2160 J.C.S. Perkin ITotal Syntheses of (-)-0-Methylandrocymbine, (-)-Kreysigine, andAlkaloid CC-10 Methyl Ether tBy T. Kametani," Y . Satoh, and K. Fukumoto, Pharmaceutical Institute, Tohoku University, Aobayama, Sendai,Japan(-)-0-Methylandrocymbine (1 ) was obtained from (-)-1- (2-bromo-3,4,5-trimethoxyphenethyl)-1,2,3,4-tetra-hydro-7-hydroxy-6-methoxy-2-methylisoquinoline (1 3a) by irradiation. The corresponding (+)-phenolicbromoisoquinoline (1 3b) gave alkaloid CC-10 methyl ether (+)-0-methylandrocymbine (3) and (-)-krey-sigine (6).( -)-~-METHYLANDROCYMBINE (1) is a homomorphin-andienone-type alkaloid isolated from Colchicum autum-?zaZe,l and has been derived by methylation of andro-cymbine (2) with dizomethane. (+)-0-Methylandro-cymbine (3), its optical antipode, has been obtained bymethylation of alkaloid CC-10 (4), isolated from CoZchi-cum cornigerum.3 Racemic kreysigine (5) has beenisolated from Kreysigia muZtiJEora ; * the optically activeform, (-)-kreysigine (6), was later found in BuZbocodiurnvernum L.5Recently Battersby 3 reported that O-methylandro-cymbine is a key precursor of colchicine (8) and relatedalkaloids, implying that these tropolone derivatives areto be classed as highly modified 1-phenethylisoquinolinesystems.We have previously 6*7 reported syntheses of(amp;)-0-methylandrocymbine and ( j-)-kreysigine by iradi-ation of the 2'-bromophenethylisoquinoline (9) and by aphoto-Pschorr reaction of the diazonium salt of the2'-aminophenethylisoquinoline (10). We now describethe total syntheses of (-)-0-methylandrocymbine (l),(-)-kreysigine (6), and their optical antipodes (3) andMe0 U O Me0 (1) R1 = R2 = Me(2) R1 = Me, R2 = H(3) R1 = R2 = Me(4) R1 = H, R2 = MeMeO'(6) X = -H(6) X = H(7) x = .*..H(7) from the optically active 2'-bromophenethylisoquino-lines (13a and b) by the former method.t Part CDLXXV of ' Studies on the Syntheses of HeterocyclicCompounds,' Part CDLXXIV, T. Kametani, S . Takano, andH. Takeda, J . Pharm. SOC. Japan., 1972,92, 743.R. Ramage, Ann. Reports, 1967, 64B, 516.2 A. R. Battersby, R. B. Herbert, L. Pijewska, and F.A. R. Battersby, R. Ramage, A. F. Cameron, C. Hannaway,Santavy, Chem. Comm., 1965, 228.and F. Santavq, J . Chem. SOC. (C), 1971, 3614.The (amp;)-2'-bromophenethylisoquinoline (1 1) wasreadily resolved with di-9-toluoyltartaric acid.The(-)-compound (12a), obtained from the (-)-di-P-toluoyltartrate, showed two positive Cotton effects, at290 and 250 nm, and the (+)-base (12b), recovered fromthe (+)-di-P-toluoyltartrate, showed two negative Cottoneffects at the same positions (Figure 1). It has beencx 't-15'I I I 12 50 300 350A / n mFIGURE 1 0.r.d. (A) and c.d. (B) curves of compound (12a) and0.r.d. (C) and c.d. (D) curves of compound (12b) (in methanol)reported 8 that in 1-phenethyltetrahydroisoquinolinederivatives, the S-series show two positive Cotton effects,a t 290 and 245 nm, whereas the R-series have doublenegative curves. We therefore expected that the(-)-base (12a) (S-configuration) would be converted into(-)-0-methylandrocymbine (l), whereas the (+)-' isomer(12b) (R-configuration) would give the optical antipode(3) of natural 0-methylandrocymbine and (-)-krey-sigine (6).4 G.amp;I. Badger and R. B. Bradbury, J . Chem. SOC., 1960,445.5 F. Santavjr, P. Sedmera, G. Snatzke, and T. Reichstein,Helv. Chim. Acta, 1971, 54, 1084.6 T. Kametani, Y. Satoh, S. Shibuya, M. Koizumi, and K.Fukumoto, J . Org. Chem., 1971, 36, 3733.7 T. Kametani, M. Koizumi, and K. Fukumoto, J . Chem. SOC.(C), 1971, 1792.8 A. Brossi, J. O'Brien, and S. Teitel, Helv. Chirn. Acta, 1969,52, 6781972 2161The (-)-2'-bromophenethylisoquinoline (12a) wasdebenzylated with ethanolic hydrochloric acid and theresulting phenolic bromoisoquinoline (13a) in ethanolwas irradiated with a Hanovia 450 W mercury lamp-OR Me0(9) R = H, X = ~ l h H, Y = Br11) R = CH,Ph, X = -H, Y = Br12a) R = CH,Ph, X = - H, Y = Br12b) R = CH,Ph, X = iiii1~111( H, Y = Br13a) R = H, X = 4 H, Y = Br13b) R = H, X = lliiitilll H, Y = Br10) R = CH,Ph, X = - H, Y = NH,(Pyrex filter) at room temperature for 7 h to give (-)-0-methylandrocymbine (1) and (+)-kreysigine (7).The(+ )-2'-bromophenethylisoquinoline (12b) was similarlyconverted into (+)-0-methylandrocymbine (3) and (-)-kreysigine (6).Both the (-)-enantiomeric compounds were shown tobe identical with 0-methylandrocymbine derived fromnatural androcymbine and with kreysigine prepared byI I I I 1250 350 4500.r.d. (A) and c.d.(B) curves of (-)-0-methylandro-cymbine (1) and 0.r.d. (C) and c.d. (D) curves of (+)-0-methyl-androcymbine (3) (in methanol)FIGURE 2photo-Pschorr reaction, respectively, by spectral com-parisons.EXPERIMENTALM.p.s were determined with a Yanagimoto microappa-ratus. 1.r. and U.V. spectra were taken with HitachiEPI-3 and EPS-3 recording spectrophotometers, respec-tively. Mass spectra were measured with a HitachiRMU-7 spectrometer. N.m.r. spectra were measured witha Hitachi R-20 spectrometer for solutions in deuteriochloro-form with tetramethylsilane as an internal standard.Optical rotations were measured with a JASCO PIP-SLautomatic polarimeter. 0.r.d. and c.d. curves were201-250 350 450AI nmFIGURE 3 0.r.d. (A) and c.d.(B) curves of natural O-methyl-androcymbine (in methanol)h l n mFIGURE 4 0.r.d. (A) and c.d. (B) curves of (+)-kreysigine (7)and 0.r.d. (C) and c.d. (D) curves of (-)-kreysigine (6) (inmethanol2162 J.C.S. Perkin Imeasured for solutions in methanol with a JASCO/UV-5spectropolarimeter (1 0.1 and 0.02 dm).( -)- and (+)-7-Benzyloxy-l-(2-bromo-3,4,5-trirnethoxy-phenethyl) - 1,2,3,4-tetrahydro- 6-methoxy-2-methylisoquinolines(12a and b).-( -)-Di-p-toluoyltartaric acid (13 g) was addedto a solution of the base (9) (9 g) in acetone (300 ml). Thesalt which crystallised afforded the ( - )-2'-bromophenethyl-isoquinoline (-)-di-p-toluoyltartrate (7.8 g), m.p. 158-159"(from methanol), aIDl5 +46-1" (c 0.40 in MeOH) (Found:C, 62.6; H, 5.6; N, 1-65.C,,H,,BrNO,, requires C,62.4; H, 5.55; N, 1.5). To a solution of this salt (7.5 g)in chloroform (ca. 200 ml) was added 10 sodium carbonatesolution, and the mixture was shaken for a few minutes.The chloroform layer was separated, washed with water,and dried (K,CO,). Removal of the solvent left a yellowishsolid, which crystallised from n-hexane to give the (-)-2'-bromophenethylisoquinoline (12a) ( 3 g) as needles, m.p. 94-95" (Found: C, 62-45; H, 6-3; N, 2.55. C,,H,,BrNO, re-quires C, 62.6; H, 6-15; N, 2-5), aID16 -22" (c 0-42 inMeOH), v,,, (CHCl,) 2780 cm-l (NCH,). The motherliquors from the salt of the (-)-base were worked up for thefree base (5 g) and this was treated with (+)-di-p-toluoyl-tartaric acid (7.5 g) in acetone (200 ml).The salt whichcrystallised afforded the (+)-2'-bromophenethyZisoquinoline(+)-di-p-toluoyltartrate (7.2 g) as needles, m.p. 158-159"(from methanol) (Found: C, 62.2; H, 5-55; N, 1.7y0),aD15 -46O Ic 0.40 in MeOH). This salt gave the (+)-2'-bromophenethylisoquinoline (12b) (3 g) as needles, m.p.94-95' (from n-hexane) (Found: C, 62-8; H, 5-95; N,2-7), aIDz0 +23" (c 0.50 in MeOH), vmX. (CHC1,) 2780cin-l (NCH,) .(-)- and (+)- 1-(2-Bromo-3,4,5-trimetho~y~henethyZ)-1,2,3,4-telrahydro- 7-hy droxy- 6-methoxy- 2-methylisoquinoline(13a and b).-A mixture of the preceding isoquinoline (12a)(3 g), concentrated hydrochloric acid (30 ml), and ethanol(30 ml) was refluxed for 5 h. The usual work-up gave com-pound (13a) (2.5 g) as a yellowish oil, which was difficult tocrystallise and therefore used in the following reaction with-out purification vmx.(CHCl,) 3510 (OH) and 2730 cm-l(NCHdI.Similar treatment of compound (12b) (3 g) gave compound(13b) (2-5 g) as a yellowish oil, vmx. (CHCl,) 3510 (OH) and2730 cm-l (NCH,).Irradiation of the Phenolic Bromophenethylisoquinoline(13a).-A stirred water-cooled mixture of the phenolic iso-quinoline (13a) (2.5 g), sodium hydroxide (0-7 g), ethanol(200 mi), and water (800 ml) was irradiated with a 450 WHanovia mercury lamp (Pyrex filter) for 7 h. The usualwork-up 13 left a brownish oil (2-2 g), which was chromato-graphed on silica gel (50 g) with methanol-chloroform (1 : 99)as eluant to give a dienone fraction (750 mg). Furtherchromatography on silica gel (10 g) with chloroform-methanol (99 : 1) as eluant afforded the dienone (300 mg),which was rechromatographed on neutral alumina (10 g).Elution with benzene-chloroform (9 : 1) gave (-)-O-methyl-androcymbine ( 1) (45 mg), identical (spectroscopic data)with an authentic specimen.' Further elution after collec-tion of the dienone fraction in the first chromatographyafforded (+)-kreysigine (7) (80 mg), m.p.112-113" (fromether), a),1s f60" (c 0.40 in CHCl,), otherwise identicalspectroscopic data) with an authentic specimen.6Photolysis of Irradiation of the Phenolic Bromophenethyl-isoquinoline (13b) .-Similar irradiation of compound ( 13b),followed by chromatography as in the case of (13a), gave(+)-O-methylandrocymbine (3) (35 mg), identical (spectro-scopic data) with an authentic specimen apart from the0.r.d. and c.d. spectra.' Chloroform eluted ( -)-kreysigine(6) (80 mg), aJD16 - 65" (c 0.40 in CHCl,), otherwise identical(spectroscopic data) with an authentic specimen.6We thank Professor Santavjr, Palaky University, Czecho-slovakia, for a gift of natural androcymbine, ProfessorM. Hatano, Tohoku University, for the 0.r.d. and c.d.measurements, and Dr. N. Koga and Dr. 0. Ikeda, DaiichiSeiyaku Co. Ltd., for their encouragement. We also thankMiss C. Yoshida, and Miss T. Yoshida, Miss R. Kato, Mr. T.Ohuchi, Miss A. Ujiie, Miss A. Kawakami, PharmaceuticalInstitute, Tohoku University, for spectral measurementsand microanalyses.2/720 Received, 27th March, 1972
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