摘要:
2416 J.C.S. Perkin ISynthesis of the lndolo[2',3':3,4] pyrido[1,2-16] [2,7] naphthyridinone Al ka-loid Nauclefine and its Ring-E IsomersBy Malcolm Sainsbury and Nigel L. Uttley, School of Chemistry, University of Bath, Claverton Down, BathNauclefine has been reported to be the only product from the photocyclisation of the enamide derived from har-maian and nicotinoyl chloride. Re-investigation has shown, however, that two compounds are formed : the alka-loid and an isomer in which cyclisation to the 2-position of the pyridyl unit has occurred. These components havebeen separated and the remaining ring-E isomers have been synthesized. I H and 13C n.m.r. data for these structuresare analysed.BA2 7AYTHE alkaloid nauclefine (parvine t) (4) has been synthe-sised by the route outline in the Scheme.192 However,t(21 R = A c(31 R = Br9 6I9(41 R = H (81 R = HI51 R = AC (9) R = A c(SIR= Er [10)R= Br(71R=CH(OHi MeSCHEMEbecause of the two possible modes of photocyclisation ofthe enamide (1) 3 it was surprising that nauclefineappeared to be the sole product of this reaction.Whenthe photolysis was repeated, t.1.c. (alumina) showed onlyone spot, identical in behaviour with the natural product(RF 0.75 in acetone; 0.62 in methanol), and a similarcorrelation of mass, i.r., and U.V. spectra was apparent.The lH n.m.r. spectrum had been recorded previouslyfor a recrystallised sample of the photolysis product,2 butthis time when the spectrum of the crude material wasdetermined, the presence of a minor component (10-12%) was revealed.This conclusion was supported byI3C n.m.r. data (see later).The isomers were separated by column chromato-graphy with dichloromethane-methanol mixtures (whichalso allows the recognition of two components on t.l.c.),t The use of this name should be discontinued since Pousset'sstudy has precedence over ours.2$ The electronic spectrum of bromoisonauclefine is not affectedby the addition of acetic acid.F. Hotellier, P. Delareau, and J. L. Pousset, Phytoclzenzistry,1975, 14, 1407.111. Sainsbury and B. Webb, Phytoclzemistry, 1975, 14, 2691.affording pure nauclefine and isonauclefine (8). lHN.m.r. assignments for ring E in each of the two com-pounds are summarized in Table 1. Chemical shifts andcoupling constants for solutions in (CD,},SO agree wellwith values calculated for model systems,4 but in tri-fluoroacetic acid solution the signals for H-17 and -19 innauclefine appear as a doublet and a triplet, respectively.This effect has been noted previously in isoquinolinesand is presumably due to N-protonation. The signalsof isonauclefine in trifluoroacetic acid solution do notshow this increased multiplicity ; interestingly, nauclefinereadily forms a methiodide whereas its isomer does not.The H-17 resonance of nauclefine is only slightly changedin trifluoroacetic acid solution, with respect to its positionin (CD,),SO (+0.24 p.p.m.), but the H-17 signal inisonauclefine undergoes a considerable downfield shift(+0.72 p.p.m.) and the H-19 resonance is actually movedupfield (-0.12 p.p.m.).These results suggest thatquaternization of the ring-E nitrogen atom in isonaucle-fine is not favoured, possibly because of steric interactionwith the peri H-14, and thus in trifluoroacetic acidsolution protonation of the oxygen atom of the amidecarbonyl group may occur preferentially.Au et aL6 note that angustoline is a strong base whichis protonated even by acetic acid. For example, drop-wise addition of acetic acid to a methanolic solution ofthe alkaloid causes a progressive, and ultimately com-plete, shift of the longest wavelength absorption bandin the electronic spectrum from 395 to 439 nm. Theseworkers propose that the conjugate acid, formed byprotonation of the ring-s nitrogen atom, is stabilizedthrough resonance with the indolic nitrogen atom.Suchstabilization is possible with both the similarly formedconjugate acids of nauclefine and isonauclefine but,significantly, whereas the electronic spectrum of theformer is slowly changed by dropwise addition of aceticacid ( I , , , 391 to 448 nrn) that of isonauclefine is not.Only in 75% acetic acid in methanol does an absorptionband start to appear at 445 nm, and even in glacialacetic acid this band does not replace the absorptionmaxima of the free base at 362 and 380 nm,: and3 (a) I. Ninomiya, H. Takasugi, and T. Saito, J.C.S. Chei3z.Corpziiz., 1973, 732; ( b ) I. Ninoniiya and T. Naito. Heterocycles,1974, 2, 607.4 ( a ) S. Castellano, C. Sun, and R. Kostelnik, J .Chew. Phys..1967, 46, 327; (b) T. Tokuhiro, N. I<. Wilson, and G. Fraenkel,J . Amer. Chenz. Soc., 1968, 90, 3622.5 D. G. Lugton, Ph.D. Thesis, Bath, 1969.6 T. Y . Au, H. T. Cheung, and S. Sternhell, J.C.S. Perkin I ,1973, 131976 2417extinction coefficient measurements indicate that ca.70% of the unprotonated form is present in this solvent.Cyclisation involving the y-carbon atom of the pyridylgroup and the exocyclic methylene group in the enamideprecursor (1) is favoured electronically, but Ninomiyanoted in the synthesis of angustoline that the enamide(2), in which the pyridine unit bears a relatively bulky3-substituent, affords the isomers (5) and (9) in a molarratio of 4 : 1.In an attempt to increase the yield of isonauclefine thebromoenamide (3) was irradiated; it was hoped that afterseparation of the products the bromo-substituent in (10)but perversely the 19-aza-isomer (12) is readily convertedinto its methiodide salt.In the first case, however, the 4: "i-"n+ He tc.caxbonyl group at C-16a imposes an additional stericconstraint to quaternary salt formation.TABLE 1isonauclefine (B) in (CD,),SO and in CF,*CO,HChemical shifts (8 values; MeSi standard) and coupling constants (J/Hz) for ring-E protons of nauclefine (A) and/H( A )H(81(B)A r(4c -'--(CD,),SO CF,CO,H (CD3)2SO CF3*CO,ZH-17 9.32br (s) 9.56 (d, J 6) H-17 8.54 (dd, J l , , l s 8, 9.26 (d, J 6)Ji,. 19 2)H-19 8.66br (d) 8.36 (t, J 6) H-18 ca. 7.4 7.70 (t, J 6 )H-20 ca.7.6 7.83 (d, J 6) H-19 8.90 (dd, Jls,le 5, 8.78 (d, J 6)Ji7.19 2)might be removed by hydrogenolysis. However, al-though the isomers (6) and (10) were obtained in a molarratio of 2.4 : 1 and were separated by column chromato-graphy, all attempts failed to remove the bromine atomin either.In order to assist in the interpretation of the lH and13C n.m.r. spectra of nauclefine and isonauclefine, theisomers (1 1) and (12) were prepared, by photocyclisation1121of the enamides derived from harmalan with picolinoyland isonicotinoyl chloride, respectively. The electronicabsorption spectra of (11) and (12) are little changed bythe addition of acetic acid. Here, however, the adverseresonance effects implicit in the N-protonated formsmight be expected to destabilize them; see, for example,part structure (13).In line with this conclusion, (11)does not form a methiodide even under forcing conditions,H. L. Rctcofsky and R. A. Friedel, J. Phys. Chem., 1968, 72,290.6 E. Wenkert, J. S. Bindra, Ching-Jer Chang, D. W. Cochran,and F. M. Schell, Accounts Chem. Res., 1974, 7, 46.Provisional 13C n.m.r. assignments for nauclefine andThese its ring-E isomers are summarized in Table 2.TABLE 2Provisional 13C n.m.r. assignments (8 values ; MeSi, standard)for nauclefine and its ring-E isomersStructuresCarbon A(8) t (11) : (12) 5134.1439.503 136.935 39.96 39.96 45.296 19.10 19.11 20.72 19.047 114.51 11.3.60 114.06 1 13.02127.77 127.38 127.64 8 127.38119.32 120.49 119.19 119.71 910 124.26 123.94 123.42 123.7411 119.51 119.52 121.73 119.5812 111.78 111.72 110.91 111.66138.10 13 138.36 138.1714 96.83 100.2s 4 96.1216 121.35 152.79 126.37 22S.6116 125.23 120.10 141.87 130.83160.2017 150.77 135.50 125.3018 121.01 141.5 145.2519 150.3220 118.73 143.30 149.2%t (CD,),SO as solvent.CF,-CO,H as solvent. Masked135.70 §no. 74 t138.1616a 160.85 161.50 9131.91 154.81b y solvent absorption.allocations are based upon chemical shift values expectedfor specific types of carbon atom , 4 b ~ 7* * and off -resonancelH decoupling studies2418 J.C.S. Perkin IEXPERIMENTALU.V. spectra were recorded for solutions in methanol; i.rspectral data refer t o Nujol mulls; lH n.m.r. spectra wererecorded a t 100 MHz with tetramethylsilane (TIUS) asinternal standard.TMS was also used as internal referencefor 13C n.m.r. spectra. Column chromatography wasconducted with Merck neutral grade alumina.Nauclefine (4) and Isonauclefine (8) .-The enamide (1)(400 mg), prepared from nicotinoyl chloride and harmalan,l.zin methanol (800 cm3), was irradiated in a Hanovia reactorwith ' soft ' U.V. light. After 20 h the solvent was removedand the brown amorphous residue subjected to spectro-scopic and chromatographic analysis ; 6 [ (CD,) ,SO] 9.32br(s) and 8.9 (4) (integral ratio 1 : 0.09), and 8.66br (s) and8.54 (4) (integral ratio 1 : 0.09). Column chromatographyand elution with 3% methanol in dichloromethane gaveisonauclefine { 8 , l 3-dihydroindolo[2',3': 3,4]$yrido[ 1,2-g]-[1,6]nuphthyridin-5(7H)-one} (S), m.p.>350 "C, mle 287(Mf, loo%), 286 (85), 272 (12), and 258 (13), Am= 362 and380 nm, vmaX. 3 240, 1 650, 1 606, and 1 593 cm-l, 6[(CD3),SO]11.76 (1 H, s, NH), 8.90 (1 H , dd, J 5 and 2 Hz, 19-H), 8.54(1 H, dd, J 8 and 2 Hz, 17-H), 7.7-7.0 (5 H, m), 4.4 (2 H , t,J 7 Hz, 5-H,), and 3.12 (2 H, t, J 7 Hz, 6-HJ (Found:C, 75.2; H, 4.5; N, 14.2. C,,H,,N,O requires C, 75.2; H ,4.6; N, 14.6%).Elution with 5% methanol in dichloromethane affordednauclefine, identical (m.p. and mixed m.p. 298-299 "C)with the natural alkaloid (MI2 m.p. 293-294 "C); meth-iodide, m.p. 330 "C (lit.,, 330 "C), m/e 287 (M+, loo%),286 (80), 272 (12), and 258 (13%), kx. 372 and 391 nm,vmX. 3 180, 1650, 1615, and 1597 cm-l (Found: C, 75.2;H , 4.4; N, 14.3%).2-( 5-Bromonicotinoyl)-l, 2,3,4-tetrahydro- l-methylene-P-car-boline (3) .-Compound (3), from harmalan and 5-bromonico-tinoyl chloride, had m.p.158 "C; vmx. 3 330, 1 650, 1620,and 1 580 crn-l, &(CDCl,) 8.93 (1 H , s, NH), 8.66 (1 H, dd,J 2.2 and 0.3 Hz), 8.51 (1 H, dd, J 2 and 0.3 Hz), 7.98 (1 H ,dd, J 2.2 and 2 Hz), 5.03 (1 H, d, J 2.2 Hz), 4.32 (1 H, d, J2.2 Hz), 4.2 (2 H , t, J 6 Hz), and 3.0 (2 H , t , J 6 Hz), 60[(CD3)2SO) 136.2 (C-3), 44.65 (C-5), 22.96 (C-6), 113.67 (C-7),128.68 (C-8), 119.26 (C-g), 124.20 (C-lo), 120.36 (C-11),111.33 (C-12), 138.3 (C-13), 103.33 (C-14), 137.45 (C-15),126.7 (C-16), 166.18 (C-l6a), 151.75 (C-17), 146.81 (C-19),2nd 133.4 (C-20) (Found C, 58.6; H , 3.7; N, 11.2.C,,H,,-BrN,O requires C. 58.7; H , 3.8; N, 11.4%).20-Bromonauclefine (6) and 18-Bromoisonauclefine (10) .-The enamide (3) (0.8 g) was irradiated in the usual way andthe product chromatographed. Elution with dichloro-methane gave 18-bromoisonazdefine (50 mg), m.p. > 350 "C,mle 367, 365 (Mf, 68%), 364 (40%), 257 (14), 215 (21), and125 (loo), Lx 260, 360, and 380 nm, v,,,. 3 200, 1 640,1 600, and 1 580 cm-l, 6 [(CD,),SO] 11.3 (1 H, s, NH), 8.88(1 H, d, J 2.5 Hz, 17-H), 8.58 (1 H , d, J 2.5 Hz, 20-H),7.7-7.0 (4 H, m), 7.18 (1 H, s, 14-H), 4.4 (2 H , t , J 7 Hz,5-H,), and 3.1 (2 H , t, J 7 Hz, 6-H.J (Found: C, 59.2; H ,3.5; N, 4.1. C,,H,,BrN,O requires C, 59.0; H, 3.3; N,4.4%). With 1% methanol in dichloromethane, 20-bromo-nauclefine (6) 120 mg), m.p. >350", was obtained, mle 367,365 (68%), 364 (40), 257 (14), 215 (21), and 125 (loo), Lx.240, 254, 295, 306, 373, and 403 nm, v,, 3 200br, 1660,1635, and 1 600 cm-l, 6 [(CD,),SO] 12.0 (1 H, s, NH), 9.23(1 H , s, 17-H), 8.84 (1 H, s, 20-H), 7.7-7.0 (4 H , m), 7.12(1 H , s, 14-H), 4.38 (2 H, t, J 7 Hz, 5-H,), and 3.17 (2 H, t,J 7 Hz, 6-HJ (Found: C, 59.3; H , 3.3; N, 4.1%).Nauclefine Ring-E Isomers ( 11) and ( 12) .-The isomer (1 1){ 8 , l 3-dihydroindoZo[2', 3': 3,4]pyrido[2,l-gJ [ 1,7]naphthyridZn-5( 7H)-one} was obtained by irradiation of the enamidcfrom picolinoyl chloride and harmalan (this enamide wasnot purified, but used directly); i t had m.p.250-251 "C(decomp.) (from methanol), vn/e 287 (iW+, looyo), 286 (85),272 (12), 258 (13); A,,,. 354 and 375sh nm, vmaL 3 210,1 650, 1 620, 1 605, and 1 595 cm-l, 6 [(CD,),SO] 11.76(1 H, s, NH), 8.76br (1 H, s, 18-H), 8.08 (1 H, d, J 8 Hz,20-H), 7.66 (1 H , m, 19-H), 7.6-7.0 ( 4 H, m), 7.04 (1 H,s, 14-H), 4.44 (2 H , t, J 7 Hz, 5-H,), and 3.12 (2 H , t,J 7 Hz, Ci-H,) (Found: C, 75.2; H, 4.5; N, 14.3.C,,H,,N,O requires C, 75.2; H, 4.6; N, 14.6%).The isomer (12) (8,13-dihydroindol0-[2',3' : 3,4]pyrido-[1,2-b][2,6]nuphthyridin-5(7H)-one} was prepared insimilar manner from the enamide from isonicotinoylchloride and harmalan (the enamide had m.p.206 O C ,6 [(CD,),SO] 11.2 (1 H, s), 8.6 (2 H , dd, J 4.25 and1.5 Hz), 7.7-6.9 (4 H, m), 7.32 (2 H, dd, J 4.25 and1.5Hz), 5.36br (1 H, s, J (1 Hz), 4.54br (1 H, s, J (1 Hz),4.06 (2 H, t , J 6 Hz), 2.92 (2 H , t, J 6 Hz) (Found: C, 74.7;H , 5.55; N, 13.9. C,,H,,N,O requires C, 74.7; H , 5.2;N, 14.0%)). After removal of the solvent used in theirradiation experiment, the crude isomer (12) was purifiedby elution (4% methanol in dichloromethane) through asilica column to afford yellow prisms, n1.p. > 350 "C, pn/e 287(M+, loo%), 286 (63), 272 (12), and 258 (13); A,, 353 and390shnm, 6 [(CU,),SO] 11.6 (1 H , s, NH), 9.02 (1 H , s, 20-H),7.7-7.0 (4 H , m), 7.14 (1 H, s, 14-H), 4.4 (2 H, d, J 7 Hz,5-H,), and 3.08 (2 H, t, J 7 Hz, 6-H,) (Found: C, 75.1;H , 4.6; N, 14.5%); methiodide, m.p. >350 "C, 8 [(CD,),SO]17-H), 8.53 (1 H, d, J 6 Hz, 18-H), 7.7-7.0 (4 H, m), 7.16(1 H , s, 14-H), 4.44 (2 H , t , J 6 Hz, 5-H,), and 3.16 (2 H, t,8.58 (1 H, d, J 5 €32, 17-H), 8.02 (1 H , d, J 5 Hz, 18-H),11.98 (1 H, S, NH), 9.68 (1 H, S, 20-H), 8.67 (1 H , d, J 6 Hz,J 6 Hz, 6-H2).N. L. U. is supported by an S.R.C. studentship; M. S.thanks the Cancer Research Campaign for interest andfinancial assistance.[6/996 Received, 25th May, 1976
ISSN:1472-7781
DOI:10.1039/P19760002416
出版商:RSC
年代:1976
数据来源: RSC