Synthesis of Hexahydropyrazino[1,2-b]isoquinolines as Simplified Saframycin Analogues

Abstract

Various hexahydropyrazino[1,2-b]isoquinolines were synthesised as simplified saframycin analogues. Construction of this core proceeded through a tetrahydroisoquinoline synthesis followed by acylation/alkylation of the tetrahydroisoquinoline nitrogen and subsequent ring closure using various aliphatic and aromatic amines. The resulting piperazinones were reacted with LiAlH₄ or LiAlH(OEt)₃ to synthesise further analogues.

Key words

saframycins - piperazinones - diketopiperazines - cyclisation - tetrahydroisoquinolines

• References and Notes

• 1 Current address: Institute of Chemistry, Vietnam Academy of Science & Technology, 18 Hoang Quoc Viet, Cau Giay, Ha Noi, Viet Nam.
• 2a Arai T, Takahashi K, Kubo A. J. Antibiot. 1977; 30: 1015
• 2b Arai T, Takahashi K, Ishiguro K, Yazawa K. J. Antibiot. 1980; 33: 951

For a review on tetrahydroisoquinoline antitumor antibiotics, see:
• 2c Scott JD, Williams RM. Chem. Rev. 2002; 102: 1669
• 3a Wright AE, Forleo DA, Gunawardana GP, Gunasekera SP, Koehn FE, McConnell OJ. J. Org. Chem. 1990; 55: 4508
• 3b Rinehart KT, Holt TG, Fregeau NL, Stroh JG, Keifer PA, Sun F, Li LH, Martin DG. J. Org. Chem. 1990; 55: 4512
• 3c Garcia-Rocha M, Garcia-Gravalos MD, Avila J. Brit. J. Cancer 1996; 73: 875
• 3d Schwartsmann G, Brondani da Rocha A, Berlinck RG. S, Jimeno J. Lancet Oncol. 2001; 2: 221
• 3e Rinehart KL. Med. Res. Rev. 2000; 20: 1
• 4 Martinez EJ, Owa T, Schreiber SL, Corey E. J. Proc. Natl. Acad. Sci. U.S.A. 1999; 98: 3496
• 5a Kubo A, Saito N, Yamato H, Masubuchi K, Nakamura M. J. Org. Chem. 1988; 53: 4295
• 5b Saito N, Harada S, Inouye I, Yamaguchi K, Kubo A. Tetrahedron 1995; 51: 8231
• 5c Obika S, Yasui Y, Yanada R, Takemoto Y. J. Org. Chem. 2008; 73: 5206
• 5d Martinez EJ, Corey EJ. Org. Lett. 1999; 1: 75
• 5e Dong W, Liu W, Liao X, Guan B, Chen S, Liu Z. J. Org. Chem. 2011; 76: 5363
• 6 Huck L, González JF, de la Cuesta E, Menéndeza JC, Avendaño C. Org. Biomol. Chem. 2011; 9: 6271
• 7a González JF, de la Cuesta E, Avendaño C. Bioorg. Med. Chem. 2007; 15: 112
• 7b Ortín I, González JC, de la Cuesta E, Manguan-García C, Perona R, Avendaño C. Bioorg. Med. Chem. 2008; 16: 9065
• 7c Ortín I, González JC, de la Cuesta E, Avendaño C. Bioorg. Med. Chem. 2010; 18: 6813
• 8 Nguyen Van T, Claes P, De Kimpe N. Synlett 2013; 24: 1006
• 9 Mash EA, Williams LJ, Pfeiffer SS. Tetrahedron Lett. 1997; 38: 6977
• 10a Syper L, Mlochowski J, Kloc K. Tetrahedron 1983; 39: 781
• 10b Ardecky RJ, Kerdesky FA. J, Cava MP. J. Org. Chem. 1981; 46: 1483
• 10c Eskildse J, Christensen T, Reenberg T, Larsen U, Christensen JB. Org. Prep. Proced. Int. 2000; 32: 398
• 10d Mendez-Rojas MA, Ejsmont K, Watson WH. J. Chem. Crystallogr. 2002; 32: 177
• 10e Claessens S, Jacobs J, Van Aeken S, Abbaspour Tehrani K, De Kimpe N. J. Org. Chem. 2008; 73: 7555
• 11 Ethyl 5,8-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (7b) To a solution of ethyl N-(diphenylmethylene)glycinate (4, 801 mg, 3 mmol), freshly recrystallized 2,3-bisbromo-methyl-1,4-dimethoxybenzene (5b, 972 mg, 3 mmol), and Bu₄NHSO₄ (1017 mg, 3 mmol) in CH₂Cl₂ (10 mL) was added an aq solution of KOH (30%, 5 mL). The reaction mixture was stirred at r.t. for 30 min. Next, the mixture was poured onto H₂O and exhaustively extracted with CH₂Cl₂. The combined organic phases were washed with sat. aq NaHCO₃, dried (MgSO₄), filtered, and evaporated in vacuo. To this crude residue was added THF (20 mL) and HCl (2 M, 20 mL). The reaction mixture was stirred at r.t. for 30 min and subsequently neutralized by treatment with a solution of aq Na₂CO₃ (2 M). Next, the solvent was evaporated in vacuo, and the residue was exhaustively extracted with EtOAc. The combined organic phases were washed with sat. aq NaHCO₃, dried (MgSO₄), filtered, and evaporated in vacuo. This crude mixture was purified column chromatography on silica (hexane–EtOAc) to obtain ethyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (7b, 637 mg, 80%). Note: In order to obtain a good yield, it is of utmost importance to use freshly recrystallized starting materials 4 and 5. Analytical Data Colourless crystals; mp 90.5–91 °C. ¹H NMR (270 MHz, CDCl₃): δ = 1.31 (3 H, t, J = 7.0 Hz, Me), 1.63 (1 H, br s, NH), 2.64 (1 H, dd, J = 9.9, 16.5 Hz, H-4a), 3.09 (1 H, dd, J = 16.5, 4.6 Hz, H-4b), 3.59 (1 H, dd, J = 4.6, 9.9 Hz, H-3), 3.76 (3 H, s, OMe), 3.78 (3 H, s, OMe), 3.80 (1 H, d, J = 15.8 Hz, H-1a), 3.84 (1 H, d, J = 15.8 Hz, H-1b), 4.19–4.27 (2 H, m, OCH₂), 6.60 (1 H, d, J = 8.9 Hz, H-6) 6.64 (1 H, d, J = 8.9 Hz, H-7). ¹³C NMR (68 MHz, CDCl₃): δ = 14.2 (Me), 26.3 (C-4), 42.9 (C-1), 55.3 (C-3), 55.4 (OMe), 55.6 (OMe), 60.9 (OCH₂), 106.9 and 107.2 (C-6, C-7), 123.7 and 125.1 (C-5a, C-8a), 149.9 (=COMe), 151.2 (=COMe), 173.3 (C=O). IR (KBr): ν = 3250 (NH), 2971, 2954, 2829, 1724 (C=O), 1605, 1484, 1464, 1438, 1260, 1225, 1182, 1091 cm^–1. MS: m/z (%) = 266 (100) [M + H⁺], 262 (20), 261 (20), 192 (20). HRMS (ES⁺): m/z calcd for [C₁₆H₂₂NO₄]⁺: 266.1392; found: 266.1396. Spectroscopic data are in accordance with literature data: Al-Horani RA, Desai UR. Tetrahedron 2012; 68: 2027
• 12 Ethyl 2-(2-Chloroacetyl)-5,8-dimethoxy-6,7-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (8a) A mixture of ethyl 5,8-dimethoxy-6,7-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (7a, 586 mg, 2 mmol) and Et₃N (222 mg, 2.2 mmol) in anhydrous CH₂Cl₂ (10 mL) was cooled to 0 °C and chloroacetyl chloride (264 mg, 2.2 mmol) was added dropwise. The reaction mixture was stirred at r.t. for 2 h. Then the mixture was poured onto H₂O and exhaustively extracted with CH₂Cl₂. The combined organic phases were washed with sat. NaHCO₃, dried (MgSO₄), filtered, and evaporated in vacuo. Purification by column chromatography on silica (hexane–EtOAc) gave pure ethyl 2-(2-chloroacetyl)-5,8-dimethoxy-6,7-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (8a, 688 mg, 93%). Analytical Data ¹H NMR (300 MHz, CDCl₃): δ = 1.15 (3 H, t, J = 6.9 Hz, Me), 2.17 (6 H, s, 2 × Me), 2.90 (1 H, dd, J = 5.9, 16.5 Hz, H-4a), 3.47 (1 H, dd, J = 3.0, 16.5 Hz, H-4b), 3.65 (3 H, s, OMe), 3.68 (3 H, s, OMe), 4.00–4.17 (2 H, m, OCH₂), 4.24 (1 H, d, J = 12.5 Hz, H-1a), 4.29 (1 H, d, J = 12.5 Hz, H-1b), 4.73 (2 H, br s, 2 × H-2′), 5.46 (1 H, dd, J = 3.0, 5.9 Hz, H-3). ¹³C NMR (75 MHz, CDCl₃): δ = 12.51 (Me), 12.54 (Me), 14.0 (OCH₂Me), 24.8 (C-4), 41.2 (C-2′), 41.4 (C-1), 51.3 (C-3), 60.4 (2 × OMe), 61.4 (OCH₂), 122.6 and 123.2 (C-5a, C-8a), 129.2 and 129.8 (C-6, C-7), 150.6 (=COMe), 152.0 (=COMe), 166.6 and 170.3 (2 × C=O). IR (NaCl): ν = 2942, 2838, 1738 (C=O), 1732 (C=O), 1660, 1652, 1606, 1486, 1483, 1260, 1203, 1096 cm^–1. MS: m/z (%) = 370/372 (100) [M + H⁺], 324 (20), 296 (55), 294 (80), 266 (30), 220 (10). HRMS (ES⁺): m/z calcd for [C₁₈H₂₅ ³⁵ClNO₅]⁺: 372.1392; found: 372.1401.
• 13 Ethyl 2-(2-Bromoethyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (9b) A mixture of tetrahydroisoquinoline 7b (800 mg, 3.02 mmol), 1,2-dibromoethane (11.35 g, 60.4 mmol), and K₂CO₃ (417 mg, 3.02 mmol) was stirred at reflux for 24 h. Then, the mixture was poured onto H₂O and exhaustively extracted with EtOAc. The combined organic phases were washed with sat. NaHCO₃, dried (MgSO₄), filtered, and evaporated in vacuo. Purification chromatography on silica (hexane–EtOAc) gave pure ethyl 2-(2-bromoethyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (9b, 786 mg,70%). Analytical Data ¹H NMR (300 MHz, CDCl₃): δ = 1.23 (3 H, t, J = 7.0 Hz, Me), 2.95 (1 H, dd, J = 6.3, 17.3 Hz, H-4a), 3.08–3.18 (2 H, m, CH₂-1′), 3.20 (1 H, dd, J = 6.1, 17.3 Hz, H-4b), 3.50 (2 H, t, J = 7.2 Hz, CH₂-2′), 3.75 (3 H, s, OMe), 3.76 (3 H, s, OMe), 3.76 (1 H, dd, overlap, H-3), 3.85 (1 H, d, J = 16.8 Hz, H-1a), 3.96 (1 H,d, J = 16.8 Hz, H-1b), 4.07–4.18 (2 H, m, OCH₂), 6.60 (1 H, d, J = 9.1 Hz, H-6), 6.62 (1 H, d, J = 9.1 Hz, H-7). ¹³C NMR (75 MHz, CDCl₃): δ = 14.4 (Me), 25.8 (C-4), 30.3 (C-1′), 46.9 (C-1), 55.5 (OMe), 55.8 (OMe), 57.1 (CBr), 59.7 (C-3), 60.7 (OCH₂), 107.0 and 107.4 (C-6, C-7), 122.6 and 123.8 (C-5a, C-8a), 150.1 (=COMe), 151.2 (=COMe), 172.5 (C=O). IR (NaCl): ν = 2930, 1731 (C=O), 1650, 1483, 1464, 1438, 1257, 1181, 1082 cm^–1. MS m/z (%) 372/374 (M+H⁺, 10), 310 (7), 393 (15), 392 (100). HRMS (ES⁺): m/z calcd for [C₂₀H₁₄NO₂]⁺: 300.1025; found: 300.1027.
• 14 7,10-Dimethoxy-8,9-dimethyl-2-propyl-2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]isoquinoline-1,4-dione (10a) A mixture of ethyl 2-(2-chloroacetyl)-5,8-dimethoxy-6,7-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (8a, 184.5 mg, 0.5 mmol) and n-propylamine (132.5 mg, 2.5 mmol) in anhydrous EtOH (10 mL) was stirred for 24 h at r.t. Then, the mixture was poured onto H₂O and exhaustively extracted with EtOAc. The combined organic phases were washed, dried (MgSO₄), filtered, and evaporated in vacuo. Purification by chromatography on silica (hexane–EtOAc) gave pure 7,10-dimethoxy-8,9-dimethyl-2-propyl-2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]isoquinoline-1,4-dione (10a, 150 mg, 87%). Analytical Data White powder, mp 169–169.5 °C. ¹H NMR (270 MHz, CDCl₃): δ = 0.96 (3 H, t, J = 7.3 Hz, H-3), 1.57–1.68 (2 H, m, 2 × H-2′), 2.18 (6 H, s, 2 × Me), 2.74 (1 H, dd, J = 12.2, 16.4 Hz, H-11a), 3.28–3.47 (2 H, m, H-1′a, H-1′b), 3.59 (1 H, dd, J = 3.4, 16.4 Hz, H-11b), 3.66 (3 H, s, OMe), 3.71 (3 H, s, OMe), 4.04 (2 H, s, H-3a, H-3b), 4.10 (1 H, d, J = 17.5 Hz, H-6a), 4.17 (1 H, dd, J = 12.2, 3.6 Hz, H-12), 5.40 (1 H, d, J = 17.5 Hz, H-6b). ¹³C NMR (68 MHz, CDCl₃): δ = 11.1 (C-3′), 12.45 (Me), 12.54 (Me), 19.8 (C-2′), 28.5 (C-11), 40.1 (C-6), 47.6 (C-1′), 49.4 (C-3), 55.6 (C-12), 60.3 (2 × OMe), 122.9 and 123.9 (C-7a, C-10a), 129.3 and 129.5 (C-8, C-9), 151.0 (=COMe), 152.1 (=COMe), 162.3 (C=O), 165.0 (C=O). IR (KBr): ν = 2958, 2834, 1661 (C=O), 1658 (C=O), 1479, 1465, 1334, 1260, 1274, 1086, 1061 cm^–1. MS: m/z (%) = 347 (30) [M + H], 345 (70), 314 (15), 218 (35), 191 (100), 176 (70), 124 (50), 83 (70). HRMS (ES⁺): m/z calcd for [C₁₉H₂₇N₂O₄]⁺: 347.1971; found: 347.1981.
• 15 7,10-Dimethoxy-2-propyl-3,4,11,11a-tetrahydro-2H,6H-pyrazino[1,2-b]isoquinolin-1-one (11b) A mixture of ethyl 2-(2-bromoethyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (9b) (186 mg, 0.5 mmol) and n-propylamine (132.5 mg, 2.5 mmol) in anhydrous EtOH (10 mL) was stirred for 24 h at r.t. Then, the mixture was poured onto H₂O and exhaustively extracted with EtOAc. The combined organic phases were washed, dried (MgSO₄), filtered, and evaporated in vacuo. Purification by chromatography on silica (hexane–EtOAc) gave pure 7,10-dimethoxy-2-propyl-3,4,11,11a-tetrahydro-2H,6H-pyrazino[1,2-b]isoquinolin-1-one (11b, 120 mg, 79%). Analytical Data ¹H NMR (270 MHz, CDCl₃): δ = 0.91 (3 H, t, J = 7.3 Hz, Me), 1.55–1.64 (2 H, m, CH₂-2′), 2.59–2.69 (2 H, m, H-11a, H-3a), 2.96 (1 H, dd, J = 3.9, 11.5 Hz, H-12), 3.09–3.29 (4 H, m, H-3b, H-4a, H-6a, H-1′a), 3.41–3.70 (3 H, m, H-4b, H-1′b, H-11b), 3.74 (3 H, s, OMe), 3.76 (3 H, s, OMe), 4.10 (1 H, d, J = 15.5 Hz, H-6b), 6.61 (1 H, d, J = 8.1 Hz, H-8), 6.63 (1 H, d, J = 8.1 Hz, H-9). ¹³C NMR (68 MHz, CDCl₃): δ = 11.2 (Me), 20.2 (C-2′), 27.6 (C-11), 46.1 (C-4), 48.4 (C-1′), 50.4 (C-3), 53.2 (C-6), 55.6 (OMe), 55.7 (OMe), 61.5 (C-12), 107.1 and 107.7 (C-8, C-9), 123.4 and 124.7 (C-7a, C-10a), 149.7 (=COMe), 151.5 (=COMe), 168.6 (C=O). IR (NaCl): ν = 2931, 1654 (C=O), 1645, 1485, 1463, 1438, 1259, 1181, 1097 cm^–1. MS: m/z (%) = 305 (100) [M + H⁺], 301 (10), 227 (20). HRMS (ES⁺): m/z calcd for [C₁₇H₂₅N₂O₃]⁺: 305.1865; found: 305.1871.
• 16 7,10-Dimethoxy-2-propyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (14a) To a solution of 7,10-dimethoxy-2-propyl-3,4,11,11a-tetrahydro-2H,6H-pyrazino[1,2-b]isoquinolin-1-one (11b, 100 mg, 0.33 mmol) in anhydrous Et₂O (5 mL) under a nitrogen atmosphere at 0 °C, was added LiAlH₄ (53 mg, 1.32 mmol) portionwise. The reaction mixture was stirred for 12 h at r.t. Afterwards, the mixture was poured onto H₂O and exhaustively extracted with Et₂O. The combined organic phases were washed, dried (MgSO₄), filtered, and evaporated in vacuo. Purification by chromatography on silica (hexane–EtOAc) gave pure 7,10-dimethoxy-2-propyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (14a, 76 mg, 80%). Analytical Data Pale white solid; mp 105 °C. ¹H NMR (270 MHz, CDCl₃): δ = 0.92 (3 H, t, J = 7.3 Hz, CH₃), 1.50–1.59 (2 H, m, CH₂-2′), 1.93 (1 H, dd, J = 9.7, 11.0 Hz, H-1a), 2.21–2.36 (3 H, m, overlap, H-3a, H-1′a, H-1′b), 2.41–2.53 (2 H, m, overlap, H-11a, H-4a), 2.79 (1 H, d, J = 14.2 Hz, H-11b), 2.95 (1 H, dd, J = 2.3, 11 Hz, H-1b), 3.01–3.09 (2 H, m, H-3b, H-4b), 3.13 (1 H, d, J = 16.0 Hz, H-6a), 3.77 (6 H, s, 2 × OMe), 4.06 (1 H, d, J = 16.0 Hz, H-6b), 6.62 (2 H, s, H-9, H-8). ¹³C NMR (68 MHz, CDCl₃): δ = 12.0 (Me), 20.0 (C-2′), 28.2 (C-11), 52.1 (C-6), 53.2 (C-4), 54.6 (C-3), 55.6 (2 × OMe), 60.1 (C-1′), 60.7 (C-1), 76.6 (C-11a), 107.0 and 107.2 (C-8, C-9), 123.6 and 124.2 (C7a, C-10a), 149.8 (=COMe), 150.9 (=COMe). IR (ATR): ν = 2925, 1654, 1482, 1438, 1258, 1086, 1060, 810, 714 cm^–1. MS: m/z (%) = 291 (100) [M + H⁺]. HRMS (ES⁺): m/z calcd for [C₁₇H₂₇N₂O₂]⁺: 291.2073; found: 291.2065
• 17 7,10-Dimethoxy-2-propyl-1,2,3,4,6,11-hexahydro-pyrazino[1,2-b]isoquinoline-11a-carbonitrile (13a) To a mixture of fresh LiAlH₄ (40 mg, 1.0 mmol) in anhydrous Et₂O (5 mL) was added anhydrous EtOH (0.175 mL, 3.0 mmol) under a nitrogen atmosphere at 0 °C. After 90 min, a solution of 11a (30 mg, 0.1 mmol) in anhydrous THF (5 mL) was added, and the reaction mixture was stirred at 0 °C for 30–50 min. Next, AcOH (0.226 mL, 4 mmol) was added. After 5 min, KCN (40 mg, 0.61 mmol) in H₂O was added dropwise (CAUTION: HCN formation!). The reaction mixture was stirred for 5 h at r.t., then the mixture was poured onto H₂O, neutralised with sat. aq NaHCO₃ solution and exhaustively extracted with EtOAc. The combined organic phases were washed, dried (MgSO₄), filtered, and evaporated in vacuo. Purification by chromatography on silica (hexane–EtOAc) gave pure 7,10-dimethoxy-2-propyl-1,2,3,4,6,11-hexahydropyrazino[1,2-b]isoquinoline-11a-carbonitrile (13a, 26 mg, 84%). Analytical Data White powder; mp 128.5–129.3 °C. ¹H NMR (300 MHz, CDCl₃): δ = 0.94 (3 H, t, J = 7.3 Hz, CH₃-3), 1.52–1.57 (2 H, m, 2 × H-2′), 2.11 (1 H, d, J = 11.3 Hz, H-1a), 2.27–2.38 (3 H, m, overlap, H-3a, H-1′a, H-1′b), 2.63–2.71 (2 H, m, overlap, H-11a, H-4a), 2.84–2.91 (2 H, m, overlap, H-3b, H-4b), 3.12 (1 H, d, J = 17.0 Hz, H-11b), 3.21 (1 H, d, J = 11.3 Hz, H-1b), 3.28 (1 H, d, J = 16.8 Hz, H-6a), 3.76 (3 H, s, OMe), 3.78 (3 H, s, OMe), 4.00 (1 H, J = 16.8 Hz, H-6b), 6.63 (2 H, s, H-9, H-8). ¹³C NMR (75 MHz, CDCl₃): δ = 11.7 (Me), 19.8 (C-2′), 32.3 (C-11), 49.1 (C-6), 51.5 (C-4), 52.7 (C-3), 55.5 (2 × OMe), 56.7 (C-11a), 59.5 (C-1′), 61.7 (C-1), 107.5 and 107.6 (C-7, C-8), 117.5 (CN), 119.9 and 122.7 (C7a, C-10a), 149.6 (=COMe), 150.7 (=COMe). IR (KBr): ν = 2931, 2835, 2183 (CN), 1652, 1607, 1486, 1463, 1456, 1259, 1172, 1080 cm^–1. MS: m/z (%) = 316 (15) [M + H⁺], 301 (15), 290 (25), 289 (100). HRMS (ES⁺): m/z calcd for [C₁₈H₂₆N₃O₂]⁺: 316.2025; found: 316.2025.
• 18 2-Benzyl-3,4,11,11a-tetrahydro-2H,6H-pyrazino[1,2-b]isoquinoline-1,7,10-trione (12) To a solution of 7,10-dimethoxy-2-benzyl-3,4,11,11a-tetrahydro-2H,6H-pyrazino[1,2-b]isoquinolin-1-one (11d, 176 mg, 0.5 mmol) in anhydrous CH₂Cl₂ (20 mL) was added dropwise BBr₃ (1035 mg, 1.05 mmol) under a nitrogen atmosphere at –78 °C. After 1 h, the reaction mixture was warmed to 0 °C and left for 30 min. Then, HNO₃ (10 M, 10 mL) was added to the reaction mixture and stirring was continued for 45 min. Next, the mixture was poured onto H₂O, neutralised with a sat. aq NaHCO₃ solution and exhaustively extracted with CH₂Cl₂. The combined organic phases were washed, dried (MgSO₄), filtered, and evaporated in vacuo. Purification by chromatography on silica (hexane–EtOAc) gave pure 2-benzyl-3,4,11,11a-tetrahydro-2H,6H-pyrazino[1,2-b]isoquinoline-1,7,10-trione (12, 110 mg, 68%). Analytical Data ¹H NMR (270 MHz, CDCl₃): δ = 2.47–2.60 (1 H, m, H-11a), 2.64 (1 H, dt, J = 3.6, 12.3 Hz, H-3a), 3.02 (1 H, dd, J = 4.1, 10.6 Hz, H-12), 3.06–3.19 (3 H, m, overlap, H-4a, H-3b, H-6a), 3.33 (1 H, td, J = 3.6, 19.8 Hz, H-4b), 3.49 (1 H, dt, J = 4.1, 11.2 Hz, H-11b), 3.90 (1 H, dd, J = 1.3, 19.8 Hz, H-6b), 4.53 (1 H, d, J = 14.5 Hz, H-1′a), 4.73 (1 H, d, J = 14.5 Hz, H-1′b), 6.71 (1 H, d, J = 10.2 Hz, H-8), 6.76 (1 H, d, J = 10.2 Hz, H-9), 7.26–7.37 (5 H, m, 5 × =CH). ¹³C NMR (68 MHz, CDCl₃): δ = 26.4 (C-11), 45.2 (C-4), 49.8 (C-3), 49.9 (C-1′), 51.5 (C-6), 60.4 (C-12), 127.7 (=CH), 128.1 (2 × =CH), 128.7 (2 × =CH), 136.0 (C-8), 136.3 (C_quat), 136.5 (C-9), 138.6 (C_quat), 140.4 (C_quat), 167.4 (C=O), 185.7 (C=O), 185.9 (C=O). IR (NaCl): ν = 2924, 1660 (C=O), 1641 (C=O), 1496, 1453, 1352, 1311, 1250 cm^–1. MS: m/z (%) = 323 (5) [M + H⁺], 322 (20), 321 (100), 178 (7).