), 9.07(3 H, s, 19-H,), 9.15 (6 H, d, J 7 Hz, 26- and 27-H,), 9.22(6 H, d, J 6.5 Hz, 21- and 28-H3), and 9.44 (3 H, s, 18-H,)(Found: C, 78.45; H, 10.85. c3&5,@, requires C, 78.55;H, l l . O % ) , m/e 440 (M - H,O)+, 438, 380, 379, 336, 341,and 340.22,23-Dihydroergosteryl Acetate (3 ; R = Ac) .-Redis-tilled thionyl chloride (0.2 ml) in dry pyridine (0.5 m1) wasadded to compound (14) (100 mg) in dry pyridine (8 ml) atroom temperature under nitrogen. After 45 min thesolution was diluted to 50 ml with water and extractedwith toluene (2 x 25 ml). The combined organic layerwas wcashecl with water (2 x 25 ml) and brine (2 x 25 ml),dried (MgSO,), and evaporated.The residue afforded theacetate (3; R = Ac) (77 mg, 80%) as plates (from acetone-methanol), m.p. 140-145". A purified sample had m.p.146-148" and other constants in agreement with theliterature .6(Ergosteryl Benzoate)tricarbonyliron (15 ; R = PhCO) .-Amixture of ergosteryl benzoate (2.00 g) and pentacarbonyl-iron (10 ml) in anhydrous di-n-butyl ether (80 ml) wasrefluxed (bath temperature 155-165 "C) under a slightlypositive pressure of nitrogen for 17-20 h (u.v. control).The mixture was cooled to room temperature and filteredthrough a short bed of alumina (grade V). The blackresidue was washed several times with di-n-butyl ether toobtain a yellow solution. Evaporation at ca. 20 mmHg and60 "C afforded a yellow crystalline solid (1.99 g, 78y0), theU.V.spectrum of which showed the presence of ca. 3-5%of the starting material. It was purified by the followingprocedure.To a well stirred solution of the solid (1.99 g) in drydichloromethane (20 ml) was added dropwise 4-phenyl-1,2,4-triazoline-3,5-dione (10% in anhydrous acetone) at-78 "C, until the mixture became permanently red.Stirring was continued for 3 h at this temperature, alumina(grade V; 5.0 g) was added, the cooling bath was removed,and the solution was allowed to warm to room temperature.It was filtered and the yellow solution thus obtained wasevaporated to dryness. The residue was taken up inhexane and the solution filtered through a column ofalumina (grade V). The eluates belonging to the distinctyellow band were evaporated to yield a yellow crystallinesolid, which when recrystallised from ethyl acetate-methanol afforded bright yellow needles of (ergosterylbenzoate)lricarbonyZiron (15; R = PhCO) (1.81 g, 70%),vmx.2 040, 1965, 1715, 1600, 1585, and 975 cm-1, T1.88-2.05 (2 H, m, ArH), 2.4@-2.70 (3 H, m, ArH), 4.83(2 H, m, 22- and 23-H), 4.96 (2 H, ABq, JAB 4 Hz, 6- and7-H), 5.03br (1 H, m, 3c(-H), 7.27-8.83 (CH, envelope),and 8.93, 9.03, 9.13, 9.23, and 9.27 (Me), A,, (cyclohexane)230 nm (log E 4.42), wz/e 640 (M+), 612, 584, 556, 541, 529,500, and 378 (100%) (Found: C, 71.15; H, 7.45.C38H,,Fe05 requires C, 71.25; H, 7.65%).p-Methoxybenzy1ideneacetonetrica~bonyZiron.-To a solu-tion of p-methoxybenzylideneacetone (29 g) in toluene(100 ml) was added nonacarbonyldi-iron (29 g).After24 h at room temperature under nitrogen, the yellowsolution was warmed at 60 'C until t.1.c. showed completetransformation into the complex (ca. 4 h). The solution wascooled and chromatographed on silica gel (elution first withlight petroleum and then with mixtures progressively en-riched in ether). The red solution was concentrated undervacuum and the complex precipitated on cooling as redcrystals (8.05 g, 32%), m.p. 110-112° (decornp.) (Found:C, 53.1; H, 3.85. C,,H12Fe05 requires C, 53.2; H, 3.8%),mJe 316 (M+) 288, 260, 232, 176, and 161 (100%).Complex Formation with Arylwzethyleneacetonetricarbonyl-iron.-(i) The following procedure was used for runs 2-7in the Table. Ergosteryl acetate (0.44 g, 1 mmol) and thearylmethyleneacetone complex (4 mmol) in toluene (10 ml)were warmed at 60 or 90 "C under nitrogen during 1 6 -48 h.The cooled solution was diluted with ether, filtered,and evaporated. The residue was fractionated by p.1.c.[light petroleum-ether (9 : l)] to give a yellow oil. Crystal-lisation from methanol gave the complex (15; R = Ac),m.p. 96-95'.(ii) (with Dr. A. FERNANDEZ MATEOS) Ergosteryl benzo-ate (4.5 g , 9 mmol), p-methoxybenzylideneacetone (5.4 g,17 mmol), and nonacarbonyldi-iron (10.9 g, 30 mmol) intoluene (40 ml) were warmed to 55 "C under nitrogen for5 days. T.1.c. (4% light petroleum-ethyl acetate, 4 timesdeveloped) showed complete reaction. The solution wasfiltered and evaporated in v a c m to give an oily residue.Trituration with methanol and recrystallisation from ethylacetate gave the complex (15; R = COPh) (4.3 g, SO%),m.p.163-165', [E]~ -67.9' (c 1.20).Catalytic Hydrogenation of (Evgosteryl benzoate) tricarbonyl-iron.-(Ergosteryl benzoate) tricarbonyliron (640 mg) inAnalaR ethyl acetate (35 ml) was hydrogenated at atmos-spheric pressure and room temperature for 14 days overAdams platinum oxide (100 mg) and benzyldimethylsilane(10 drops). The resulting black solution was filteredthrough Celite and the Celite was washed with ether. Thecombined solutions were evaporated under reduced pressureto yield a yellow solid which was taken up in ethyl acetate.2O G. F. Laws, J . Clzem. Soc., 1963, 4185826 J.C.S. Perkin ITrituration with methanol afforded a mixture of 22,23-dihydroergosterol benzoate and cyclohexanecarboxylatetricarbonyliron complexes (16; R = COPh or COC,H1,,respectively) as bright yellow plates (602 mg, 94%), Y-2 040, 1 965, 1 715, 1 600, and 1 585 cm-l.To a stirred solution of the above mixture (325 mg) intetrahydrofuran (20 ml), absolute ethanol (15 ml), andwater (2 ml), was added powdered iron(m) chloride hexa-hydrate (2.5 9).After 2 h at room temperature the mixturewas refluxed over a steam-bath for 4 h and cooled to roomtemperature, and a solution of potassium hydroxide (4.5 g)in absolute ethanol (25 ml) was added. The mixture wasrefluxed for a further Q h, cooled, diluted with brine, andextracted into ether. The organic layer was washed withbrine until neutral, dried (MgSO,), and evaporated to yielda pale yellow crystalline solid which when recrystallisedfrom chloroform-methanol afforded needles of 22,23-di-hydroergosterol (3; R = H) (184 mg, 92%), m.p. 129-A portion of the above sterol was acetylated with acetic131", -131" (C 0.75).anhydride-pyridine to obtain the acetate (3; R = Ac).The benzoate was analogously obtained as plates, m.p.151-152" {from acetone-methanol), [uJDB5 -59.3' (C 0.44),T 1.90-2.05 (2 H, m, ArH), 2.40-2.70 (3 H, m, ArH), 4.60(2 H, ABq, J 6 Hz, 6- and 7-H), 5.00 (1 H, m, 3a-H), 7.43(2 H, m, 4-H), 7.60-9.00 (CH, envelope), and 9.00, 9.07,9.13, 9.17, 9.23, and 9.37 (Me) (Found: C, 83.7; H, 9.85.C,,H,,O,, requires C, 83.6 and H, 10.0%).4-Phenyl-l,2,4-triazoline-3,5-dione Adduct (1 1) of 22,23-DihydroergosteryE Benzoate.-The benzoate (1 ; R = PhCO)was treated with 4-phenyl- 1,2,4-triazoline-3,5-dione (7) asbefore4 to obtain the adduct as needles, m.p. 201-202"(from light petroleum-benzene), mixed m.p.* 201-203".We thank the Nuffield Foundation and the S.R.C. forsupport. We acknowledge a gift of ergosterol fromRoussel-Uclaf, the help of Dr. J. E. T. Corrie in the earlystages of this work, and that of Dr. A. Fernandez Mateosfor the experiment indicated.[6/1730 Received, 9th September, 1976

ISSN:1472-7781    

DOI:10.1039/P19760000821

出版商:RSC    

年代:1976

数据来源: RSC