Formal Synthesis of Hepatitis C Virus NS5B Polymerase Inhibitor

Abstract

A formal synthesis of a hepatitis C virus (HCV) inhibitor is described. The synthesis features a benzyne-mediated one-pot indoline formation–methylation sequence and an In(OTf)₃-mediated mild oxa-Pictet–Spengler reaction for the synthesis of substituted electron-rich pyranoindole.

Key words

benzyne - magnesium - one-pot - tandem reaction - total synthesis

• References and Notes

• 1a Choo Q.-L, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Science 1989; 244: 359
• 1b Kuo G, Choo Q.-L, Alter HJ, Gitnick GL, Redeker AG, Purcell RH, Miyamura T, Dienstag JL, Alter MJ, Stevens CE, Tegtmeier GE, Bonino F, Colombo M, Lee W.-S, Kuo C, Berger K, Shuster JR, Overby LR, Bradley DW, Houghton M. Science 1989; 244: 362
• 1c Choo Q.-L, Weiner AJ, Overby LR, Kuo G, Houghton M, Bradley DW. Br. Med. Bull. 1990; 46: 423
• 2a Summa V, Petrocchi A, Pace P, Matassa VG, De Francesco R, Altamura S, Tomei L, Koch U, Neuner P. J. Med. Chem. 2004; 47: 14
• 2b Tedesco R, Shaw AN, Bambal R, Chai D, Concha NO, Darcy MG, Dhanak D, Fitch DM, Gates A, Gerhardt WG, Halegoua DL, Han C, Hofmann GA, Johnston VK, Kaura AC, Liu N, Keenan RM, Lin-Goerke J, Sarisky RT, Wiggall KJ, Zimmerman MN, Duffy KJ. J. Med. Chem. 2006; 49: 971
• 2c Hirashima S, Suzuki T, Ishida T, Noji S, Yata S, Ando I, Komatsu M, Ikeda S, Hashimoto H. J. Med. Chem. 2006; 49: 4721
• 2d Chan L, Reddy TJ, Proulx M, Das SK, Pereira O, Wang W, Sidduqui A, Yannopoulos CG, Poisson C, Turcotte N, Drouin A, Alaoui-Ismaili MH, Bethell R, Hamel M, L’Heureux L, Bilimoria D, Nguyen-Ba N. J. Med. Chem. 2003; 46: 1283
• 3a Gopalsamy A, Lim K, Ciszewski G, Park K, Ellingboe JW, Bloom J, Insaf S, Upeslacis J, Mansour TS, Krishnamurthy G, Damarla M, Pyatski Y, Ho D, Howe AY. M, Orlowski M, Feld B, O’Connell J. J. Med. Chem. 2004; 47: 6603
• 3b LaPorte MG, Draper TL, Miller LE, Blackledge CW, Leister LK, Amparo E, Hussey AR, Young DC, Chunduru SK, Benetatos CA, Rhodes G, Gopalsamy A, Herbertz T, Burns CJ, Condon SM. Bioorg. Med. Chem. Lett. 2010; 20: 2968
• 3c Jackson RW, LaPorte MG, Herbertz T, Drasper TL, Gaboury JA, Rippin SR, Patel R, Chunduru SK, Benetatos CA, Young DC, Burns CJ, Condon SM. Bioorg. Med. Chem. Lett. 2011; 21: 3227
• 4 LaPorte MG, Jackson RW, Draper TL, Gaboury JA, Galie K, Herbertz T, Hussey AR, Rippin SR, Benetatos CA, Chunduru SK, Christensen JS, Coburn GA, Rizzo CJ, Rhodes G, O’Connell J, Howe AY. M, Mansour TS, Collett MS, Pevear DC, Young DC, Gao T, Tyrrell DL. J, Kneteman NM, Burns CJ, Condon SM. ChemMedChem 2008; 3: 1508
• 5a Noji T, Fujiwara H, Okano K, Tokuyama H. Org. Lett. 2013; 15: 1946
• 5b Okano K, Fujiwara H, Noji T, Fukuyama T, Tokuyama H. Angew. Chem. Int. Ed. 2010; 49: 5925
• 5c Tokuyama H, Okano K, Fujiwara H, Noji T, Fukuyama T. Chem. Asian J. 2011; 6: 560

For a construction of the pyrroloquinoline skeleton using the benzyne-mediated strategy, see:
• 5d Oshiyama T, Satoh T, Okano K, Tokuyama H. RSC Adv. 2012; 2: 5147
• 5e Oshiyama T, Satoh T, Okano K, Tokuyama H. Tetrahedron 2012; 68: 9376
• 6a Eaton PE, Lee C.-H, Xiong Y. J. Am. Chem. Soc. 1989; 111: 8016
• 6b Eaton PE, Xiong Y, Gilardi R. J. Am. Chem. Soc. 1993; 115: 10195
• 6c Henderson KW, Kerr WJ. Chem. Eur. J. 2001; 7: 3430
• 6d Clososki GC, Rohbogner CJ, Knochel P. Angew. Chem. Int. Ed. 2007; 46: 7681
• 6e Rohbogner CJ, Clososki GC, Knochel P. Angew. Chem. Int. Ed. 2008; 47: 1503
• 6f Rohbogner CJ, Wagner AJ, Clososki GC, Knochel P. Org. Synth. 2009; 86: 374
• 7a Yamada K, Kurokawa T, Tokuyama H, Fukuyama T. J. Am. Chem. Soc. 2003; 125: 6630
• 7b Okano K, Fukuyama T, Tokuyama H. J. Synth. Org. Chem. Jpn. 2010; 68: 1036
• 7c Kurokawa T, Isomura M, Tokuyama H, Fukuyama T. Synlett 2009; 775
• 8a Nitroolefin 11 was synthesized according to the procedure of Williams and Edmont^8b from 3-[(4-methoxybenzyl)oxy]propanal^8c as a yellow oil; R_f 0.41 (hexanes–EtOAc, 3:1). IR (neat): 2863, 1613, 1515, 1353, 1248, 1095, 1033, 957, 820 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.21–7.34 (m, 3 H), 7.03 (dt, J = 13.2, 1.6 Hz, 1 H), 6.86–6.93 (m, 2 H), 4.46 (s, 2 H), 3.81 (s, 3 H), 3.59 (t, J = 6.0 Hz, 2 H), 2.54 (tdd, J = 6.0, 6.0, 1.6 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 159.3, 140.6, 139.5, 129.7, 129.3, 113.8, 72.8, 66.9, 55.2, 28.9. HRMS (EI⁺): m/z [M⁺] calcd for C₁₂H₁₅NO₄: 237.1001; found: 237.1005.
• 8b Edmont D, Williams DM. Tetrahedron Lett. 2000; 41: 8581
• 8c Das B, Nagendra S, Reddy CR. Tetrahedron: Asymmetry 2011; 22: 1249
• 9 We carried out the formation of indoline using a similar substrate and subsequent trapping of the 7-magnesioindoline with deuterium.^5b The anion species also react with a variety of electrophiles to provide the corresponding 7-substituted indolines.^5a These results indicate that 7-magnesioindoline 14a should be useful for the derivatization at 7 position of indoline.
• 10 Procedure for the Synthesis of Indoline 15: A 500-mL two-necked round-bottomed flask equipped with a magnetic stirring bar, a rubber septum, and a three-way stopcock was charged with dibromobenzene derivative 13 (1.83 g, 2.82 mmol) and anhyd THF (28 mL). To the solution was added Mg(TMP)₂·2LiCl (see ref 5a; 0.17 M in THF, 85.2 mL, 14 mmol) dropwise at –78 °C. The resulting solution was stirred at –78 °C for 10 min. The resulting solution was warmed to 0 °C and stirred for 30 min, after which time TLC (hexanes–EtOAc, 3:1) indicated complete consumption of the starting dibromobenzene 13. To the resulting solution was added CuI (5.43 g, 28.3 mmol) at –78 °C, and the mixture was stirred for 1 h. To the reaction mixture was added MeI (1.76 mL, 28.3 mmol). The resulting mixture was warmed to 0 °C and stirred for 1 h. The reaction mixture was then treated with 10% aq NaCl in 7% aq NH₃ and filtered. The filtrate was extracted with EtOAc (3 ×). The combined organic extracts were washed with 1 M aq HCl, brine, dried over anhyd MgSO₄, and filtered. The organic solvents were removed under reduced pressure to give a crude material (2.21 g), which was purified by flash silica gel column chromatography (hexanes–EtOAc, 7:1) to afford indoline 15 (1.31 g, 2.25 mmol, 80%) as a brown oil; R_f 0.60 (hexanes–EtOAc, 3:1). IR (neat): 2931, 2861, 1709, 1610, 1513, 1454, 1330, 1248, 1162, 1144, 1099, 1036, 820, 738, 697 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.30–7.48 (m, 5 H), 7.23–7.30 (m, 2 H), 6.88 (d, J = 8.4 Hz, 2 H), 6.77 (s, 1 H), 5.02 (s, 2 H), 4.50 (d, J = 11.6 Hz, 1 H), 4.42 (d, J = 11.6 Hz, 1 H), 4.23 (d, J = 11.6 Hz, 1 H), 3.76–3.85 (m, 4 H), 3.48–3.64 (m, 2 H), 3.11 (dddd, J = 11.6, 11.6, 7.6, 3.6 Hz, 1 H), 2.06–2.15 (m, 4 H), 1.58–1.69 (m, 1 H), 1.48 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 159.1, 157.7, 154.3, 143.7, 136.9, 130.5, 129.2, 128.5, 127.9, 127.1, 117.8, 114.8, 113.7, 111.3, 81.0, 72.4, 70.6, 68.0, 55.9, 55.2, 40.2, 31.7, 28.2, 13.6. HRMS (ESI⁺): m/z [M + Na⁺] calcd for NaC₃₁H₃₆ ⁷⁹BrNO₅: 604.1669; found: 604.1647.
• 11 Appel WP. J, Portale G, Wisse E, Dankers PY. W, Meijer EW. Macromolecules 2011; 44: 6776
• 12a Nagarajan R, Perumal PT. Tetrahedron 2002; 58: 1229
• 12b Mineno T. Tetrahedron Lett. 2002; 43: 7975
• 13a Mobilio D, Humber LG, Katz AH, Demerson CA, Hughes P, Brigance R, Conway K, Shah U, Williams G, Labbadia F, De Lange B, Asselin A, Schmid J, Newburger J, Jensen NP, Weichman BM, Chau T, Neuman G, Wood DD, Engen DV, Taylor N. J. Med. Chem. 1988; 31: 2211
• 13b Brenna E, Fuganti C, Fuganti D, Grasselli P, Malpezzi L, Pedrocchi-Fantoni G. Tetrahedron 1997; 53: 17769
• 13c Raghavan BV, Ramana KV, Khera B, Kumar N. WO2000077006A1, 2000
• 13d Zhang X, Li X, Lanter JC, Sui Z. Org. Lett. 2005; 7: 2043
• 14 The authors described that the bismuth triflate worked as a source of triflic acid. See: Bouguerne B, Hoffmann P, Lherbet C. Synth. Commun. 2010; 40: 915
• 15 Procedure for the Synthesis of Pyranoindole 18: A sealed tube equipped with a magnetic stirring bar was charged with indolylethanol 7 (83.3 mg, 0.231 mmol), ketoester 17 (80.9 mg, 0.47 mmol), and anhyd CH₂Cl₂ (2.3 mL). To the solution was added In(OTf)₃ (130.0 mg, 0.23 mmol) at 0 °C. The resulting solution was warmed to r.t. and stirred for 15 h, after which time TLC (hexanes–EtOAc, 3:1) indicated complete consumption of indolylethanol 7. The reaction mixture was treated with sat. aq NaHCO₃, and the mixture was extracted with CH₂Cl₂ (3 ×). The combined organic extracts were washed with brine, dried over anhyd Na₂SO₄, and filtered. The organic solvents were removed under reduced pressure to give a crude material, which was purified by preparative TLC (hexanes–CH₂Cl₂, 1:1) to afford pyranoindole 18 (90.8 mg, 0.176 mmol, 76%) as a colorless oil; R_f 0.77 (hexanes–EtOAc, 3:1). IR (neat): 3392, 2962, 2931, 1715, 1620, 1497, 1454, 1370, 1229, 1189, 1120, 1076, 1025, 736, 697 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.16 (br s, 0.5 H), 9.13 (br s, 0.5 H), 7.46 (d, J = 7.6 Hz, 2 H), 7.39 (dd, J = 7.6, 7.6 Hz, 2 H), 7.30–7.35 (m, 1 H), 6.99 (s, 1 H), 5.07 (s, 2 H), 4.02–4.25 (m, 3 H), 3.76 (ddd, J = 11.6, 11.6, 3.6 Hz, 1 H), 3.08–3.16 (m, 2 H), 2.95–3.08 (m, 2 H), 2.33 (s, 3 H), 2.11–2.21 (m, 1 H), 1.26–1.34 (m, 4.5 H), 1.07–1.15 (m, 0.5 H), 1.02 (d, J = 7.2 Hz, 1.5 H), 0.93 (t, J = 7.6 Hz, 1.5 H), 0.75 (t, J = 7.6 Hz, 1.5 H), 0.66 (d, J = 7.2 Hz, 1.5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.3, 173.2, 152.2, 137.5, 137.4, 137.2, 137.1, 128.5, 127.8, 127.4, 120.39, 120.36, 111.6, 110.2, 110.1, 109.6, 109.4, 108.3, 76.5, 72.2, 61.3, 60.99, 60.97, 48.1, 47.7, 41.7, 41.5, 41.1, 40.9, 25.6, 24.01, 23.97, 23.4, 22.8, 15.5, 14.12, 14.09, 12.9, 12.5, 12.2, 11.4, 9.9. HRMS (ESI⁺): m/z [M + H⁺] calcd for C₂₇H₃₃ ⁷⁹BrNO₄: 514.1587; found: 514.1567.
• 16 Beher D, Bettati M, Checksfield GD, Churcher I, Doughty VA, Oakley PJ, Quddus A, Teall MR, Wrigley JD. WO2005013985A1, 2005
• 17 Littke A, Soumeillant M, Kaltenbach RF. III, Cherney RJ, Tarby CM, Kiau S. Org. Lett. 2007; 9: 1711
• 18 Ethyl 2-{7-(benzyloxy)-1-[(S)-sec-butyl]-5-cyano-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetate (6): white solid. IR (neat): 3372, 2965, 2933, 2217, 1715, 1619, 1455, 1359, 1305, 1234, 1190, 1077, 1021, 755, 698 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.43 (br s, 0.5 H), 9.40 (br s, 0.5 H), 7.45 (d, J = 7.2 Hz, 2 H), 7.40 (dd, J = 7.2, 7.2 Hz, 2 H), 7.30–7.35 (m, 1 H), 7.10 (s, 1 H), 5.11 (s, 2 H), 4.07–4.32 (m, 3 H), 3.76 (dt, J = 11.2, 6.8 Hz, 1 H), 2.93–3.16 (m, 4 H), 2.44 (s, 3 H), 2.12–2.24 (m, 1 H), 1.25–1.37 (m, 4.5 H), 1.07–1.20 (m, 0.5 H), 1.03 (d, J = 7.2 Hz, 1.5 H), 0.94 (t, J = 7.2 Hz, 1.5 H), 0.75 (t, J = 7.2 Hz, 1.5 H), 0.65 (d, J = 7.2 Hz, 1.5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.34, 173.28, 151.5, 139.6, 139.4, 137.0, 136.6, 128.6, 128.0, 127.3, 122.1, 119.5, 115.58, 115.56, 111.8, 108.7, 108.5, 97.84, 97.81, 76.4, 71.9, 61.1, 60.92, 60.89, 41.7, 41.4, 41.2, 41.0, 23.4, 22.7, 22.3, 22.2, 14.12, 14.08, 12.9, 12.5, 12.1, 10.6, 10.5. HRMS (ESI⁺): m/z [M + H⁺] calcd for C₂₈H₃₃N₂O₄: 461.2435; found: 461.2412.
• 19 Ethyl 2-{7-(benzyloxy)-1-[(S)-sec-butyl]-5,8-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetate (19): colorless oil. IR (neat): 3407, 2963, 2933, 2873, 1717, 1617, 1454, 1371, 1233, 1188, 1115, 1079, 1027, 754, 737, 698 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.90 (br s, 0.5 H), 8.87 (br s, 0.5 H), 7.47 (d, J = 7.6 Hz, 2 H), 7.38 (dd, J = 7.6, 7.6 Hz, 2 H), 7.35–7.38 (m, 1 H), 6.61 (s, 1 H), 5.08 (s, 2 H), 4.00–4.25 (m, 3 H), 3.78 (td, J = 11.2, 3.6 Hz, 1 H), 2.93–3.16 (m, 3 H), 2.83–2.92 (m, 1 H), 2.59 (s, 3 H), 2.34 (s, 3 H), 2.13–2.26 (m, 1 H), 1.62–1.74 (m, 0.5 H), 1.20–1.36 (m, 3.5 H), 1.05–1.14 (m, 1 H), 1.05 (d, J = 7.2 Hz, 1.5 H), 0.93 (t, J = 7.2 Hz, 1.5 H), 0.75 (t, J = 7.2 Hz, 1.5 H), 0.68 (d, J = 7.2 Hz, 1.5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.1, 173.0, 152.1, 138.3, 136.31, 136.28, 135.8, 135.6, 128.4, 127.7, 127.6, 127.41, 127.36, 120.29, 120.27, 109.4, 109.3, 109.2, 109.1, 106.44, 106.41, 72.3, 61.1, 61.0, 60.84, 60.82, 41.8, 41.6, 41.2, 41.0, 24.71, 24.67, 23.5, 22.9, 19.5, 14.13, 14.10, 13.0, 12.59, 12.55, 12.2, 9.7. HRMS (ESI⁺): m/z [M + H⁺] calcd for C₂₈H₃₆NO₄: 450.2639; found: 450.2624.
• 20 Ethyl 2-{7-(benzyloxy)-1-[(S)-sec-butyl]-5-ethyl-8-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl}acetate (20): colorless oil. IR (neat): 3405, 2963, 2932, 2872, 1717, 1617, 1451, 1371, 1231, 1188, 1118, 1079, 1026, 736, 698, 504 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.96 (br s, 0.5 H), 8.92 (br s, 0.5 H), 7.48 (d, J = 7.2 Hz, 2 H), 7.38 (dd, J = 7.2, 7.2 Hz, 2 H), 7.32 (dd, J = 7.2, 7.2 Hz, 1 H), 6.66 (s, 1 H), 5.09 (s, 2 H), 4.01–4.25 (m, 3 H), 3.80 (td, J = 11.2, 3.6 Hz, 1 H), 3.14 (d, J = 16.8 Hz, 0.5 H), 3.12 (d, J = 16.8 Hz, 0.5 H), 2.98–3.09 (m, 2 H), 2.93 (q, J = 7.6 Hz, 2 H), 2.78–2.86 (m, 1 H), 2.36 (s, 3 H), 2.14–2.25 (m, 1 H), 1.68 (qd, J = 7.2, 2.8 Hz, 0.5 H), 1.22–1.32 (m, 6.5 H), 1.07–1.14 (m, 1 H), 1.03 (d, J = 6.8 Hz, 1.5 H), 0.94 (t, J = 7.6 Hz, 1.5 H), 0.75 (t, J = 7.6 Hz, 1.5 H), 0.67 (d, J = 6.8 Hz, 1.5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.1, 173.0, 152.2, 138.3, 136.44, 136.41, 135.9, 135.6, 134.43, 134.41, 128.4, 127.6, 127.4, 119.43, 119.41, 108.7, 108.5, 107.7, 106.6, 106.5, 72.3, 61.1, 61.0, 60.84, 60.83, 41.8, 41.6, 41.3, 41.0, 26.3, 24.74, 24.71, 23.4, 22.9, 16.33, 16.31, 14.13, 14.10, 13.0, 12.59, 12.55, 12.2, 9.8. HRMS (ESI⁺): m/z [M + H⁺] calcd for C₂₉H₃₈NO₄: 464.2795; found: 464.2799