Synthesis of the naturally occurring indolequinone BE 10988, an inhibitor of topoisomerase II

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1993 2561 Synthesis of the Naturally Occurring lndolequinone BE 10988, an Inhibitor of Topoisomerase 11' Christopher J. Moody and Elizabeth Swann Department of Chemistry, University of Loughborough, Leicestershire LEl 1 3TU, UK A short synthesis (28 overall yield) of the naturally occurring indolequinone BE 10988 1 is described. The synthesis starts from 4-benzyloxy-5-methoxyindole and involves, as key steps, the use of chlorosulfonyl isocyanate to introduce the amide side-chain into the indole 3-position, followed by thioamide formation and construction of the thiazole ring using a Hantzsch reaction. Topoisomerases, DNA-modifying enzymes, are becoming increasingly important as biological targets for potential anticancer agents,2 and in the search for new compounds of this type, natural products have produced interesting leads.One example of this is the compound designated BE 10988, a potent inhibitor of topoisomerase 11, recently isolated from culture broths by Japanese worker^.^^^ The structure of BE 10988 1, which contains a novel thiazole substituted indolequinone, was established by spectroscopic methods. In view of our own interest in indolequinones and their anticancer proper tie^,^^^ we ? 2 H / H 3 a R=Me b R=CH2Ph decided to investigate the synthesis of BE 10988. The details of this first synthesis of the natural product are reported herein; ' a second synthesis has recently been published.' 1 BE 10988 Results and Discusion The overall strategy for the synthesis of BE 10988 was based on (a) the construction of the thiazole ring using a classical Hantzsch reaction and (b) the formation of the key 5-aminoindole-4,7-quinoneunit from the corresponding 5-methoxyindolequinone, itself derived by oxidation of a 4-(or 7-) hydroxyindole.Therefore, we investigated several approaches to the required indole. The first approach was based on the reported conversion of indole-3-carbaldehyde into 4-alkoxyindoles by reaction with thallium(1n) trifluoroacetate, followed by iodine and the alk~xide.~Attempts to carry out a similar reaction on 5-methoxyindole-3-carbaldehyde2, readily prepared by formylation of commercially available 5-methoxyindole, were unsuccessful, and none of the desired product 3 was obtained.The conversion could be carried out by isolation of the intermediate iodide 4 (70 on a small scale)," followed by reaction with the sodium salts of methanol or benzyl alcohol in the presence of copper(1) iodide (Scheme 1). However the yields of 3 were low (R = Me, 22; R = CH,Ph, 19) and the method was not considered viable on a larger scale. Secondly, we investigated the indole synthesis described by Makosza and co-workers based on the reductive cyclisation of ortho-nitrophenylacetonitriles,prepared by vicarious nucleo- philic substitution (VNS) of hydrogen ortho to the nitro gr0up.l The required starting material, the protected nitro- phenol 5 was readily prepared from 3-methoxyphenol by nitration,' followed by 0-alkylation. Unfortunately, the key VNS step using 4chlorophenoxyacetonitrilegave the required ortho-nitrophenylacetonitrile6 in only 20 yield and, therefore, H 4 Scheme 1 Reagents: i, (CF,CO,),Tl, CF,CO,H; ii, CuI, I,; iii, NaOR (R = Me or CH,Ph); iv, aq.KI; v, CuI, NaOR (R = Me or CH,Ph) the cyclisation to the indole 7 was not investigated further (Scheme 2). We also attempted to prepare the indole 7by reac- tion of the nitro compound 5 with vinylmagnesium bromide, in the so-called Bartoli reaction,' again without success. 'NO2 6CHPhp Ph2HCb 5 6 7 Scheme 2 Reagents: i, 4-chlorophenoxyacetonitrile,Bu'OK, DMF With the failure to prepare the appropriately substituted indole by the above routes, we decided to use a starting material, 4-benzyloxy-5-methoxyindole-2-carbaldehyde8, that was read- ily available to us from our work on the synthesis of mitomycin analogue^.^^'^*'^ This indole is easily prepared on a 10 g-scale using the route described for its 6-methyl deri~ative,~ and can be decarbonylated to the indole 9 in high yield using a rhodium catalyst.Decarboxylation of the corresponding carboxylic acid was unsatisfactory. Initial attempts to introduce the correct side chain into the indole 3-position were based on Vilsmeier formylation (69) to give, after N-methylation (78), the indole-3-carbaldehyde 10 (Scheme 3). However, the subsequent oxidation to the carboxylic acid 11using potassium permanganate' proceeded in poor yield. This oxidation step was investigated in more detail using other reagents for conversion of aldehydes into acids (silver nitrate, pyridinium dichromate), or directly into amides (nickel peroxide/ ammonia,18 sodium cyanide/ ammonia/manganese dioxide,lg N-bromosuccinimide/ammonia,'), although none of these methods showed any improvements over the original. The problem was solved by use of the highly electrophilic chlorosulfonyl isocyanate (CSI) to introduce the amide side OBn ?Bn CHO I H H a 9 ii,iii1 OBn OBn he Me 11 10 Scheme 3 Reugents: i,Rh( Ph, P) ,CO C1, Ph, P( CH,) ,PPh, ,mesi tyl- ene; ii, POCl,, DMF; iii, MeI, KH, DMF; iv, KMnO,, acetone chain directly into the indole 3-position.” Thus, reaction of the N-methylindole 12 with freshly distilled CSI in dry ether resulted in precipitation of the N-chlorosulfonylamide 13 in excellent yield (97) (Scheme 4).Attempts to remove the chlorosulfonyl group under the usual reductive hydrolytic conditions (Na2S0,-KOH) were unsuccessful 22 and, therefore, a new procedure was developed involving treatment of the chlorosulfonylamide 13 with tributyltin hydride in benzene in the presence of AIBN as radical initiator, to give the desired amide 14 in 88 yield. As far as we are aware, this represents the first use of tributyltin hydride to cleave the chlorosulfonyl group from nitrogen; the reaction presumably involves homo- lytic cleavage of the S-C1 bond, followed by loss of sulfur dioxide. Subsequently, it was found that 13 can be converted into 14 simply by stirring in THF at room temperature! This reaction proceeds only in the light; when the reaction mixture is protected from daylight, little cleavage of the chlorosulfonamide is observed.The amide 14 was converted into the thioamide 15 (94) with Lawesson’s reagent (LR). The synthesis was completed by a Hantzsch reaction of the thioamide 15 with ethyl bromo- pyruvate, resulting not only in formation of the thiazole ring, but also, somewhat surprisingly, in debenzylation. Although the 4-hydroxyindole 16 could be purified by chromatography, it was best oxidised directly to the quinone 17 (65 from 15) with Fremy’s salt in buffered acetone solution. Finally, reaction of the methoxy ester 17 with liquid ammonia in a sealed tube at room temperature for 34 days gave BE 10988 1 in 72 yield.The overall yield of BE 10988 is 28 (from 8), and the spectroscopic properties of the synthetic material closely matched those described in the literature for the natural product .4,5 Experimental Commercially available solvents and reagents were used throughout without further purification, except for those detailed below which were purified as described. ‘Light petroleum’ refers to the fraction boiling between 40 and 60 OC, and was distilled through a 36 cm Vigreux column before use. Diethyl ether, xylene, benzene and toluene were dried where necessary by storage over sodium wire for several days. THF was distilled from sodium benzophenone ketyl under nitrogen, prior to use.Dichloromethane was distilled from phosphorus pentoxide. DMF was dried by stirring over calcium hydride for 15 h, decanted, and distilled under reduced pressure before storage over 4 8, molecular sieves under nitrogen. Pyridine and triethylamine were distilled from, and stored over, potassium J. CHEM. SOC.PERKIN TRANS. 11993 OBn OBn Meo+J--i MeoT+J--I H H 9 121ii NHSO IMeofi-fNH2-Meo6-iiii r r Me H 14 13 iv I I Me Me 15 161vi 17 1 Scheme 4 Reagents: i, KH, MeI, DMF; ii, CSI, Et,O; iii, Bu,SnH, AIBN, PhH; iv, LR, PhH; v, BrCH,COC02Et, EtOH, reflux; vi, Fremy’s salt, acetone, NaH,PO, buffer; vii, liq. NH, hydroxide pellets. Methanol and ethanol were distilled from magnesium turnings and iodine, and stored over activated 4 8, molecular sieves under nitrogen.Analytical thin layer chromatography was carried out using aluminium-backed plates coated with Merck Kieselgel 60 GF254. Plates were visualised under UV light (at 254 and/or 360 nm) or by staining with Ehrlich’s reagent or phospho- molybdic acid reagent, followed by heating. Flash chrom- atography was carried out using Merck Kieselgel 60 H silica or Matrex silica 60. Pressure was applied at the column head with hand bellows. Samples were applied pre-adsorbed on silica or as a saturated solution in an appropriate solvent. IR spectra were recorded in the range 4000-600 cm-’ using a Nicolet FT-205 spectrometer, with internal calibration. Spectra were recorded as solutions in chloroform, thin films or as KBr discs.UV/visible spectra were obtained using a Shimadzu W-160 spectrophotometer. Elemental analyses were carried out on a Perkin-Elmer 2400 Elemental Analyser. ‘H and 13C NMR spectra were recorded using Bruker AC-250 and Bruker WH-400 (SERC NMR Spectroscopy Centre, Warwick) instruments; J values are recorded in Hz. High- and low-resolution mass spectra were recorded on a Kratos MS80 instrument or on a VG Analytical ZAB-E instrument (SERC J. CHEM. SOC. PERKIN TRANS. 1 1993 mass spectrometry service Swansea). M.p.s. were measured on an Electrothermal digital melting point apparatus and are uncorrected. 5-Methoxyindole-3-carbaldehyde2.-DMF (7.6 g, 51.7 mmol) and phosphorus oxychloride (3.5 g, 22.8 mmol) were stirred at -5 "C for 30 min after which a solution of 5-methoxyindole (3.1 g, 20.8 mmol) in DMF (3 an3)was added slowly dropwise, the temperature being maintained .c 10 "C.After the addition was completed the mixture was stirred at 35 "C for 1 h after which ice-water (10 an3),followed by aqueous sodium hydroxide (37; 10 cm3) were added to it; the mixture was then extracted with ether. The ether layer was dried (MgS0,) and concentrated. The crude solid was recrystallized (light petroleumdichloromethane) yielding the aldehyde 2 (3.3 g, 93) as colourless crystals, m.p. 174-175 "C (lit.,,, 177-178 "C) (Found: M', 175.0640. CloH,N02 requires M, 175.0633); ~~~,(CHCl,)/crn-~2936, 2832 and 1622; 6,(250 MHz; CDCl,/DMSO) 11.38 (1 H, br s, NH), 9.96 (1 H, s, CHO), 7.81 (1 H, d, J3.2), 7.73 (1 H, d, J2.5), 7.35 (1 H, J8.5), 6.90 (1 H, dd, J 8.8, 2.5) and 3.88 (3 H, s, OMe); 6,(62.9 MHz; CDCl,/DMSO) 184.75 (CHO), 155.96, 137.23 (CH), 132.04, 125.09, 118.44, 113.70 (CH), 112.93 (CH), 102.83 (CH) and 55.46 (OMe); m/z (EI) 175 (M+, loo), 160 (26) and 132 (43).4-Iodo-5-methoxyindole-3-carbaldehyde4.-A solution of thallium(Ir1) trifluoroacetate (0.23 g, 0.42 mmol) in TFA (4 cm3) was added to the carbaldehyde 2 (0.05 g, 0.28 mmol) and the mixture stirred for 2 h at 30 "C. After evaporation of excess of solvent under reduced pressure, aqueous potassium iodide (0.33 g, 2.0 mmol) was added to the residue. This blue/black suspension was stirred for 15 min after which solid sodium metabisulfate was added to it until it turned yellow.The mixture was basified with aqueous sodium hydroxide (3 mol drn-,) and extracted with ether. The combined organic layers were dried (MgSO,) and concentrated. Purification of the residue by column chromatography (ethyl acetate elution) yielded the iodide 4 (0.06 g, 70) as an off-white solid, m.p. 167-168 "C (Found: M+, 300.9617. CloH81N02 requires M, 300.9600); ~~,~(CHCl,)/crn-~2936, 2832 and 1622; 6,(250 MHz; CDC1,/ was added to freshly prepared sodium benzylate and copper iodide (0.029 g, 0.15 mmol). The sodium benzylate was prepared by addition of sodium (0.028 g, 1.2 mmol) to benzyl alcohol (0.66 g, 6.1 mmol). The mixture was heated at 100 "C for 2 h after which the DMF was removed under reduced pressure; and water (1 cm3) and 5 methanol in dichloromethane (10 cm3) were added to the residue.The mixture was filtered through Celite. The layers were separated and the organic layer was washed with brine, dried (MgS0,) and concentrated. The crude residue was purified by column chromatography (50 ethyl acetate/50 light petroleum+thyl acetate, gradient elution). The desired benzylindole 3b (0.004 g, 19) was obtained as an off-white solid, m.p. 113-1 14 "C (Found: M', 281.1050. C1,H15N03 requires M, 281.1052); v,(film)/cm-' 3055,2987, 1656 and 1514; 6,(250 MHz; CDCl,) 10.32 (1 H, s, CHO), 9.43 (1 H, brs, NH), 7.84(1 H, d,J3.2), 7.37 (5 H,m, Ar), 7.1 1 (1 H, d, J8.8), 6.99 (1 H, d, J8.8), 5.22 (2 H, s, CH,Ph) and 3.94 (3 H, s, OMe); 6,(62.9 MHz; CDCl,) 187.04 (CHO), 147.83, 141.83, 141.07,137.35, 133.39, 132.43 (CH), 128.66 (CH), 128.47 (CH), 128.20 (CH), 120.94, 118.28, 11 1.93 (CH), 108.28 (CH), 75.43 (CH,Ph) and 57.62 (OMe); m/z (EI) 281 (M+, 16), 253 (13), 190 (57) and 91 (100).2-Benzhydryloxy-4-methoxynitrobenzene 5.-To a stirred suspension of potassium hydride (0.16 g, 6.6 mmol) in DMF (30 an3),at 0 "C was added dropwise a solution of 5-methoxy- 2-nitrophenol (0.55 g, 3.3 mmol) in DMF (10 cm3). The mixture was stirred at room temperature for 45 min after which a solution of benzhydryl bromide (0.96 g, 3.9 mmol) in DMF (10 cm3) was added dropwise to it at 0°C; the mixture was then allowed to warm to room temperature.After 1 h saturated aqueous ammonium chloride was added to the mixture which was then extracted with ether. The ether layer was washed twice with water, dried (MgS04) and concentrated. The crude product was purified by column chromatography (1 : 1, light petroleum-ether elution) to give the benzhydryl ether 5 (0.47 g, 47) as a colourless solid, m.p. 90-91 "C (Found: M+ -OCHPh,, 153.0609. C7H7N03 requires 153.0426); vm,x(film)/cm-l 3055,3000 and 161 5; 6,(250 MHz; CDCl,) 7.96 (1 H, d, J9.1), 7.36 (10 H, m, Ph,), 6.42 (2 H, m), 5.85 (1 H, s,DMSO)11.87(1H,brs,NH),11.20(1H,s,CHO),8.08(1H,d,CHPh,) and 3.72 (3 H, s, OMe); 6,(62.9 MHz; CDCl,) 164.87, J3.3), 7.38 (1 H, d, J8.7), 6.91 (1 H, d, J8.7) and 3.94 (3 H, s, OMe); 6,(62.9 MHz; CDCl,/DMSO) 185.00 (CHO), 154.17, 133.53, 133.12(CH), 130.09, 118.50, 113.64(CH), 108.31 (CH), 74.73 (CI) and 57.74 (OMe); m/z (FAB) 302 (MH', loo), 301 (M+, 86) and 175 (MH' -I, 68).4,5-Dimethoxyindole-3-carbaldehyde3a.-A solution of the carbaldehyde 4 (0.02 g, 0.07 mmol) in DMF (1 cm3) was added to freshly prepared sodium methoxide and copper iodide (0.025 g, 0.13 mmol). The sodium methoxide was prepared by addition of sodium (0.024 g, 1 .O mmol) to methanol (1 cm3). The mixture was heated for 45 min at 110-120 "C. The DMF was removed under reduced pressure, and water (1 cm3)and 5 methanol in dichloromethane (10 cm3) were added to the residue. The mixture was filtered through Celite. The layers were separated and the organic layer was washed with brine, dried (MgSO,) and concentrated.The crude residue was purified by column chromatography (ethyl acetate elution) to yield the diether 3a (0.003 g, 22) as a brown oil (Found: M', 205.0737. C, ,H, ,NO, requires M, 205.0739); vmaX(film)/cm-' 3065,2955,2850 and 1675; 6,(250 MHz; CDCl,) 10.42 (1 H, s, CHO),9.04(1 H, brs,NH),7.89(1 H,d, J3.1), 7.16(1 H,d, J 8.7), 7.01 (1 H, d, J8.7), 3.94 (3 H, s, OMe) and 3.89 (3 H, s, OMe); m/z (EI) 205 (M', 85), 190 (43) and 175 (100). 4-Benzyloxy-5-methoxyindole-3-carbaldehyde3b.-A solu-tion of the carbaldehyde 4 (0.023 g, 0.07 mmol) in DMF (1 cm3) 154.81,140.29,128.83 (CH), 128.41, 128.21 (CH), 128.04 (CH), 127.38, 126.51, 126.35 (CH), 105.35 (CH), 102.25 (CH), 82.81 (CHPh,) and 55.69 (OMe); m/z(EI) 184 (+OCHPh,, 38), 165 (lo), 153 (M' -OCHPh,) and 105 (100).3-Benzhydryloxy-5-methoxy-2-nitrophenylucetonitrile 6.-A solution of the nitrobenzene 5 (0.095 g, 0.28 mmol) and 4-chlorophenoxyacetonitrile (0.052 g, 0.31 mmol) in DMF (5 cm3) was added dropwise to a solution of potassium tert-butoxide (0.069 g, 0.62 mmol) in DMF (10 an3) at -20 to -10 "C. The reaction mixture was stirred at this temperature for 30 min after which it was poured into ice-cold hydrochloric acid (5). The oily products were extracted with ether and the extract washed with aqueous sodium hydroxide (2) and water, dried (MgSO,) and concentrated. The crude material was purified by chromatography (50 light petroleum/50 ether elution) yielding the nitrile 6 (0.021 g, 20) as colourless crystals, m.p.142-144 "C (Found: M+, 374.1273. C22H18N,04 requires M, 374.1266); ~~,~(CHCl,)/crn-~ 3026, 2900 and 1598; 6,(250 MHz; CDCl,) 7.34 (10 H, m, Ph,), 6.61 (1 H, d, J2.3), 6.47 (1 H, d, J2.3), 6.27 (1 H, s, CHPh,), 3.81 (2 H, s, CH,CN) and 3.74 (3 H, s, OMe); m/z(EI) 375 (MH', 479,374 (M', 6), 357 (29) and 356 (100). 4-Benzyloxy-5-rnethoxyindole 9.-Bis(tripheny1phosphine)-carbonylrhodium(1) chloride (1.04 g, 1.5 1 mmol) was suspended in dry degassed mesitylene (65 cm3) and warmed to 80 "C. After 10 min, 1,3-bis(diphenylphosphino)propane (1.25 g, 4.41 mmol) was added to the mixture to give a yellow precipitate. After a further 10 min, 4-benzyloxy-5-methoxyindole-2-carbaldehyde8 (5.31 g, 18.9 mmol) was added to the mixture and the flask plunged into a Woods metal bath at 190 "C.The mixture was refluxed for 2 h after which it was concentrated and the residue purified by column chromatography (50 light petroleum/50 ether solution) yielding the indole 9 as a colourless solid (3.85 g, 75), m.p. 83-84 "C (Found: C, 75.9; H, 5.9; N, 5.5.C16H1 5N02 requires C, 75.9; H, 6.0; N, 5.5) (Found: M', 253.1100. C16H1~N02 requires M, 253.1 103); vma,(film)/m-l 3023, 2960 and 1475; 6,(250 MHz; CDCl,) 8.09 (1 H, br s, NH), 7.53 (2 H, m), 7.35 (3 H, m), 7.14 (2 H, m),6.93 (1 H, d, J 8.7), 6.55 (1 H, H, J l.O), 5.24 (2 H, s, CH,Ph) and 3.89 (3 H, s, OMe); 6,(62.9 MHz; CDC13) 144.93, 141.06, 138.25, 133.17, 128.31 (CH), 128.24 (CH), 128.16 (CH), 128.08 (CH), 127.77 (CH), 122.98, 11 1.85 (CH), 106.44 (CH), 99.60 (CH), 75.00 (CH,Ph) and 58.45 (OMe); m/z (EI) 253 (M', 29), 162 (100) and 91 (58).4-Benzyloxy-5-methoxyindole-3-carbaldehyde3b.-DMF (1.2 g, 16 mmol) and phosphorus oxychloride (0.56 g, 3.7 mmol) were stirred at -5 'C for 30 min after which a solution of the methoxyindole 9 (0.84 g, 3.3 rnmol) in DMF (3 cm3) was added slowly dropwise to the mixture the temperature being main- tained 300°C (Found: M', 302.0474. C, ,H,,N403S requires M, 302.0473); v,,(DMSO)/cm-' 3444,3390,1680 and 1610; A,,(MeOH)/nm 505, 384, 279 and 237; 6,(400 MHz; DMSO) 8.17 (1 H, s, SCH=C), 7.94 (1 H, s, NCH=C), 7.79 and 7.65 (2 H, 2 s, CONH,), 7.20 (2 H, br s, NH,), 5.38 l H, s (H,N)C=€H and 3.97 (3 H, s, NMe); 6,(100.6 MHz; DMSO) 178.66 (CO), 177.74 (CO), 162.47 (CONHZ), 158.99 (SGN), 151.06 (HZNC), 149.81 =NC=(CONH,), 131.60 COC=C(NMe), 130.07 (NCH), 123.76 (SCH-C), 117.04 (COW), 116.40 (C-thiazole), 98.35 (H,NC=C) and 36.53 (NMe); m/z (EI) 303 (MH', 2079, 302 (M', loo), 284 (12), 275 (15), 258 (29), 229 (20) and 202 (14) lit.,' dark red crystals m.p.> 300 OC (Found: M', 302.051 1. C, 3H10N403S requires M, 302.0473); v,,(KBr)/cm-' 3450, 3390,1662,1620, 1590,1540 and 1500; rZ,,(MeOH)/nm 503.5, 385, 280 and 213; dH(DMS0) 8.15 (1 H, s), 7.89 (1 H, s), 7.78 and 7.62 (2 H, 2 br s, CONH,), 7.15 (2 H, br s, NH,), 537 (1 H, s)and3.94(3H,s,NMe);Gc(DMSO)178.5,177.6, 162.4,158.9, 150.9, 149.7, 131.5, 129.9, 123.6, 116.3,98.3 and 36.41. Acknowledgements We thank the Cancer Research Campaign for support of this work, Fisons Pharmaceuticals for additional support of our research programmes, the SERC MS and NMR Services at Swansea and Warwick and Professor H.Vorbriiggen and Dr. J. Nally for helpful discussions. References 1 Preliminary communication, C. J. Moody and E. Swann, Tetra-hedron Lett., 1993,34, 1987. 2 R. J. Epstein, Lancet, 1988, 521; W. E. Ross, Biochem. Pharmacol., 1985,34,4191. 3 For some recent examples, see: D. C. Radisky, E. S. Radisky, L. R. Barrows, B. R. Copp, R. A. Kramer and C. M. Ireland, J. Am. Chem. SOC.,1993,115, 1632. 4 H. Oka, T. Yoshinari, T. 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