An approach to (8,3prime;)- and (8,5prime;middot;7,3prime;)-neolignans

摘要

J. CHEM. SOC. PERKIN TRANS. I 1988 An Approach to (8,3')- and (8,5'.7,3')-Neolignans Simon V. Mortlock, Joanna K. Seckington, and Eric J. Thomas * The Dyson Perrins Laboratory, South Parks Road, Oxford, OX I 30Y The neolignan analogues (13), (14), and (17) have been prepared by treatment of the corresponding p-quinols with methanesulphonyl chloride-triethylamine in the presence of an excess of 1-(3,4-dimethoxyphenyl) propene The (8,3')-neolignans comprise a group of natural products which includes denudatins A and B (1) and (2),* mirandins B and A (3) and (4),3and the potent platelet activating factor antagonist kadsurenone (5).4 Related neolignans also include (I) Ar = 3,4-methylenedioxyphenyl (4) Ar = 3,4,5-trimethoxyphenyl (2) Ar = 3,4-dimethoxyphenyl (5) Ar = 3,4-dimethoxyphenyl (3) Ar = 3,4,5-trimethoxyphenyl the (8,5'-7,3')-group represented by liliflodione (6) and macrophyllin B (7).6The total synthesis of these neolignans is of interest because of their biological activity,' and the first synthesis of kadsurenone was recently described.8 We now report an approach to the synthesis of (8,3')- and (8,5'-7,3')-neolignans as exemplified by the synthesis of the analogues (13) and (14).This work is based upon the elegant cycloaddition strategy developed for the synthesis of (8,l')- and (8,1'*7,3')-neolignans by BUchig Thus the methyl, butyl, and phenyl p-quinols (9a-c) were prepared from 2,5-diethoxy- 1,4-benzoquinone (8) by mono-protection Me,SiCN, KCN, 18-crown-6 (18-c-6)," treat-ment with the corresponding alkyl-or aryl-lithium, and deprotection. This sequence was found to be easier than direct addition of the alkyl-lithium to the quinone l1 because of the low solubility of the quinone in ethereal solvents.Treatment of the methyl p-quinol (9a) with methanesulphonyl chloride-triethylamine in the presence of an excess of 1-(3,4-dimethoxyphenyl)propenethen gave two products which were separated and identified as the bicycloC3.2. lloctenedione (13a) and the hydrobenzofuran (14a); (13a): (14a) = 75: 25, combined yield 53. These products were identified by comparison of their spectroscopic data with those reported for denudatin B (2)8 and 0-methyl liliflodione (19)5 (see Table), and the stereochemistry shown was assigned by analogy with the work of BUchig who established that the alkene aryl substituent adopts the endu position in cyclo- additions of this type.The butyl and phenyl p-quinols (9b,c) similarly gave adducts (13b,c) and (14b,c). The formation of products (13) and (14) can be explained in terms of the cycloaddition rearrangement sequence outlined in the Scheme.* Buchi has generated 4,5-dialkoxycyclohexa- oEbo -OEt OEt (8) (9) 1.3 -shift/ (12) (13) R OR' (14) (15) Scheme. a, R = Me; b, R = Bu; c, R = Ph; Ar = 3,4-dimethoxyphenyl * The detailed mechanisms of these reactions were not investigated. Other possible mechanisms include the formation of the hydrobenzo- furan (14) by direct addition of cation (10) to the alkene to give the intermediate (12) without participation of (11).2306 J. CHEM. SOC. PERKIN TRANS. I 1988 Table. Selected 'H n.m.r. data (6) of adducts (13a), (14a), 0-methyl-liliflodione (19), and denudatin B (2); Ar = 3,4-dimethoxyphenyl OEt 1.16 (3 H, d, J 7 Hz, CHCH,) 2.63 (1 H, m, 6-H) 3.18 (1 H, dd, J 6, 7.5 Hz, 7-H) 3.73 (1 H, d, J 7 Hz, 1-H) 3.84 (6 H, s, 2 x OCH,) 6.53 (2 H, m, ArH) 6.76 (1 H, d, J 7 Hz, ArH) 7.35 (1 H, narrow m, 4-H) (144 1.13 (3 H, d, J 7 Hz, CHCH,) 2.2 1 (1 H, m, 9-H) 3.9 (6 H, s, 2 x OCH,) 5.38 (1 H, d, J 10 Hz, 8-H) 5.78 (1 H, S, 5-H) 6.35 (1 H, br s, 2-H) 6.7-6.9 (3 H, m, ArH) dienone cations (15) and trapped them by cycloaddition to electron-rich alkenes.' The present work extends this approach to include 4-alkyl substituted cyclohexadienone cations, and shows that these can be generated and trapped without interference from competing dienone-phenol rearrangements. Finally, the monomethoxy quinol(l6) was used as a substrate for the cycloaddition.Treatment of this quinol ' with methanesulphonyl chloride-triethylamine in the presence of an excess of 1-(3,4-dimethoxyphenyl)propenegave a modest yield of the aromatic adduct (17). The formation of this product is explained by loss of a proton from the intermediate cation (18). Experimental 1.r. spectra were recorded on a Perkin-Elmer 257 spectrometer, and 'H n.m.r. spectra on a Bruker WH-300 spectrometer using solutions in chloroform and 2Hchloroform, respectively.M.p.s were determined on a Biichi 510 apparatus, and mass 1.18 (3 H, d, J 7 Hz, CHCH,) 2.48-2.8 (1 H, m, 6-H) 3.2 (1 H, dd, J 5, 7.5 Hz, 7-H) 3.76 (1 H, d, J 7.5 Hz, 1-H) 3.84 (6 H, s, 2 x OCH,) 6.5-6.64 (2 H, m, ArH) 6.78 (1 H, d, J 8 Hz, ArH) 7.32 (1 H, br s, 4-H) 7 (2) 1.15 (3 H, d, J 7 Hz, CHCH,) 2.21 (1 H, m, 9-H) 3.92 (6 H, s, 2 x OCH,) 5.38 (1 H, d, J 9.5 Hz, 8-(H) 5.86 (1 H, S, 5-H) 6.30 (1 H, t, J 1.5 Hz, 2-H) 6.83-6.92 (3 H, m, ArH) spectra were measured on V.G. Micromass 16F and ZAB-1F spectrometers. Flash chromatography used Merck silica 60. All solvents were dried and distilled before use.Ether refers to diethyl ether; light petroleum to the fraction b.p. 40-60 "C. The potassium cyanide-1 8-c-6 complex was prepared by dissolving potassium cyanide (0.15 g, 2.3 mmol) and 18-c-6 (0.6 g, 2.3 mmol) in methanol (20 ml). In all reactions requiring this catalyst, the volume of the stock solution containing the required amount of catalyst was added to the reaction vessel and the methanol removed under reduced pressure. Preparation of p-Quinols (9).-2,5-Diethoxy-4-hydroxy-4-methylcyclohexa-2,5-dienone(9a).2,5-Diethoxy- 1,4- benzoquin- one (1 g, 5.1 mmol) and anhydrous tetrahydrofuran (THF) (50 ml) were added to KCN-18-c-6 (16 mg, 0.05 mmol), fol- lowed dropwise at 0 "C by trimethylsilyl cyanide (0.81 ml, 5.1 mmol). After being stirred for 1 h at OOC, the solution was cooled to -78 OC, and methyl-lithium (1.5~solution in ether; 4 ml, 6.12 mmol) was added, and the mixture stirred at -78 "C for 4 h before being allowed to warm to room temperature and quenched (excess of saturated aqueous NH4C1).The mixture was extracted with ether and the extract concentrated under reduced pressure to give a dark orange solid which was purified by flash chromatography using light petroleum-ethyl acetate (4 : 1) as eluant to give l-cyano-2,5-diethoxy-4-hydroxy-4-methyl-l-trimethylsilyloxycyclohexa-2,5-diene(0.66 g, 41). To this dissolved in anhydrous THF (25 ml) was added at 0 "C an anhydrous 1M solution of tetrabutylammonium fluoride in THF (2.5 ml, 2.5 mmol). After 2 h, the mixture was extracted with dichloromethane, and the extract concentrated under reduced pressure; flash chromatography of the residue using light petroleum-ethyl acetate (1:2) as eluant gave the title compound (9a) (0.29 g, 65) as a crystalline solid, m.p.119-121 "C (from ether) (Found: C, 62.3; H, 7.7. C, 1H1604 requires J. CHEM. SOC. PERKIN TRANS. I 1988 C, 62.25;H, 7.6); v,,,, 3 600, 3 300, 1675, 1650, and 1610 cm-'; 6, 1.40and 1.42(each 3 H, t, J 7 Hz, CH,CH,), 1.53(3 H, s, CH,), 2.65(1 H, br s, OH), 3.82 (2 H, m, CH,CH,), 3.98 (2H, q, J 7 Hz, CH,CH,), and 5.45and 5.53(each 1 H,s, vinylic H);m/z 212 (M', 573, 197(M+ -15,50), 195 (M+ -17,4573, 169(M+ -43,3579,and 141 (M+ -71,100). The butyl p-quinol (9b) was similarly prepared from 2,5-diethoxy- 1,4-benzoquinone using butyl-lithium.Recrystal-lisation from ether gave 4-butyl-2,5-diethoxy-4-hydroxycyclo-he.uu-2,5-dienone(9b),as white needles, m.p. 97-99 "C (Found: C, 66.2;H, 8.85.C14H2204 requires C, 66.1;H, 8.7);v,,,, 3 600,3430,l670,l 650, and 1 610cm-'; 6,0.85 (3 H, t, J7Hz, CH,), 1 .0 and 1.1 7(each 1 H, m, HCH), 1.25 (2 H, m, CH,), 1.42 and 1.43(each 3 H, t, J7 Hz, CH,), 1.75and 1.94(each 1 H, m, HCH), 2.4(I H, br s, OH), 3.85 (2 H, q,J7.5Hz, OCH,CH,), 3.98(2H. m, OCH,CH,), and 5.45and 5.52(each 1 H, s, vinylic H); mjr 254 (M+,573, 197 (M+ -57, 7573, 169 (Mt -85, 60",), and 141 (M+ -113,100). The phenyl p-quinol (9c) was similarly prepared from 2,5-diethoxy-1 .4-benzoquinone using phenyl-lithium. Recrystal-lisation from ether gave 2,5-diethoxy-4-hydroxy-4-phenylcyclo-h~.xtr-2,5-dIenone(Sc), as white needles, m.p.125-1 27 "C (Found: C. 69.9;H, 6.65.C16H1804requires C, 70.1;H, 6.6); v,,, 3 700,3 570, 1 670,l 650, and 1 615cm-'; 6, 1.28and 1.38 (each 3 H. t. J 7.5 Hz, CH,CH,), 3.22(1 H, br s, OH), 3.77and 3.97(each 2 H, m, CH,CH,), 5.53and 5.67(each 1 H, s, vinylic H), and 7.25--7.45(5 H, m,ArH); m/z 274 (M+,15), 245 (Mi-29,92"/,),and 105(M' -169,100). Cl,ck,udtlitions.-Methanesulphonyl chloride (22 p1, 0.29 mmol) was added to a cooled solution (0deg;C) of the methyl p-quinol (9a) (50 mg, 0.24mmol) in dichloromethane (0.5ml) containing triethylamine (0.36mmol) and 1 -(3,4-dimethoxy-pheny1)propene (0.2ml, 1.2mmol), and the mixture stirred for 5 h at 0deg;C and then at room temperature for 17 h; it was then quenched by addition of water.The products were extracted into dichloromethane, and the extracts washed with aqueous Na2C03, water, and brine, before being dried (MgSO,), and concentrated under reduced pressure to leave an oil. Flash chromatography using light petroleum-thy1 acetate as eluant gave first 8-(3,4-dimethoxyphenyl)-1-ethoxy-3,9-dimethyl-7-o uabicyclo4.3.0nona-2,5-dien-4-one(14a) (12mg, 15); v,,,. 1 745, 1675, 1 650,and 1635 cm-'; 6, 1.13 (3 H, d, J 7 Hz, CHCH,), 1.1 5 (3 H, t, J 7 Hz, CH,CH,), 2.0(3 H, d, J 0.5 Hz, CCH,), 2.16(1 H,m,9-H), 3.3(2H, q, J7.5Hz, OCH,CH,), 3.9 (6 H, s, 2 x OCH,), 5.38(1 H, d, J 10Hz, 8-H), 5.78(1 H, s, 5-H), 6.35( 1 H,br s, 2-H), and 6.7-6.9 (3 H, m, ArH); mi-.344 (M', 100)J.Secondly, 7-(3,4-dimethoxyphenyl)-5-ethoxy-3,6-~imeth~~lbic~~~c~lo3.2.loct-3-ene-2,8-dione(13a) (33 mg, 41) was eluted. m.p. 90-92 "C (from ethyl acetate) (Found: C, 69.9; H, 7.25.CzoH2,0, requires C, 69.75;H, 7.0); vmaX,1 775 and 1 690cm ': 6,, 1.16(3 H, d, J7Hz, CHCH,), 1.33(3 H, t, J7Hz, CH,CH3), 1.82(3 H, d, J0.5Hz, CCH,), 2.63(1 H, m, 6-H), 3.18 (1 H, dd, J6, 7.5Hz, 7-H), 3.72 (1 H, m, HCH), 3.73(1 H, d, J7 Hz, 1-H),3.84(6H, s, 2 x OCH,), 4.12(1 H, m, HCH), 6.53 (2 H, m, ArH), 6.76(1 H, d, J 7 Hz, ArH), and 7.35(1 H, narrow m, 4-H);mnir 344 (M+,4573 and 178 (M' -166,100). Similar treatment of the butyl and phenyl p-quinols (9b,c) gave mixtures of the corresponding adducts (13) and (14) (35-40"/,),identified by spectroscopic comparison with (13a) and 2307 (14a); (13b):(14b) = 5:1; (13c):(14c) = 3:1 ('H n.m.r.).Repeated chromatography of these mixtures gave samples of the major adducts. 3-Butyl-7-(3,4-dimethoxyphenyl)-5-ethoxy-6-methylbicyclo3.2.loct-3-ene-2,8-dione(13b) so obtained was an oil, v,,,. 1 770,1 680,and 1 520cm-'; 6,0.93 (3 H, t, J 7 Hz, CH,CH,), 1.23 (3 H, d, J 7 Hz, CHCH,), 1.2--1.6 (4 H, m, CH,CH,), 1.39(3 H, t, J7Hz, CH,CH,), 2.2 (2 H, m, CH,), 2.68 (1 H, m, 6-H), 3.25(1 H, dd, J 5,7.5Hz, 7-H), 3.75(1 H, m, HCH),3.8(1 H,d,J7SHz, l-H),3.92(6H,s,2x OCH,),4.15(1 H, m, HCH), 6.5-6.9 (3 H, m, ArH), and 6.93(1 H, br s, 4-H); m/z 386 (M+, 40), 191 (M+ -195, 800/;), and 178 (M+ -208, 100).7-(3,4-Dimethoxyphenyl)-5-ethoxy-6-methyl-3-phenylbicyclo3.2.loct-3-ene-2,8-dione(13c) had v,,,. 1767, 1714, 1685, and 1520 cm-'; 6, 1.23(3 H, d, J 7 Hz, CHCH,), 1.38(3 H, t, J 7 Hz, CH,CH,), 2.82(1 H, m, 6-H), 3.32 (1 H, dd, J5,7Hz, 7-H), 3.72and 3.85(each 3 H, s, OCH,), 3.82 (1 H, m, HCH), 3.89(1 H,d, J7 Hz, 1-H), 4.21(1 H, m, HCH), 6.6-6.8 (3H, m, ArH), 7.15-7.4 (5 H, m, ArH), and 7.68(1 H, s, 4-H); m/z407 (M' + 1). Following a similar procedure the monomet hoxy p-quinol (16) (232 mg, 1.5 mmol) gave a single product after flash chromatography (light petroleum+thyl acetate, 10:1 as eluant) identified as 2-(3,4-dimethoxyphenyl)-6-metho~x~~-3,5-dimethgl-2,3-dihydrobenzobfuran (17) (70mg, 15), m.p. 137-139 "C (from ether-hexane) (Found: C, 72.4;H, 7.15.CI9H2,O4 requires C, 72.6;H, 7.05);v,,,.1 620,1 600,1 262,1 160,1 140, and 1 027 cm-'; 6, 1.38(3 H,d, J 7 Hz, CHCH,), 2.19(3 H, s, Ar-CH,), 3.4(1 H, m,3-H), 3.83, 3.88, and 3.89(each 3 H, s, OCH,), 5.07(1 H, d, J8 Hz, 2-H), 6.48(1 H, s, ArH), and 6.8-7.0(4 H, m, ArH); m/z314 (M+,100). Acknowledgements We thank the S.E.R.C. for support (for S. V. M.), Dr. A. E. Derome and Mrs. McGuinness for 'H n.m.r. spectra, Dr. R. T. Aplin for mass spectra, and Dr. G. Kneen for drawing our attention to this problem. References 1 D. A. Whiting, Nut. Prod. Rep., 1985, 2, 191. 2 J. Iida, K. Ichino, and K. Ito, Phytochemistry, 1982, 21, 2939. 3 C. J. Aiba, 0.R. Gottlieb, F. M. Pagliosa, M. Yoshida, and M. T. Magalhaes, Phytochemistry, 1977, 16, 745. 4 T. Y. Shen, S.-B. Hwang, M. N. Chang, T. W. Doebber, M.-H. T. Lam, J. S. Wu, X. Wang, C. Q. Han, and R. Z. Li, Proc. Natl. Acad. Sci.,U.S.A., 1985, 82, 672. 5 J. Iida and K. Ito, Phytochemistry, 1983, 22, 763. 6 R. B. Filho, R. Figlinolo, and 0.R. Gottlieb, Phj~tochemistry,1980, 19, 659. 7 R. S. Ward, Chem. Soc. Rev.,1982, 11, 75. 8 M. M. Ponpipom, B. Z. Yue, R. L. Bugianesi, D. R. Brooker, M. N. Chang, and T. Y. Shen, Tetrahedron Lett., 1986, 27,309. 9 G. Buchi and C.-P. Mak, J. Am.Chem. Soc., 1977,99,8073; G. Buchi and P.-S. Chu, J.Org. Chem., 1978,43,3717;G. Buchi and P.-S.Chu, J. Am. Chem. Soc., 1981, 103,2718. 10 A. J. Guildford and R. W. Turner, Synthesis, 1982, 46. 11 A. Fischer and G. N. Henderson, Tetrahedron Lett., 1980, 21, 701. 12 D. Liotta, M. Saindane,and C. Barnum, J. Org. Chem., 1981,46,3369. Received 21st January 1988; Paper 8/00237A