J. CHEM. SOC. PERKIN TRANS. 1 1992 Reactions of 19-Ethoxycarbonyl-19-demethylvincadifformine: Synthesis of 19-Ethoxycarbonyl-19-demethylapovincaminet Abdelhamid Belattar and J. Edwin Saxton * School of Chemistry, The University, Leeds LS2 WT, UK ( f) -1 9-Ethoxycarbonyl-19-demethylapovincamine has been prepared by the oxidative rearrangement of ( f) -19-ethoxycarbonyl-19-demethylvincadifformine. An attempt to prepare strem- peliopine by the reductive rearrangement of 1 9-ethoxycarbonyl-I 9-demethyl-l,2-dehydroaspido-spermidine, obtained from the same starting material, was unsuccessful. ( f)-19-Ethoxycarbonyl-19-demethylvincadifformine1, which we prepared earlier ' en route to (+)-12-demethoxycylin-drocarine 2 and related alkaloids, is a versatile intermediate which we hoped to transform into a number of other alkaloids by taking advantage of the several rearrangement reactions reported on the parent alkaloid, vincadifformine.2 In our first experiments we envisaged the possibility of converting 1 by an oxidative rearrangement into (+)-19- ethoxycarbonyl- 19-demethylvincamine 3.However, the 16-hydroxyindolenine derivative 4, prepared by reaction of 1with rn-chloroperbenzoic acid, followed by reduction of the N,-oxide function by means of hydrogen and palladium, did not rearrange smoothly in acid solution to give the corresponding vincamine derivative as has been reported3 for the analogous derivative of vincadifformine; instead, inseparable mixtures, which may have contained some of the desired product 3, or intractable gums, were obtained.Similarly, ozonization of 1 in methanol and sulfuric acid at 60deg;C, as described by Danieli at ~l.,~resulted in the formation of a very polar, unidentified product. In contrast, the 16-hydroxyindolenine derivative 5, prepared by the reaction of 1 with N-chlorosuccinimide, rearranged smoothly when heated in trifluoroacetic acid, to give (+)-19- ethoxycarbonyl- 19-demethylapovincamine 6 in 56 unopti- mised yield. The apovincamine derivative 6 was identified from its spectroscopic properties, and in particular its mass and 13C NMR spectra. Its mass spectrum is dominated by McLafferty loss of the elements of ethyl acetate from the molecular ion, which gives rise to the base peak at m/z 306, owing to the ion a (Scheme 1).The second important fragmentation is the familiar retro-Diels-Alder fission of ring C; the resulting ion b then loses either the acetic ester residue to give the second most intense peak at rn/z 307, owing to the ion c, or it loses the remnants of ring D to give the ion at rn/z 324, owing to d. The facility of both these primary fragmentations is a direct consequence of the cis stereochemistry at the C/D and D/E ring junctions. The further fragmentation follows that observed with apovincamine (methyl apovincaminate, 7a).6 The 3C NMR spectrum of 19-ethoxycarbony1-19-demethy1-apovincamine also confirms the structure 6. The spectrum is very closely similar to that of ethyl (+)-apovincaminate 7b (see Experimental section),$ apart from the signals owing to C-18 and C-19.Hydrolysis and decarboxylation of the vincadifformine ~ ~~~~ ~~ ~ t Throughout this paper the biogenetic numbering system is adopted. $ The I3CNMR spectrum ofethyl apovincaminate appears not to have been recorded in the literature. We therefore wish to thank Dr. Cs. Szantay very warmly for the generous gift of a sample of ethyl apovincaminate, on which the quoted ''C NMR data were determined. 5 3 IHH C02Me H 1 12-Demethoxycylindrocarine 2 C0,Me 3 4 SITamp;Me02C amp;02Me bsol;CO2Et 5 /9 6 derivative 1has already been shown ' to give the rather unstable indolenine derivative 8, which adds the elements of hydrogen cyanide to give the more stable, easily isolated nitrile ester 9.Regeneration of the indolenine 8 by means of silver tetra- fluoroborate, followed by a reductive rearrangement, should give the amino ester 10, which is conveniently set up for cyclization to strempeliopine 11, the alkaloid of Strempeliopsis strempelioides K. Schum.' This alkaloid has already been synthesised by Trojanek and HajiEek by a procedure which involved the reductive rearrangement of the indolenine related to 8, but with an allyl group in place of the acetic ester residue, followed by appropriate manipulation of the allyl group in the rearranged species. This reductive rearrangement, which in- volved the use of zinc and copper sulfate in acetic acid, proved to 1584 J. CHEM. SOC. PERKIN TRANS.I 1992* (McLafferty) Me02C C02Et 6+'M+,394 bsol; a, m/z 306 -CH2C02Et1 'C02Et m/z 307 b, m/z 394 / CO2Et c, m/z 307 d,m/z 324 Scheme 1 7a R=Me 7b R=Et be a very capricious reaction, in which the quality and particle size of the zinc used were of crucial importance. Unfortunately, we have been unable to obtain information concerning the exact source of the zinc used by the Czech workers. In our hands the analogous reduction of the indolenine 8, using the zinc samples available in our laboratory, gave a multiplicity of products, of which three were identified. However, none of these was the result of the desired rearrangement to the strempeliopine ring system. The three products identified were 19-ethoxycarbonyl-Na-ethyl-19-demethylaspidospermidine 12, which presumably arises by reduction of the second product, Na-acetyl- 19-ethoxycarbonyl- 19-demethylaspidospermidine 13, and 19-ethoxycarbonyl- 19- demet hylaspidospermidine 14.Experimental M.p.s were determined on a Kofler hot-stage apparatus and are uncorrected. IR spectra were recorded on either a Perkin- Elmer 1420 or 13 10 spectrophotometer. UV absorption spectra were obtained on a Unicam PU 8800 spectrometer. NMR spectra were recorded on either a JEOL FX90Q FT ('H 90 MHz and ' ,C), GE QE 300 ('H 300 MHz and ' 3C) or a Bruker 400 MHz spectrometer ('H 400 MHz and ',C). Solutions in deuteriochloroform, with tetramethylsilane as internal stan-dard, were used, unless otherwise stated. J values are given in Hz.Mass spectra were recorded on a Kratos MS 25 CO2Et I I CN/i C02Me H 1 9 ,.*-*. i,N -CO2Et *.-* C02Et 10 8 1 H Strempeliopine 11 12 R=Et 13 R=Ac 14 R=H instrument; accurate mass measurements were carried out on an AEI/Kratos MS 902/50 spectrometer. 19-Ethoxycarbonyl- 19-demethylapovincamine 6.-A solution of 19-ethoxycarbonyl- 19-demethylvincadifformine 1 (0.2 g, 0.5 mmol)' and N-chlorosuccinimide (66 mg, 0.5 mmol) in dry trifluoroacetic acid (20 cm3) was stirred at room temp. for 4 h in a nitrogen atmosphere, then heated at reflux for 3 h. The solution was concentrated under reduced pressure, the residue was taken up in ethyl acetate, washed with 2 mol dm-3 sodium hydroxide and dried (MgS04).The crude product was chromatographed on Kieselgel G (35 g), using ethyl acetate as eluent, which gave 19-ethoxycarbonyl- 19-demethylapouinca- mine (105 mg, 55) as a colourless gum (Found: C, 69.75; H, 6.8; N, 6.85; M+, 394.1905. C,,H,,N,O, requires C, 70.05; H, 6.60; N, 7.1; M, 394.1893); ~,~,(CHCl,)/crn-' 1720 and 1638; I1,,,(EtOH)/nrn 202, 226, 272 and 313; Lmi,,/nm 215, 244 and 294; G,(CDCl,; 400 MHz) 7.47-7.1 (4 H, m, Ar-H), 6.47 (1 H, s, 17-H), 4.28 (1 H, br s, 21-H), 4.18 (2 H, q, J7, CO,CH,CH,), 3.94 (3 H, s, OMe), 2.17 (2 H, s, 19-H), 3.3-1.2 (10 H, m) and 1.28 (3 H, t, J7, CO2CH,CH3); hC 171.37 (CO,Et), 163.65 (C02Me), 134.13 (C-13), 130.34 (C-2), 128.96 (C-8), 127.61 (C-16), 126.86 (C-l7), 122.07 (C-1 l), 120.33 (C-lo), 118.26 (C-9), 112.52 (C-12), 108.98 (C-7), 60.45 (CH,CH3), 56.32 (C-21), 52.47 (OMe), 51.40 (C-5), 44.71 (C-3), 39.53 (C-19), 36.81 (C-20), 29.31 (C-15), 20.42 (C-14), 16.35 (C-6) and 14.24 (C02CH2CH3); m/z () 394 (M+, 3.8), 324 (1.6), 321 (1.2), 307 (24.7), 306 (47.3) and 248 (0.7).Ethyl apouincaminate 7b.-hc 163.34 (CO,Et), 133.89 (C-l3), 130.93 (C-2), 128.93 (C-8), 128.32 (C-16), 127.84 (C-l7), 121.62 (C-1 l), 120.03 (C-lo), 118.05 (C-9), 112.42 (C-12), 108.51 (C-7), 61.64 (CO,CH,CH,), 55.58 (C-21), 51.37 (C-5), 44.81 (C-3), 37.57 (C-20), 28.60 (C-19), 27.20 (C-15), 20.28 (C-14), 16.28 (C- 6), 14.12 (CO,CH,CH,) and 8.68 (C-18). 19-Ethoxycarbonyl- 19-demethyl- 1,2-dehydroaspidosperm- idine 8.-(a) A stirred mixture of 19-ethoxycarbonyl-19-demethylvincadifformine 1 (1.8 g, 4.5 mmol) and sodium cyanide (4.5 g, 92 mmol) in dry hexamethylphosphoramide J.CHEM. SOC. PERKIN TRANS. 1 1992 (HMPA) (225 cm3) was heated at 75deg;C for 4.5 d in an atmosphere of nitrogen. The mixture was cooled, diluted with water (400 cm3) and extracted with diethyl ether (5 x 250 cm3). The combined extracts were washed with water (5 x 400 cm3), dried (Na,SO,) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (100 g), with chloroform as eluent, to give 2-cyano-19-ethoxycarbonyl-19-demethylaspidospermidine 9 (0.78 g, 4779, which was crystallised from aqueous methanol and obtained as colourless prisms, m.p. 113-1 14 "C (lit.,' m.p. 115.5 "C) (Found: M+, 365.19768.C2,H,,N,O, requires M, 365.2103 1); vmax(Nujol)/ cm-' 3340, 2220, 1720, 1604 and 1590; A,,,(EtOH)/nm 204, 239 and 290 6,(CDCl,; 90 MHz) 7.0 (2 H, m, Ar-H), 6.8 (2 H, m, Ar-H), 4.0 (2 H, q, J 7, CO,CH,CH,), 3.4-1.3 (18 H, m) and 1.2 (3 H, t, J 7, C0,CH2CH3); m/z () 365 (M', 4.9), 338 (20.6), 320 (3.1), 277 (13.9), 250 (18.2), 210 (4.3, 182 (loo), 154 (16.2) and 109 (9.1). The second fraction, eluted with chloroform containing 1 methanol, contained 19-ethoxycarbonyl- 19-demethyl- 1,Zdehy- droaspidospermidine 8 (0.32 g, 21) as an orange-yellow oil (lit.,' unstable); vma,(CHC13)/cm-' 1720 and 1570; A,,,-(EtOH)/nm 220, 225 and 259; 6,(CDC13 ; 90 MHz) 7.67.0 (4 H, m, Ar-H), 3.95 (2 H, q, J7, C02CH2CH3), 3.29-1.2 (17 H, m) and 1.1 (3 H, t, J 7, C02CH2CH,); m/z () 338 (M+, 100), 294 (7.9), 268 (40.2), 250 (84.7) and 251(57).(b) Silver tetrafluoroborate (31 mg, 0.15 mmol) in dry tetrahydrofuran (THF) (10 cm3) was added, dropwise by syringe, to a solution of 2-cyano- 19-ethoxycarbonyl- 19- demethylaspidospermidine 9 (48 mg, 0.12 mmol) in dry THF (20 cm3) under a nitrogen atmosphere. The resulting black suspension was stirred at room temp. for 4 h, then the reaction mixture was diluted with dilute aqueous ammonium hydroxide (7 cm3) and extracted with dichloromethane (3 x 30 cm3). The combined organic fractions were washed with dilute aqueous ammonium hydroxide and water, filtered through a short column of Celite, dried (MgS04), and concentrated under reduced pressure. The crude product was purified by chromatography on Kieselgel G (15 g), using chloroform as eluent, which gave 19-ethoxycarbonyl-l9-demethyl-l,2-dehy-droaspidospermidine 8 (15 mg, 34) as a pale yellow oil (Found: C, 74.55; H, 7.55; N, 8.5.C21H26N202requires C, 74.0; H, 7.70; N, 8.30), identical (IR, UV, NMR and mass spectra) with that obtained by procedure (a). Attempted Reductive Rearrangement of 19- Ethoxycarbonyl- 1 9 -deme thyI-1,2 -deh ydroasp idosperm idine.-A suspension of silver tetrafluoroborate (0.75 g, 3.8 mmol) in dry THF (20 cm3) was added dropwise to a stirred solution of the mixture of cyano compound 9 (0.78 g, 2.1 mmol) and indolenine 8 (0.32 g, 0.94 mmol) prepared as in (a) in dry THF (40 cm3), kept in the dark and under nitrogen.After 15 min the solution became dark and stirring at room temp. was continued for 4 h, then the solvent was removed under reduced pressure. The residue was taken up in glacial acetic acid (125 an3).Zinc dust (12.5 g) and copper(i1) sulfate pentahydrate (61 mg) were added to the solution, which was then heated to 105deg;C and kept at this temperature for 6 h under nitrogen. After 3 h, more zinc (7.3 g) and copper sulfate (42 mg) were added. The mixture was then filtered while hot and the solid residue washed with hot acetic acid. The solution was concentrated under reduced pressure and the residue partitioned between diethyl ether (550 cm3) and 7 aqueous ammonium hydroxide (340 cm3). The combined organic extracts were washed with water (250 cm3) and brine (200 cm3), dried (MgSO,) and concentrated.The residue was purified by chromatography on neutral alumina (20 g), using benzenehloroform (100: 1) as eluent. Four fractions were obtained. The first fraction yielded l9-etho.xycarbonyl-Na-ethyl-19-demethylaspidospermidine12 (267 mg, 16) (Found: C, 75.0; 1585 H, 8.85; N, 7.85; Mf, 368.24633. C2,H3,N202 requires C, 75.0; H, 8.7; N, 7.6; M,368.246365); v,,,(CHC13)/cm-" 1720 and 1600, I,,,(MeOH)/nm 226,258 and 304, A,,,/nm 236 and 280; 6,(CDC13; 300 MHz) 7.5-6.4 (4 H, m, Ar-H), 4.0 (2 H, q, J 7.5, CO,CH,CH,), 3.6-1.2 (20 H, m) and 1.15 (6 H, 2t, J 7.5, C02CH2CH, and NCH,CH3); m/z () 368 (12.7), 340 (1.8), 339 (4.0), 323 (9.6), 295 (6.7), 294 (3.6), 281 (33.1), 280 (loo), 252 (14.2), 210 (4.4), 183 (14.6), 182 (99.7), 144 (10.9) and 130 (10.4).The second fraction was mainly impure N,-acetyl- 19- et hox ycarbonyl- 1 9-demethy laspidospermidine contaminated with an unidentified product. The third fraction yielded N,-acetyl- 19-ethoxycarbonyl- 19- demethylaspidospermidine13 (0.3 1 g, 1873, which was obtained as a colourless oil (Found: C, 72.15; H, 7.8; N, 7.2; M+, 382.2262. C23H30N203 requires C, 72.25; H, 7.85; N, 7.3; M, 382.22563); v,,,/cm-' 1720, 1640 and 1600; I,,,(MeOH)/nm 210, 251, 278 and 288; I,,,/nm 224; G,(CDCl,; 300 MHz) 8.15 (1 H, m, 12-H), 7.27-7.0 (3 H, m, Ar-H), 4.1 (2 H, q, J 7, CO2CH,CH3), 4.0 (1 H, dd, J 2 and 7, 2-H), 3.3-2.9 (2 H, m), 2.53 (1 H, s, 21-H), 2.26 (3 H, s, COCH,), 2.4-1.2 (14 H, m) and 1.2 (3 H, t, J7, CO,CH,CH,); 6,171.4 (C-l8), 168.38 (COCH,), 140.8 (C-13), 137.35 (C-8), 127.81 (C-11), 124.33 (C-9), 122.23 (C-lo), 118.36 (C-12), 69.15 (C-21), 67.56 (C-2), 60.05 (C02CH,CH3), 53.46 (C-7), 52.8 (C-3), 52.23 (C-5), 42.47 (C-19), 39.22 (C-6), 35.84 (C-20), 34.55 (C-15), 25.81 (C-16), 24.37 (C-17), 23.22 (COCH3), 21.47 (C-14) and 14.25 (CO,CH,CH,); m/z () 382 (M+, 15.9), 340 (3.9, 337 (5.6), 295 (32), 294(88.1), 293 (4.5), 251 (4.2), 210(4.8), 182(100), 144(6), 130(11S)and43 (8.2).The fourth fraction contained 19-ethoxycarbonyl- 19- demethylaspidospermidine14 (0.17 g, 11), which was obtained as a colourless oil (Found: C, 74.4; H, 8.25; N, 8.1; M+, 340.21571. C21H28N202 requires C, 74.1; H, 8.20; N, 8.20; M, 340.21506); v,,,(CHCl,)/cm-' 3380, 1720, 1630 and 1604; I,,,(MeOH)/nm 210, 244 and 295; I,,,/nm 226 and 275; 6,(CDC13; 300 MHz) 7.1-6.9 (2 H, m, Ar-H), 6.7-6.6 (2 H, m, Ar-H),4.0(2H,q,J7,CO,CH,CH3),3.5(1H,dd,Jlland10), 3.1 (2 H, m), 2.9-1.3 (16 H, m) and 1.2 (3 H, t, J 7, CO2CH2CH3); 6,171.7 (C-18), 149.6 (C-l3), 134.30 (C-8), 127.5 (C-1 l), 122.7 (C-9), 119.1 (C-lo), 110.58 (C-12), 69.83 (C-21), 64.80 (C-2), 59.8 (C02CH,CH3), 53.52 (C-7), 53.50 (C-3), 52.5 (C-5), 42.4 (C- 19), 38.0 (C-6), 36.13 (C-20), 34.9 (C- 15),28.1 (C- 16), 24.3 (C-17), 21.55 (C-14) and 14.2 (CO,CH,CH,); m/z (?) 340 (M+, 14.9), 312 (7.2), 295 (21.0), 252 (52.5), 210 (5.9), 182 (loo), 144 (16.9) and 130 (15.6).Acknowledgements We thank the Algerian Government for financial support (to A. B.). References 1 J. M. Brennan and J. E. Saxton, Tetrahedron, 1986,42,6719. 2 For a summary see J. E. Saxton, in The Monoterpenoidlndole Alkaloids, ed. J. E. Saxton, Wiley-Interscience, New York, 1983, ch. 8. 3 G. Hugel, G. Massiot, J. Ltvy and J. Le Men, Tetrahedron, 1981,37, 1369; G.Hugel, J. LCvy and J. Le Men, C. R. Hebd. Seances Acad. Sci., Ser. C, 1972,274,1350. 4 B. Danieli, G. Lesma, G. Palmisano and B. Gabetta, J. Chem. SOC., Chem. Commun., 1981,908. 5 G. Lewin and J. Poisson, Tetrahedron Lett., 1984,25, 3813. 6 G. Czira, J. Tamas and G. Kalaus, Org. Mass Spectrom., 1984,19,555. 7 J. HajiEek and J. Trojanek, Tetrahedron Lett., 1981,2927; Coll. Czech. Chem. Commun., 1986,51, 1731; Tetrahedron Lett., 1982, 365. Paper 2/0 1325H Received 12th March 1992 Accepted 25th March 1992
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