J. CHEM. SOC. PERKIN TRANS. I 1988 Total Synthesis of Aaptamine of Potent a-Blocking Activity via Thermal Cyclization of 1-Azahexatriene Systems Satoshi Hibino," Eiichi Sugino, Tominari Choshi, and Kohichi Sat0 Faculty of Pharmacy and Pharmaceutical Sciences, Fuku yama University, 985 Higashimura, Fuku yama, Hiroshima 729-02, Japan The total synthesis of the marine alkaloid aaptamine (I),1H-benzode1,6naphthyridine, has been completed, based on the thermal cyclization of the 1-azahexatriene system, the key intermediate for the construction of the isoquinoline moiety. 5-Nitroveratraldehyde (7) is converted, via a Wittig reaction, into the nitrostyrene (8). Reduction of (8) to the aniline (9) and subsequent treatment of (9) with ethyl 2-formylacetate gives the enamino ester (10).Preparation of the quinolone nucleus is achieved by heating compound (10) in diphenyl ether, which affords the N-benzylquinolone (12)along with the quinoline (13). Treatment of an inseparable mixture of (12) and (13) with hydroxylamine gives the debenzylated quinolone oxime (II), methylation of which affords a separable mixture of the N,O-dimethyl quinolones (14)and (15).The methyloxime (14) (the 1-azahexatriene system) when heated in o-dichlorobenzene gives the unnatural 1-methylaaptamine (3). In a similar way, benzylation of (15) affords the N,O-dibenzyl quinolone derivatives (16) and (17). The benzyloxime (16) when heated in o-dichlorobenzene affords N-benzylaaptamine (18).Subsequent cleavage of the N-benzyl protecting group with concentrated hydrochloric acid gives aaptamine hydrochloride (1). Aaptamine (l), demethylaaptamine (2), and demethyl(oxy)- aaptamine (4) isolated from the Okinawan sea sponge Auptos uuptos are of interest because of their remarkable pharma- cological properties and for the novel lH-benzode1,6-naphthyridine ring system.' We were interested in the total synthesis of this unique heterocyclic natural product (1).To (11 R' = Me. R2= H (2) R' = R2= H (31 R' = R2 = Me date, four synthetic efforts have been reported by Cava,2 Kelly,3 Yamanaka,4 and Tollari.' The total synthesis of aaptamine (1) by Kelly involved using a Pomeranz-Fritsch-type reaction for the construction of the isoquinoline moiety. The other three groups have established the total synthesis of (1) via the construction of the quinoline part. We have developed the synthesis of condensed hetero-aromatics based on the thermal cyclization of intramolecular hexa- 1,3,5-triene '7' or monoazahexa-1,3,5-trienesystems.' We now describe the total synthesis of aaptamine (1) via the construction of the isoquinoline nucleus using this methodology.As shown in retrosynthetic pathway (Scheme l), the o-iminostyrene-type intermediate (5) derived from the breakage of the 4, 5-bond of (l), that is 1-azahexatriene system, was envisaged as the key intermediate in this synthesis. We also considered that the R substituents (OH, OMe, OCH,Ph) attached to the nitrogen of o-iminostyrene intermediate (5) would contribute to the stability of the intermediate and would act as a good leaving group thus facilitating the final aromatization.Initially we aimed at deriving the intermediate (5) and its precursor (6) from 5-nitroveratraldehyde (7).9 For the Me0 bsol; HNamp; (11U (5) R :OH, OMe,0CH2 Ph Scheme 1. Me0 bsol;"eooR' R2 (7) R' = CHO, R2 = NO2 (8) R' = CH=CH2,R2 = NO, (9) R' = CH=CH,, R2 = NH, (10) R' = CH=CH2,R2 = NHCH=CHCO,Et synthesis of quinolone ring system (6), the readily available 5-nitroveratraldehyde (7) was treated with methylenetriphenyl- phosphorane to give the nitrostyrene (8) (70). Reduction of compound (8) with sodium dithionite in aqueous methanol provided the aminostyrene (9) in 42 yield. This product was treated with ethyl 2-formylacetate" in ethanol at room temperature to give the enamino ester (10) (62).Subsequent cyclization of (10) in diphenyl ether at reflux, for 40 min afforded the appropriate quinolone ring system (6) in 30 yield. The conversion of quinolone (6) into the oxime intermediate (11) was unsuccessful. No products could be 2430 J. CHEM. SOC. PERKIN TRANS. I 1988 1121 (13) (111 Scheme 2. Scheme 3. detected, and a near quantitative amount of the starting material was recovered. It was assumed that the failure to obtain oxime (11) under the various conditions used was a result of the vinylogous amide. The protection of the nitrogen function in the quinolone (6) with benzyl bromide and sodium hydride in dimethylformamide gave an inseparable mixture of the N- benzylquinolone (12) and the quinoline (13) (1: 1).When the mixture of (12) and (13) was refluxed with hydroxylamine hydrochloride and sodium acetate for 1 h in ethanol, the debenzylated quinolone oxime (1 1) was obtained in 33 yield from (6) (Scheme 2). Subsequent thermal cyclization of the quinolone oxime (1 1) was unsuccessful in various solvents such as xylene and o-dichlorobenzene. It seems to us that the failure of the thermal cyclization is a result of the tautomerism between the quinolone and quinoline forms. Our attention was then turned to the alkylation of quinolone oxime (1 1) in order to prevent the aromatization of quinolone (11) and to investigate the final cyclization process.Methylation of (14) with methyl iodide and sodium hydride in dimethyl- formamide gave the N-methylated quinolone methyloxime (14) (19) along with the quinoline (15) (41). Compound (14) was then heated to 180 "C in o-dichlorobenzene to afford l-methyl- aaptamine (3) in 73 yield. Similarly, benzylation of (14) with benzyl bromide and sodium hydride in dimethylformamide gave the N-benzylated quinolone benzyloxime (16) (13) and the unexpected quinoline (17) (21). Thermal cyclization of the 1 -azahexatriene intermediate (16) afforded the aaptamine derivative (18) in 67 yield. Finally, treatment of (18) with concentrated hydrochloric acid at reflux provided aaptamine hydrochloride (1) in 90 yield, which was identified by direct comparison with an authentic sample. Experimental Melting points were determined with a Yanagimoto micro melting point apparatus and are uncorrected.Infrared spectra were measured with a Shimadzu IR-408 spectrometer. Proton nuclear magnetic resonance spectra were taken with JEOL PMX-60 and JEOL JNM-GX 400 instruments with SiMe, as an internal standard unless otherwise stated. Mass spectra and high-resolution mass spectra (ei) were recorded on Shimadzu GC-MS 6020 and Hitachi M-80 spectrometers, respectively. Silica gel (60-100 mesh, Merck Art 7734) and Iatrobeads (Iatron Chem. Prod.) were used for column chromatography. 3,4-Dimethoxy-5-nitrosfyre~e@).-A solution of BuLi 1.56~ in hexane; (38.5 ml, 60.5 mmol) was added to a stirred sus- pension of methyl triphenylphosphonium bromide (21.7 g, 60.5 mmol) and anhydrous THF (100 ml) at 0 "C under N,.After the ylide had been formed (ca. 30 min), a solution of the aldehyde (7) (10.6 g, 50.4 mmol) in anhydrous THF (100 ml) was added dropwise under the same conditions. The stirring was continued for 14 h at room temperature whereupon it was worked up with water and extracted with benzene. The benzene layer was washed with brine, dried (Na,SO,), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; 150 g) with 1 EtOAc-hexane as the eluant to give the styrene (8) (7.4 g, 70), m.p. 54-56 "C (EtOH) (Found: C, 57.4; H, 5.35; N, 6.8. C,,H,,NO, requires C, 57.41; H, 5.30; N, 6.70); v,,,,(KBr) 1 530 and 1335 cm-' (NO,); 6,(60 MHz; CDC1,) 3.90 (6 H, s, OMe x 2), 5.23 (1 H, d, J 10 Hz, vinyl-H), 5.58 (1 H, d, J 17Hz, vinyl-H), 6.52 (1 H, dd, J 10 and 17 Hz, vinyl-H), 7.00 (1 H, d, J 2 Hz, 2-H), and 7.17 (1 H, d, J 2 Hz, 6-H); m/z 209 (Mf).3-Amino-4,5-dimefhoxyst~re~e(9).-A solution of Na,S,O, (41 g, 235 mmol) in aqueous MeOH (200 ml; 1 : 1) was added to a solution of the nitro compound (8) (7.07 g, 33.8 mmol) in MeOH (50 ml) and the reaction was stirred for 10 min. After the solvent had been removed, brine (200 ml) was added. This mixture was extracted with CHCl, (200 ml x 3). The combined CHCl, layers were washed with brine, dried (Na,SO,), and evaporated to dryness. The residue was distilled to give amine J.CHEM. SOC. PERKIN TRANS. I 1988 (9), b.p. 125 OC/1Torr (2.52g, 42) (Found: C, 67.05;H, 7.2; N, 7.2. Cl,H13N0, requires C, 67.02;H, 7.31;N, 7.82);6,(60 MHz; CDCl,) 3.73(3H, s, OMe), 3.77 (3 H, s, OMe),5.07(1H, dd, J 11 and 2 Hz, vinyl-H), 5.48 (1 H, dd, J 17 and 2 Hz, vinyl-H), 6.03 (2 H, br s, 2-and 6-H), and 6.47(1H, dd, J 17 and 11 Hz, vinyl-H); m/z179(M'). (Z)-Ethyl3-(2,3-Dimethoxy-5-ethenylanilino)acrylate(lo).-A solution of the aniline (9) (1.9g, 10.6 mmol) and ethyl 2-formylacetate (1.5g, 13.1 mmol) was stirred at room temp- erature for 14h under N,. After the solvent had been removed, the crude material was recrystallized from EtOH to give the enamino ester (10) (1.8g, 62), m.p. 92-93 "C (Found: C, 65.15;H, 7.0;N, 5.05.C15H19N04 requires C, 64.96;H, 6.91; N, 5.05);v,,,.(KBr) 1720 cm-' (ester); 6,(60 MHz; CDCl,) 1.28(3H, t, J 7 Hz, OCH,Me), 3.83 (6 H, s, OMe x 2),4.10 (2 H, q, J 7 Hz, OCH,Me), 4.72(1 H, d, J 8 Hz, CHXHCO), 5.10(I H, d, J 10 Hz, vinyl-H), 5.48 (1 H, d, J 18 Hz, vinyl-H), 6.28-6.57 (3 H, m, CHXHCO, ArH x 2),and 7.12(1 H, dd, J 18and 10Hz, vinyl-H); m/z 277 (M+). 5-Ethenyl-7,8-dimethoxy-4-quinolone(6).-A solution of the enamino ester (10) (1.5g, 0.545mmol) in diphenyl ether (15ml) was added to boiling diphenyl ether (30ml) and the solution was refluxed for 40min under N,.After the solvent had been removed, the residue was purified by column chromatography (silica gel; 100 g) with 3 MeOH-CHCl, as the eluant to give the quinolone (6) (0.63g, 30), m.p.176-178.5 "C (EtOH- Et,O) (Found: 67.8;H, 5.75;N, 6.2.Cl,Hl,NO, requires C, 67.52;H, 5.67;N, 6.06); 6,(60 MHz; CDCl,) 3.93 (3 H, s, OMe), 3.98 (3 H, s, OMe), 5.23 (1 H, dd, J 8 and 2 Hz, vinyl-H), 5.47 (1 H, dd, J 15 and 2 Hz, vinyl-H), 6.17(1 H, d, J 7 Hz, 3-H), 6.97 (1 H, s, 6-H), 7.62(1 H, br m, 2-H), 8.25 (1H, dd, J 15 and 8Hz, vinyl-H), 10.22(1H, br s, exchangeable with D,O, NH); m/z231 (M'). 1-Benzyl-5-ethenyl-7,8-dimethoxy-4-quinolone(12) and 4-Benzyloxy- 5-ethenyl- 7,8-dimethoxyquinoline (1 3).-A solution of the quinolone (6) (140g, 0.609mmol) in dimethylformamide (DMF) (2 ml) was added to a solution of NaH (60 dispersion in oil; 30 mg, 0.75mmol) in DMF (1 ml) at room temperature under N,. The reaction was stirred for 0.5h when a solution of benzyl bromide (130mg, 0.76mmol) in DMF (2ml) was added dropwise.The reaction mixture was stirred for 2 h, worked up with brine (SO ml), and extracted with CHCl, (50ml x 3).The combined CHCl, layers were washed with brine, dried (Na,SO,), and evaporated under reduced pressure. The residue was separated by column chromatography (silica gel; 40g) with EtOAc-benzene (2: 3) as the eluant to give an inseparable 1 : 1 mixture of 1-benzylquinolone (12) and quinoline (13) (30mg,65.5"/,),which was used in the next reaction. 5-Ethenyl-7,8-dimethoxy-4-quinoloneOxime (1l).-A stirred solution of a 1 : 1 mixture of the quinolones (12) and (13) (30mg), hydroxylamine hydrochloride (150mg, 2.2mmol) and NaOAc (1 80 mg, 2.2 mmol) in EtOH (5ml) was refluxed for 1 h.After the solvent had been removed the residue was purified by column chromatography (silica gel; 15 g) with 2 MeOH-CHC1, as the eluant to give the oxime (11) C54.3mg; 33 from (6),m.p. 168-1 70 "C (decomp.) (benzene) (Found: C, 63.15; H, 5.9; N, 11.4.C,,H,,N,O, requires C, 63.40;H, 5.73;N, 11.38); 6,(60 MHz; CDCI,) 3.87 (3 H, s, OMe), 3.92 (3 H, s, OMe), 5.15(1H, dd, J 10and 2 Hz, vinyl-H), 5.40(1H, dd, J 18 and 2 Hz, vinyl-H), 6.33 (1 H, d, J8 Hz, 3-H), 6.77 (1 H, s, 6-H), 6.87 (1 H, d, J8 Hz, 2-H), and 7.63(1 H, dd, J 18 and 10 Hz, vinyl-H); mi= 246 (M'). 5-Ethenyl-7,8-dimethoxy-1-methyl-4-quinolone O-Methyl- 2431 oxime (14) and 5-Ethenyl-7,8-dimethoxy-4-methoxy(methyl)-aminoquinoline (15).-A solution of the oxime (11) (70mg, 0.285 mmol) in DMF (2ml) was added to a mixture of NaH (60 dispersion in oil; 25 mg, 0.625mmol) and DMF (2ml) with ice cooling.The reaction was stirred for 0.5h, whereupon a solution of CH,I (90mg, 0.643 mmol) in DMF (1 ml) was added. Stirring was continued for 1 h at room temperature and worked up with brine (50ml), which was extracted with CHCl, (50ml x 3). The CHCl, layer was washed with brine, dried (Na,SO,), and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel; 25 g) with 5 EtOAc-hexane as the eluant to give the faster-moving oxime ether (14) (14.8mg, 19) and then with 20 EtOAc-hexane as the eluant to give the slower-moving quinoline (15) (32mg, 41).Compound (14) had m.p.58-61 "C (hexane) (Found: C, 65.25;H, 6.7;N, 10.35.Cl,H18N,0, requires C, 65.07;H, 6.61; N, 10.21); 6,(60 MHz; CDCl,) 3.63(3 H, s, NMe), 3.73(3H, s, OMe), 3.93 (6 H, s, OMe x 2), 5.10 (1 H, dd, J 10 and 2 Hz, vinyl-H), 5.35(1 H, dd, J 17 and 2 Hz, vinyl-H), 6.17(1 H, d, J 8Hz, 3-H), 6.45(1H, d, J8 Hz, 2-H), 6.87(1H, s, 8-H), and 7.67 (1 H, dd, J 17 and 10Hz, vinyl-H); m/z274 (M'). Compound (15) had m.p. 108-1 10"C (Et,O-hexane) (Found: C, 65.3;H, 6.8;N, 10.1.C15H18N203requires C, 65.07; H, 6.61;N, 10.21); 6,(60 MHz; CDCl,) 2.83 (3 H, s, NMe),3.67(3H, s, NMe), 4.02(3H, s, OMe), 4.07(3H, s, OMe), 5.23(1 H, dd, J 10and 2 Hz, vinyl-H), 5.52(1 H, dd, J 18 and 2 Hz, vinyl-H), 7.28(1 H,s, 6-H), 7.33(1H,d, J5 Hz, 3-H), 7.77(1 H, dd, J 18 and 10Hz, vinyl-H), and 8.73 (1 H, d, J 5 Hz, 2-H); m/z274 (M'). 8,9-Dimethoxy-1-methylbenzode 1,6)naphthyridine (1-Methyluaptamine)(3).-A mixture of the 0-methyloxime (14) (10mg, 0.036mmol) and o-dichlorobenzene (5 ml) was refluxed for 2 h.After the solvent had been removed, the residue was purified by column chromatography (silica gel; 10g) with 3 MeOH-CHCl, as the eluant to give 1-methylaaptamine (3) (5.8 mg, 73), m.p. 186deg;C (decomp.) (EtOH-Et,O) (Found: M', 242.1052.C14H14N,0, requires M, 242.1054); 6,(400 MHz; CDCl,) 3.76 (3 H, s, NMe), 3.97 (3 H, s, OMe), 3.98(3 H, s, OMe),6.33 (1 H,d, J7.56Hz, 3-H), 6.91(1 H,d, J7.08Hz, 6-H), 7.18(1H,s,7-H), 7.48(1H,d, J7.08Hz, 5-H),and 7.81 (1H,d, J 7.56Hz, 2-H); m/z242 (M').1-Benzyl-5-ethenyl-7,8-dimethoxy-4-guinolone 0-Benzyl-oxime (16) and 4-Benzyl(benzyloxy)amino-5-ethenyl-7,8-dimethoxyquinoline(17).-A solution of the oxime (11) (220mg, 0.9mmol) in DMF (10ml) was added to a suspension of NaH (60 dispersion in oil; 80 mg, 2 mmol) and DMF (10ml). The reaction was stirred for 0.5 h at room temperature, whereupon a solution of benzyl bromide (350mg, 2.05 mmol) in DMF (10ml) was added. The mixture was stirred for a further 1 h, then was worked up with brine (50ml) and extracted with CHCl, (SO ml x 3).The CHCl, layer was washed with brine, dried (Na,SO,) and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel; 70 g) with benzene as the eluant to give the faster-moving quinolone benzyloxime (16) (50.2mg, 13) and then with 5 EtOAc-benzene as the eluant to give the slower-moving quinoline (17) (84.2mg, 21).Compound (16) was an oily product (Found: M', 426.1942. C,7H,,N,0, requires M, 426.1942); 6,(60 MHz; CDCI,) 3.43 (3H, s, OMe), 3.80(3H, s, OMe), 4.87-5.40 (2H, m, vinyl-H), 5.10(2H,s,NCHPh),5.17(2 H,s,NOCH,Ph), 6.30(1H,d, J8 Hz, 3-H), 6.53 (1 H, d, J8Hz, 2-H), 6.70 (1 H, s, 6-H), and 6.97-7.63(11 H, m, Ph x 2 and vinyl-H); m/z 426 (M'). Compound (17) had m.p. 94-96 "C (Et,O-hexane) (Found: C, 76.15;H, 6.23;N, 6.33.C,,H,,N,O, requires C, 76.03;H, 6.15; N, 6.57); 6,(60 MHz; CDCl,) 4.02 (3 H, s, OMe), 4.07 (3 H, s, OMe), 4.68 (2 H, s, NOCH,Ph), 5.17 (1 H, dd, J 10 and 2 Hz, vinyl-H), 5.53 (1 H, dd, J 17 and 2 Hz, vinyl-H), 7.1k7.27 (12 H, m, Ph x 2,3-H and 6-H), 7.73 (1 H, dd, J 17 and 10 Hz, vinyl-H), and 8.63 (1 H, d, J 5 Hz, 2-H); m/z 426 (M').1-Benzyl-8,9-dimethoxyde1,6naphthyridine (1 -Benzyl- aaptamine) (18).-A solution of the quinolone benzyloxime (16) (20 mg, 0.047 mmol) and o-dichlorobenzene (5 ml) was refluxed for 2 h. After the solvent had been removed, the residue was purified by column chromatography (silica gel; 30 g) with 3 MeOH-CHCl, as the eluant to give l-benzylaaptamine (18) (9.7 mg, 67), m.p. 167-169 "C (Et,O) (Found: M', 318.1372. C,,H,,N,O, requires M, 318.1367); 6,400 MHz; (CD,),SO 3.52 (3 H, s, OMe), 3.92 (3 H, s, OMe), 5.59 (2 H, s, CH,Ph), 6.41 (1 H, d, J6.96 Hz, 3-H), 6.97 (1 H, d, J6.59 Hz, 6-H), 7.15-7.36 (6 H, m, Ph and 7-H), 7.57 (1 H, d, J 6.59 Hz, 5-H), and 7.92 (1 H, d, J 6.96 Hz, 2-H); m/z 318 (M').Aaptamine Hydrochloride (l).-A solution of 1-benzyl-aaptamine (18) (9 mg, 0.028 mmol) in concentrated HCl was refluxed for 2 h. After the solvent had been removed, the residue was purified by column chromatography (Iatrobeads, 10 g), with 4 MeOH-CHCl, as the eluant, to give aaptamine hydrochloride (1) (3.9 mg, 61), m.p. 105-107deg;C (MeOH-acetone) (lit.,' 105-106 "C) Found: (M' -HCI), 228.6893 C,3H12N202 requires (M -HCl), 228.68971; 6,400 MHz; (CD,),SO 3.82 (3 H, s, OMe), 3.99 (3 H, s, OMe), 6.44 (1 H, d, J6.96H~,3-H),6.89(1H,d, J7.33 Hz,6-H), 7.13 (1 H,s, 7-H), 7.43 (1 H, d, J 7.33 Hz, 5-H), and 7.85 (1 H, d, J 6.96 Hz, 2-H); m/z 228 (M' -HCl).Acknowledgements We wish to thank Professor Hiroshi Yamanaka, Pharmaceutical Institute, Tohuku University, for sending us a sample of synthetic aaptamine hydrochloride. We also thank Mr. Hideaki J. CHEM. SOC. PERKIN TRANS. I 1988 Kondo, Department of Analytical Chemistry, Research Centre, Taisho Pharmaceutical Co. Ltd., and Professor Takushi Kurihara, Osaka Pharmaceutical University for the measure- ment of 400 MHz n.m.r. spectra and high resolution mass spectra, respectively. References 1 (a) H. Nakamura, J. Kobayashi, Y. Ohizumi, and Y. Hirata, Tetrahedron Lett., 1982, 23, 5555; (b) Y. Ohizumi, A. Kajiwara, H. Nakamura, and J. Kobayashi, J. Pharm. Pharmacol., 1984, 36, 785; (c) H.Nakamura, J. Kobayashi, Y. Ohizumi, and Y. Hirata, J. Chem. Soc., Perkin Trans. I, 1987, 173. 2 (a)J. C. Pelletier and M. P. Cava, Tetrahedron Lett., 1985, 26, 1259; (6) J. C. Pelletier and M. P. Cava, J. Org. Chem., 1987, 52, 616. 3 T. R. Kelly and M. P. Maguire, Tetrahedron, 1985, 41, 3033. 4 T. Sakamoto, N. Miura, Y. Kondo, and H. Yamanaka, Chem. Pharm. Bull., 1986, 34, 2760. 5 A. Bassoli, G. Maddinelli, B. Rindone, S. Tollari, and F. Chioccara, J. Chem. SOC.,Chem. Commun., 1987, 150. 6 (a) S. Kano, E. Sugino, S. Shibuya, and S. Hibino, J. Chem. Soc., Chem. Commun., 1980, 1241; (b)S. Kano, E. Sugino, S. Shibuya, and S. Hibino, J. Org. Chem., 1981, 46, 3856; (c) S. Kano, E. Sugino, S. Shibuya, and S. Hibino, J.Org. Chem., 1981,46,2979;(d)S. Kano, E. Sugino, and S. Hibino, Heterocycles, 1982, 19, 1673; (e) S. Kano, N. Mochizuki, S. Hibino, and S. Shibuya, J. Org. Chem., 1982, 47, 3566 and related references cited therein. 7 (a) J. Moskal, R. van Stralen, D. Postma, and A. M. van Leusen, Tetrahedron Lett., 1986, 27, 2173; (b) J. Moskal and A. M. van Leusen, J. Org. Chem., 1986, 51, 4131. 8 (a)S. Hibino, S. Kano, N. Mochizuki, and E. Sugino, J. Org. Chem., 1984, 49, 5006; (b) S. Hibino, E. Sugino, T. Yamochi, M. Kuwata, H. Hashimoto, K. Sato, F. Amanuma, and Y. Karasawa, Chem. Pharm. Bull., 1987, 35, 2261; (c) S. Hibino and E. Sugino, Heterocycles, 1987, 26, 1883 and related references cited therein. 9 K. Koshi and M. Shimizu, Chem. Pharm. Bull., 1968,16, 2343. 10 M. Sato, N. Yoneda, N. Katagiri, H. Watanabe, and C. Kaneko, Synthesis, 1986, 692. Received 7th December 1987; Paper 7/2140
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